Gene Therapy For Eye Pathologies

Information

  • Patent Application
  • 20220143221
  • Publication Number
    20220143221
  • Date Filed
    April 02, 2020
    4 years ago
  • Date Published
    May 12, 2022
    2 years ago
Abstract
Compositions and methods are described for the delivery of therapeutic products (such as therapeutic proteins (for example, antibodies), therapeutic RNAs (for example, shRNAs, siRNAs, and miRNAs), and therapeutic aptamers) to the retina/vitreal humour in the eyes of human subjects to treat pathologies of the eye, involving, for example, recombinant viral vectors such as recombinant adeno-associated virus (rAAV) vectors.
Description
REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

This application incorporates by reference a Sequence Listing submitted with this application as text file entitled “12656-126-228_Sequence_Listing.txt” created on Mar. 24, 2020 and having a size of 2,025,574 bytes.


2. INTRODUCTION

Compositions and methods are described for the delivery of therapeutic products (such as therapeutic proteins (for example, antibodies), therapeutic RNAs (for example, shRNAs, siRNAs, and miRNAs), and therapeutic aptamers) to the retina/vitreal humour in the eyes of human subjects to treat pathologies of the eye, involving, for example, recombinant viral vectors such as recombinant adeno-associated virus (rAAV) vectors.


3. BACKGROUND OF THE INVENTION

The human eye is a highly intricate and highly developed sensory organ, which is prone to a host of diseases and disorders. About 285 million people in the world are visually impaired, of whom 39 million are blind and 246 million have moderate to severe visual impairment (World Health Organization, 2012, “Global Data On Visual Impairments 2010,” Geneva: World Health Organization). Some of the leading causes of blindness are cataract (47%), glaucoma (12%), age-related macular degeneration (AMD) (9%), and diabetic retinopathy (5%) (World Health Organization, 2007, “Global Initiative For The Elimination Of Avoidable Blindness: Action Plan 2006-2011,” Geneva: World Health Organization).


An extensive number of ocular diseases and diseases with pathological manifestations in the eye can be traced to genetic alterations or protein dysregulations (Stone et al., 2017, Ophthalmology 124(9): 1314-1331). Recent advances in genomics and proteomics have made a huge impact in our understanding of disease mechanisms and/or genetic basis underlying such ocular diseases or manifestations. Gene therapy has been employed in treating certain eye diseases (see, e.g. International Patent Application No. PCT/US2017/027650 (International Publication No. WO 2017/181021 A1)).


There is a significant unmet medical need for therapies that specifically address the underlying genetic anomalies to treat ocular pathologies.


4. SUMMARY OF THE INVENTION

Compositions and methods are described for the delivery of therapeutic products (such as therapeutic proteins (for example, antibodies), therapeutic RNAs (for example, shRNAs, siRNAs, and miRNAs), and therapeutic aptamers) to the retina/vitreal humour in the eyes of human subjects to treat pathologies of the eye, involving, for example, recombinant viral vectors such as recombinant adeno-associated virus (rAAV) vectors. The therapeutic products can be, for example, therapeutic proteins (for example, antibodies), therapeutic RNAs (for example, shRNAs, siRNAs, and miRNAs), or therapeutic aptamers. In a specific embodiment, the therapeutic products is a human protein or an antibody against a human protein. Antibodies include, but are not limited to, monoclonal antibodies, polyclonal antibodies, recombinantly produced antibodies, human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-heavy chain pairs, intrabodies, heteroconjugate antibodies, monovalent antibodies, antigen-binding fragments of full-length antibodies, and fusion proteins of the above. Such antigen-binding fragments include, but are not limited to, single-domain antibodies (variable domain of heavy chain antibodies (VHHs) or nanobodies), Fabs, F(ab′)2s, and scFvs (single-chain variable fragments). In certain embodiment, the therapeutic product (for example, a therapeutic protein) is post-translationally modified. In a specific embodiment, the post-translational modification is specific to the cell type, to which the therapeutic product (for example, a therapeutic protein) is delivered using a specific route as described herein. Delivery may be accomplished via gene therapy—e.g., by administering a recombinant viral vector or a recombinant DNA expression construct (collectively, a “recombinant vector”) encoding an therapeutic product to the suprachoroidal space, subretinal space (with vitrectomy, or without vitrectomy (e.g., with a catheter through the suprachoroidal space, or via peripheral injection), intraretinal space, and/or outer surface of the sclera (i.e., juxtascleral administration) in the eye(s) of a human patient, to create a permanent depot in the eye that continuously supplies the therapeutic product (e.g., a post-translationally modified therapeutic product).


In one aspect, provided herein is a method of subretinal administration without vitrectomy for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient. In certain embodiments, the administering step comprises administering to the subretinal space in the eye of said human subject the recombinant viral vector therapeutic product via the suprachoroidal space in the eye of said human subject. In certain embodiments, the administering step is by the use of a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space toward the posterior pole, where a small needle injects into the subretinal space. In certain embodiments, the administering step comprises inserting and tunneling the catheter of the subretinal drug delivery device through the suprachoroidal space.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient. In certain embodiments, the administering step comprises administering to the subretinal space in the eye of said human subject the recombinant viral vector therapeutic product via the suprachoroidal space in the eye of said human subject. In certain embodiments, the administering step is by the use of a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space toward the posterior pole, where a small needle injects into the subretinal space. In certain embodiments, the administering step comprises inserting and tunneling the catheter of the subretinal drug delivery device through the suprachoroidal space.


In one aspect, provided herein is a method of subretinal administration with vitrectomy for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient. In certain embodiments, the vitrectomy is a partial vitrectomy.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient. In certain embodiments, the vitrectomy is a partial vitrectomy.


In one aspect, provided herein is a method of suprachoroidal administration for treating a pathology of the eye, comprising administering to the suprachoroidal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye. In certain embodiments, the administering step is by injecting the recombinant viral vector into the suprachoroidal space using a suprachoroidal drug delivery device. In certain embodiments, the suprachoroidal drug delivery device is a microinjector.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the suprachoroidal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye. In certain embodiments, the administering step is by injecting the recombinant viral vector into the suprachoroidal space using a suprachoroidal drug delivery device. In certain embodiments, the suprachoroidal drug delivery device is a microinjector.


In certain embodiments, delivery to the subretinal or suprachoroidal space can be performed using the methods and/or devices described and disclosed in International Publication Nos. WO 2016/042162, WO 2017/046358, WO 2017/158365, and WO 2017/158366, each of which is incorporated by reference in its entirety.


In one aspect, provided herein is a method of administration to the outer space of the sclera for treating a pathology of the eye, comprising administering to the outer surface of the sclera in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye. In certain embodiments, the administering step is by the use of a juxtascleral drug delivery device that comprises a cannula whose tip can be inserted and kept in direct apposition to the scleral surface. In certain embodiments, the administering step comprises inserting and keeping the tip of the cannula in direct apposition to the scleral surface.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the outer surface of the sclera in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye. In certain embodiments, the administering step is by the use of a juxtascleral drug delivery device that comprises a cannula whose tip can be inserted and kept in direct apposition to the scleral surface. In certain embodiments, the administering step comprises inserting and keeping the tip of the cannula in direct apposition to the scleral surface


In certain embodiments, the therapeutic product is not an anti-human vascular endothelial growth factor (hVEGF) antibody.


In certain embodiments, the pathology of the eye is not associated with neovascular age-related macular degeneration (nAMD) (also known as the “wet,” neovascular form of AMD (“WAMD” or “wet AMD”)).


In certain embodiments, the therapeutic product is an anti-hVEGF antibody.


In certain embodiments, the pathology of the eye is associated with nAMD.


In certain embodiments, the pathology of the eye is associated with nAMD and the therapeutic product is an anti-hVEGF antibody.


In one aspect, provided herein is a method of subretinal administration accompanied by vitrectomy for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient, and wherein the therapeutic product is not anti-human vascular endothelial growth factor (hVEGF) antibody. In certain embodiments, the pathology of the eye is an ocular disease or a disease involving multiple organs including the eye. In certain embodiments, the vitrectomy is a partial vitrectomy.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient, and wherein the therapeutic product is not anti-human vascular endothelial growth factor (hVEGF) antibody. In certain embodiments, the pathology of the eye is an ocular disease or a disease involving multiple organs including the eye. In certain embodiments, the vitrectomy is a partial vitrectomy.


In one aspect, provided herein is a method of subretinal administration for treating a pathology of the eye, comprising administering to the subretinal space peripheral to the optic disc, fovea and macula located in the back of the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient. In certain embodiments, the injecting step is by transvitreal injection. In certain embodiments, the method of transvitreal administration results in uniform expression of the therapeutic product throughout the eye (e.g. the expression level at the site of injection varies by less than 5%, 10%, 20%, 30%, 40%, or 50% as compared to the expression level at other areas of the eye). In certain embodiments, the transvitreal injection comprises inserting a sharp needle into the sclera via the superior or inferior side of the eye and passing the sharp needle all the way through the vitreous to inject the recombinant viral vector to the subretinal space on the other side. In certain embodiments, a needle is inserted at the 2 or 10 o'clock position. In certain embodiments, the transvitreal injection comprises inserting a trochar into the sclera and inserting a cannula through the trochar and through the vitreous to inject the recombinant viral vector to the subretinal space on the other side. In certain embodiments, the therapeutic product is an anti-hVEGF antibody. In certain embodiments, the anti-hVEGF antibody is an anti-hVEGF antigen-binding fragment. In certain embodiments, the anti-hVEGF antigen-binding fragment is a Fab, F(ab′)2, or single chain variable fragment (scFv). In certain embodiments, the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4, and a light chain comprising the amino acid sequence of SEQ ID NO:1, or SEQ ID NO:3. In certain embodiments, wherein the anti-hVEGF antibody comprises light chain CDRs 1-3 of SEQ ID NOs:14-16 and heavy chain CDRs 1-3 of SEQ ID NOs:17-19 or SEQ ID NOs:20, 18, and 21. In certain embodiments, wherein the pathology of the eye is associated with nAMD, dry age-related macular degeneration (dry AMD), retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR). In certain embodiments, the pathology of the eye is associated with nAMD.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the subretinal space peripheral to the optic disc, fovea and macula located in the back of the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient. In certain embodiments, the injecting step is by transvitreal injection. In certain embodiments, the method of transvitreal administration results in uniform expression of the therapeutic product throughout the eye (e.g. the expression level at the site of injection varies by less than 5%, 10%, 20%, 30%, 40%, or 50% as compared to the expression level at other areas of the eye). In certain embodiments, the transvitreal injection comprises inserting a sharp needle into the sclera via the superior or inferior side of the eye and passing the sharp needle all the way through the vitreous to inject the recombinant viral vector to the subretinal space on the other side. In certain embodiments, a needle is inserted at the 2 or 10 o'clock position. In certain embodiments, the transvitreal injection comprises inserting a trochar into the sclera and inserting a cannula through the trochar and through the vitreous to inject the recombinant viral vector to the subretinal space on the other side. In certain embodiments, the therapeutic product is an anti-hVEGF antibody. In certain embodiments, the anti-hVEGF antibody is an anti-hVEGF antigen-binding fragment. In certain embodiments, the anti-hVEGF antigen-binding fragment is a Fab, F(ab′)2, or single chain variable fragment (scFv). In certain embodiments, the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4, and a light chain comprising the amino acid sequence of SEQ ID NO:1, or SEQ ID NO:3. In certain embodiments, wherein the anti-hVEGF antibody comprises light chain CDRs 1-3 of SEQ ID NOs:14-16 and heavy chain CDRs 1-3 of SEQ ID NOs:17-19 or SEQ ID NOs:20, 18, and 21. In certain embodiments, wherein the pathology of the eye is associated with nAMD, dry age-related macular degeneration (dry AMD), retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR). In certain embodiments, the pathology of the eye is associated with nAMD.


In certain embodiments of the methods described herein, (1) the pathology of the eye is associated with Batten-CLN1 and the therapeutic product is Palmitoyl-Protein Thioesterase 1 (PPT1); (2) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1); (3) the pathology of the eye is associated with Batten-CLN3 and the therapeutic product is Battenin (CLN3); (4) the pathology of the eye is associated with Batten-CLN6 and the therapeutic product is CLN6 Transmembrane ER Protein (CLN6); (5) the pathology of the eye is associated with Batten-CLN7 and the therapeutic product is Major Facilitator Superfamily Domain Containing 8 (MFSD8); (6) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Myosin VIIA (MYO7A); (7) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Cadherin Related 23 (CDH23); (8) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Protocadherin Related 15 (PCDH15); (9) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Usherin (USH2A); (10) the pathology of the eye is associated with Usher's-Type 3 and the therapeutic product is Clarin 1 (CLRN1); (11) the pathology of the eye is associated with Stargardt's and the therapeutic product is ATP Binding Cassette Subfamily A Member 4 (ABCA4); (12) the pathology of the eye is associated with Stargardt's and the therapeutic product is ELOVL Fatty Acid Elongase 4 (ELOVL4); (13) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-Interleukin 6 (IL6) monoclonal antibody; (14) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF-alpha (TNF) monoclonal antibody; (15) the pathology of the eye is associated with diabetic macular edema (DME) and the therapeutic product is an anti-IL6 monoclonal antibody; (16) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW); (17) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW); (18) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW); (19) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D); (20) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65); (21) the pathology of the eye is associated with LCA 3 and the therapeutic product is Spermatogenesis Associated 7 (SPATA7); (22) the pathology of the eye is associated with Leber congenital amaurosis-4 (LCA 4) and the therapeutic product is Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1); (23) the pathology of the eye is associated with Leber congenital amaurosis-5 (LCA 5) and the therapeutic product is Lebercilin (LCA5); (24) the pathology of the eye is associated with Leber congenital amaurosis-6 (LCA 6) and the therapeutic product is RPGR Interacting Protein 1 (RPGRIP1); (25) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX); (26) the pathology of the eye is associated with Leber congenital amaurosis-8 (LCA 8) and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1) (also known as LCA8); (27) the pathology of the eye is associated with Leber congenital amaurosis-9 (LCA 9) and the therapeutic product is Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1); (28) the pathology of the eye is associated with Leber congenital amaurosis-10 (LCA 10) and the therapeutic product is Centrosomal Protein 290 (CEP290); (29) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1); (30) the pathology of the eye is associated with Leber congenital amaurosis-12 (LCA 12) and the therapeutic product is Retinal Degeneration 3, GUCY2D regulator (RD3); (31) the pathology of the eye is associated with Leber congenital amaurosis-13 (LCA 13) and the therapeutic product is Retinol Dehydrogenase 12 (RDH12); (32) the pathology of the eye is associated with Leber congenital amaurosis-14 (LCA 14) and the therapeutic product is Lecithin Retinol Acyltransferase (LRAT); (33) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1); (34) the pathology of the eye is associated with Leber congenital amaurosis-16 (LCA 16) and the therapeutic product is Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13); (35) the pathology of the eye is associated with Leber's hereditary optic neuropathy (LHON) and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1); (36) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4); (37) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6); (38) the pathology of the eye is associated with neuromyelitis optica (NMO) and the therapeutic product is an anti-complement antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamer, or preferably an anti-complement C5 antibody; (39) the pathology of the eye is associated with NMO and the therapeutic product is an anti-IL6 monoclonal antibody or aptamer; (40) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement monoclonal antibody or aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (41) the pathology of the eye is associated with uveitis and the therapeutic product is Angiotensin I Converting Enzyme (ACE); (42) the pathology of the eye is associated with uveitis and the therapeutic product is Interleukin 10 (IL10); (43) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF monoclonal antibody; (44) the pathology of the eye is associated with choroideremia and the therapeutic product is Rab Escort Protein 1 (CHM); (45) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1); (46) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1); (47) the pathology of the eye is associated with Bardet-Biedl syndrome 2 and the therapeutic product is Bardet-Biedl Syndrome 2 (BBS2); (48) the pathology of the eye is associated with Bardet-Biedl syndrome 3 and the therapeutic product is ADP Ribosylation Factor Like GTPase 6 (ARL6) (also known as BBS3); (49) the pathology of the eye is associated with Bardet-Biedl syndrome 4 and the therapeutic product is Bardet-Biedl Syndrome 4 (BBS4); (50) the pathology of the eye is associated with Bardet-Biedl syndrome 5 and the therapeutic product is Bardet-Biedl Syndrome 5 (BBS5); (51) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS), also known as BBS6; (52) the pathology of the eye is associated with Bardet-Biedl syndrome 7 and the therapeutic product is Bardet-Biedl Syndrome 7 (BBS7); (53) the pathology of the eye is associated with Bardet-Biedl syndrome 8 and the therapeutic product is Tetratricopeptide Repeat Domain 8 (TTC8), also known as BBS8; (54) the pathology of the eye is associated with Bardet-Biedl syndrome 9 and the therapeutic product is Bardet-Biedl Syndrome 9 (BBS9); (55) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10); (56) the pathology of the eye is associated with Bardet-Biedl syndrome 11 and the therapeutic product is Tripartite Motif Containing 32 (TRIM32), also known as BBS11; (57) the pathology of the eye is associated with Bardet-Biedl syndrome 12 and the therapeutic product is Bardet-Biedl Syndrome 12 (BBS12); (58) the pathology of the eye is associated with Bardet-Biedl syndrome 13 and the therapeutic product is MKS Transition Zone Complex Subunit 1 (MKS1), also known as BBS13; (59) the pathology of the eye is associated with Bardet-Biedl syndrome 14 and the therapeutic product is Centrosomal Protein 290 (CEP290), also known as BBS14 and LCA10; (60) the pathology of the eye is associated with Bardet-Biedl syndrome 15 and the therapeutic product is WD Repeat Containing Planar Cell Polarity Effector (WDPCP), also known as BBS15; (61) the pathology of the eye is associated with Bardet-Biedl syndrome 16 and the therapeutic product is Serologically Defined Colon Cancer Antigen 8 (SDCCAG8), also known as BBS16; (62) the pathology of the eye is associated with Bardet-Biedl syndrome 17 and the therapeutic product is Leucine Zipper Transcription Factor Like 1 (LZTFL1), also known as BBS17; (63) the pathology of the eye is associated with Bardet-Biedl syndrome 18 and the therapeutic product is BBSome Interacting Protein 1 (BBIP1), also known as BBS18; (64) the pathology of the eye is associated with Bardet-Biedl syndrome 19 and the therapeutic product is Intraflagellar Transport 27 (IFT27), also known as BBS19; (65) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A); (66) the pathology of the eye is associated with optic atrophy and the therapeutic product is OPA1 Mitochondrial Dynamin Like GTPase (OPA1); (67) the pathology of the eye is associated with retinitis pigmentosa 1 and the therapeutic product is RP1 Axonemal Microtubule Associated (RP1); (68) the pathology of the eye is associated with retinitis pigmentosa 2 and the therapeutic product is RP2 Activator of ARL3 GTPase (RP2); (69) the pathology of the eye is associated with retinitis pigmentosa 7 and the therapeutic product is Peripherin 2 (PRPH2); (70) the pathology of the eye is associated with retinitis pigmentosa 11 and the therapeutic product is Pre-mRNA Processing Factor 31(PRPF31); (71) the pathology of the eye is associated with retinitis pigmentosa 12 and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1), also known as LCA8; (72) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8); (73) the pathology of the eye is associated with retinitis pigmentosa 25 and the therapeutic product is Eyes Shut Homolog (EYS); (74) the pathology of the eye is associated with retinitis pigmentosa 28 and the therapeutic product is FAM161 Centrosomal Protein A (FAM161A); (75) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3); (76) the pathology of the eye is associated with retinitis pigmentosa 38 and the therapeutic product is MER Proto-Oncogene, Tyrosine Kinase (MERTK); (77) the pathology of the eye is associated with retinitis pigmentosa 40 and the therapeutic product is Phosphodiesterase 6B (PDE6B); (78) the pathology of the eye is associated with retinitis pigmentosa 41 and the therapeutic product is Prominin 1 (PROM1); (79) the pathology of the eye is associated with retinitis pigmentosa 43 and the therapeutic product is Phosphodiesterase 6A (PDE6A); (80) the pathology of the eye is associated with retinitis pigmentosa 56 and the therapeutic product is Interphotoreceptor Matrix Proteoglycan 2 (IMPG2); (81) the pathology of the eye is associated with petinitis pigmentosa 62 and the therapeutic product is Male Germ Cell Associated Kinase (MAK); (82) the pathology of the eye is associated with retinitis pigmentosa 80 and the therapeutic product is Intraflagellar Transport 140 (IFT140); (83) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-complement monoclonal antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or an anti-complement aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (84) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-membrane attack complex (MAC) therapeutic product, preferably the anti-MAC therapeutic product is an anti-MAC monoclonal antibody, which is a monoclonal antibody against a human protein of the membrane attack complex, which is composed of four complement proteins C5b (SEQ ID NOs. 314-316), C6 (SEQ ID NO. 317), C7 (SEQ ID NO. 318), and C8 (SEQ ID NOs. 319-321); (85) the pathology of the eye is associated with dry AMD and the therapeutic product is HtrA Serine Peptidase 1 (HTRA1); (86) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1); (87) the pathology of the eye is associated with dry AMD and the therapeutic product is a complement factor B antisense oligonucleotide; (88) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-beta-amyloid monoclonal antibody; (89) the pathology of the eye is associated with dry AMD and the therapeutic product is CD59 glycoprotein (CD59); (90) the pathology of the eye is associated with dry AMD and the therapeutic product is Channelrhodopsin-1 (ChR1), which includes the human homolog of ChR1; (91) the pathology of the eye is associated with dry AMD and the therapeutic product is Channelrhodopsin-2 (ChR2), which includes the human homolog of ChR2; (92) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-complement monoclonal antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or an anti-complement aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (93) the pathology of the eye is associated with dry AMD and the therapeutic product is anti-complement factor D therapeutic product, including but not limited to an anti-complement factor D monoclonal antibody, or an anti-complement factor D aptamer; (94) the pathology of the eye is associated with age-related retinal ganglion cell (RGC) degeneration and the therapeutic product is DnaJ heat shock protein family (Hsp40) member C3 (DNAJC3), also known as P58IPK; (95) the pathology of the eye is associated with blue cone monochromacy (BCM) and the therapeutic product is L opsin (OPN1LW); (96) the pathology of the eye is associated with glaucoma and the therapeutic product is beta-2 adrenoceptor siRNA; (97) the pathology of the eye is associated with glaucoma and the therapeutic product is Caspase-2 (CASP2); (98) the pathology of the eye is associated with glaucoma and the therapeutic product is Insulin Receptor Substrate 1 (IRS1); (99) the pathology of the eye is associated with glaucoma and the therapeutic product is HIF-1 Responsive Protein RTP801 (RTP801); (100) the pathology of the eye is associated with glaucoma and the therapeutic product is Transforming Growth Factor Beta 2 (TGFB2); (101) the pathology of the eye is associated with glaucoma and the therapeutic product is Brain Derived Neurotrophic Factor (BDNF); (102) the pathology of the eye is associated with glaucoma and the therapeutic product is Ciliary Neurotrophic Factor (CNTF); (103) the pathology of the eye is associated with glaucoma and the therapeutic product is Prostaglandin-Endoperoxide Synthase 2 (PTGS2); (104) the pathology of the eye is associated with glaucoma and the therapeutic product is Prostaglandin F Receptor (PTGFR) (when the pathology of the eye is associated with glaucoma, in a specific embodiment, a recombinant viral vector comprising a nucleotide sequence encoding PTGFR can be administered to the human subject in combination with a recombinant viral vector comprising a nucleotide sequence encoding PTGS2; in another specific embodiment, a recombinant viral vector comprising a nucleotide sequence encoding PTGFR and a nucleotide sequence encoding PTGS2 can be administered to the human subject); (105) the pathology of the eye is associated with glaucoma and the therapeutic product is a hyaluronidase, e.g. HYAL1, HYAL2, HYAL3, HYAL4, and HYAL5; (106) the pathology of the eye is associated with glaucoma and the therapeutic product is Pigment Epithelium-Derived Factor (PEDF); (107) the pathology of the eye is associated with glaucoma and the therapeutic product is Vascular Endothelial Growth Factor (VEGF); (108) the pathology of the eye is associated with glaucoma and the therapeutic product is Placental Growth Factor (PGF), wherein PGF can be used in combo with VEGF; (109) the pathology of the eye is associated with glaucoma (e.g., a congenital glaucoma or juvenile glaucoma) and the therapeutic product is Myocilin (MYOC); (110) the pathology of the eye is associated with NMO and the therapeutic product is an anti-complement C5 monoclonal antibody; (111) the pathology of the eye is associated with NMO and the therapeutic product is C-C Motif Chemokine Receptor 5 (CCR5) siRNA, CCR5 shRNA, siRNA or CCR5 miRNA (preferably, a CCR5 miRNA); (112) the pathology of the eye is associated with NMO and the therapeutic product is an anti-CD19 monoclonal antibody; (113) the pathology of the eye is associated with retinitis pigmentosa that is associated with rhodopsin mutations and the therapeutic product is Channelrhodopsin-1 (ChR1), which includes the human homolog of ChR1; (114) the pathology of the eye is associated with retinitis pigmentosa that is associated with rhodopsin mutations and the therapeutic product is Channelrhodopsin-2 (ChR2), which includes the human homolog of ChR2; (115) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Ciliary Neurotrophic Factor (CNTF); (116) the pathology of the eye is associated with autosomal recessive retinitis pigmentosa and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1); (117) the pathology of the eye is associated with autosomal recessive retinitis pigmentosa and the therapeutic product is Crumbs Cell Polarity Complex Component 2 (CRB2); (118) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Histone Deacetylase 4 (HDAC4); (119) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rhodopsin (RHO); (120) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Nerve Growth Factor (NGF); (121) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Nuclear Factor, Erythroid 2 Like 2 (NRF2); (122) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Pigment Epithelium-Derived Factor (PEDF); (123) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Glutathione S-Transferase PI 1 (GSTP1), also known as PI; (124) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rod-Derived Cone Viability Factor (RDCVF); (125) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rhodopsin (RHO); (126) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Retinaldehyde Binding Protein 1 (RLBP1); (127) the pathology of the eye is associated with Stargardt's disease and the therapeutic product is an anti-complement C5 aptamer; (128) the pathology of the eye is associated with uveitis and the therapeutic product is Double Homeobox 4 (DUX4); (129) the pathology of the eye is associated with uveitis and the therapeutic product is NLR Family Pyrin Domain Containing 3 (NLRP3); (130) the pathology of the eye is associated with uveitis and the therapeutic product is Spleen Associated Tyrosine Kinase (SYK); (131) the pathology of the eye is associated with uveitis and the therapeutic product is Adrenocorticotropic Hormone (ACTH); (132) the pathology of the eye is associated with uveitis and the therapeutic product is Caspase 1 (CASP1); (133) the pathology of the eye is associated with uveitis and the therapeutic product is anti-CD59 therapeutic product (such as an anti-CD59 therapeutic protein (for example, an anti-CD59 monoclonal antibody), or an anti-CD59 therapeutic RNA (for example, an anti-CD59 shRNA, anti-CD59 siRNA, or anti-CD59 miRNA), preferably an anti-CD59 monoclonal antibody); (134) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement monoclonal antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (135) the pathology of the eye is associated with corneal neovascularization and the therapeutic product is Insulin Receptor Substrate 1 (IRS1); (136) the pathology of the eye is associated with corneal neovascularization and the therapeutic product is NOTCH Regulated Ankyrin Repeat Protein (NRARP); (137) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is NOTCH Regulated Ankyrin Repeat Protein (NRARP); (138) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Alpha-2-Antiplasmin (A2AP); (139) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Plasminogen (PLG); (140) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product can be a growth hormone; (141) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Insulin Like Growth Factor 1 (IGF1), wherein IGF1 can be used in combo with growth hormone; (142) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Interleukin 1 Beta (IL1B). (143) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Angiotensin I Converting Enzyme 2 (ACE2), wherein ACE2 can be used in combo with IL1B; (144) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is IRS1; (145) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is an anti-integrin oligopeptide; (146) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is an anti-Placental Growth Factor (PGF) monoclonal antibody; (147) the pathology of the eye is associated with Graves' ophthalmopathy (also known as Graves' orbitopathy) and the therapeutic product is an anti-CD40 monoclonal antibody; (148) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-Insulin-Like Growth Factor 1 Receptor (IGF1R) monoclonal antibody; (149) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-Insulin-Like Growth Factor 2 Receptor (IGF2R) monoclonal antibody; (150) the pathology of the eye is associated with DME and the therapeutic product is an anti-integrin oligopeptide; (151) the pathology of the eye is associated with DME and the therapeutic product is an anti-Placental Growth Factor (PGF) monoclonal antibody; (152) the pathology of the eye is associated with DME and the therapeutic product is RTP801 siRNA; (153) the pathology of the eye is associated with multiple sclerosis (MS)-associated vision loss and the therapeutic product is ND1; (154) the pathology of the eye is associated with myopia and the therapeutic product is Matrix Metalloproteinase 2 (MMP2) RNAi; (155) the pathology of the eye is associated with X-linked recessive ocular albinism and the therapeutic product is G-Protein Coupled Receptor 143 (GPR143); (156) the pathology of the eye is associated with oculocutaneous albinism type 1 and the therapeutic product is Tyrosinase (TYR); (157) the pathology of the eye is associated with optic neuritis and the therapeutic product is Caspase 2 (CASP2); (158) the pathology of the eye is associated with optic neuritis and the therapeutic product is an anti-Leucine Rich Repeat And Ig Domain Containing Protein 1 (LINGO1) monoclonal antibody; or (159) the pathology of the eye is associated with polypoidal choroidal vasculopathy and the therapeutic product is anti-complement monoclonal antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody/aptamer, an anti-complement C1s monoclonal antibody/aptamer, an anti-complement C2 monoclonal antibody/aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody.


In certain embodiments of the methods described herein, the pathology of the eye is associated with X-linked retinitis pigmentosa (XLRP) and the therapeutic product is Retinitis Pigmentosa GTPase Regulator (RPGR). In certain embodiments of any of the foregoing methods, the pathology of the eye is associated with achromatopsia (ACHM) and the therapeutic product is Cyclic Nucleotide Gated Channel Beta 3 (CNGB3). In certain embodiments of any of the foregoing methods, the pathology of the eye is associated with achromatopsia (for example, a CNGA3-linked achromatopsia) and the therapeutic product is Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3). In certain embodiments of any of the foregoing methods, the pathology of the eye is associated with biallelic RPE65 mutation-associated retinal dystrophy and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65).


In certain embodiments of the methods described herein, the pathology of the eye is associated with (1) Batten-CLN1 and the therapeutic product is Palmitoyl-Protein Thioesterase 1 (PPT1); (2) Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1); (3) Batten-CLN3 and the therapeutic product is Battenin (CLN3); (4) uveitis and the therapeutic product is an anti-Interleukin 6 (IL6) monoclonal antibody; (5) uveitis and the therapeutic product is an anti-TNF-alpha (TNF) monoclonal antibody; (6) diabetic macular edema (DME) and the therapeutic product is an anti-IL6 monoclonal antibody; (7) red-green color blindness and the therapeutic product is L opsin (OPN1LW); (8) red-green color blindness and the therapeutic product is M opsin (OPN1MW); (9) blue cone monochromacy and the therapeutic product is M opsin (OPN1MW); (10) Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D); (11) Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65); (12) Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX); (13) Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1); (14) Leber congenital amaurosis-12 (LCA 12) and the therapeutic product is Retinal Degeneration 3, GUCY2D regulator (RD3); (15) Leber congenital amaurosis-13 (LCA 13) and the therapeutic product is Retinol Dehydrogenase 12 (RDH12); (16) Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1); (17) Leber congenital amaurosis-16 (LCA 16) and the therapeutic product is Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13); (18) Leber's hereditary optic neuropathy (LHON) and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1); (19) LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4); (20) LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6); (21) neuromyelitis optica (NMO) and the therapeutic product is an anti-complement monoclonal antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (22) NMO and the therapeutic product is an anti-IL6 monoclonal antibody; (23) uveitis and the therapeutic product is an anti-complement C5 monoclonal antibody; (24) uveitis and the therapeutic product is Angiotensin I Converting Enzyme (ACE); (25) uveitis and the therapeutic product is Interleukin 10 (IL10); (26) uveitis and the therapeutic product is an anti-TNF monoclonal antibody; (27) X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1); (28) Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1); (29) Bardet-Biedl syndrome 3 and the therapeutic product is ADP Ribosylation Factor Like GTPase 6 (ARL6); (30) Bardet-Biedl syndrome 5 and the therapeutic product is Bardet-Biedl Syndrome 5 (BBS5); (31) Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS); (32) Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10); (33) Bardet-Biedl syndrome 11 and the therapeutic product is Tripartite Motif Containing 32 (TRIM32); (34) Bardet-Biedl syndrome 13 and the therapeutic product is MKS Transition Zone Complex Subunit 1 (MKS1); (35) Bardet-Biedl syndrome 18 and the therapeutic product is BBSome Interacting Protein 1 (BBIP1); (36) Bardet-Biedl syndrome 19 and the therapeutic product is Intraflagellar Transport 27 (IFT27); (37) cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A); (38) retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8); (39) retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3); or (40) Best disease and the therapeutic product is Bestrophin 1 (BEST1).


In certain embodiments of the methods described herein, the pathology of the eye is associated with biallelic RPE65 mutation-associated retinal dystrophy and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65).


In certain embodiments of the methods described herein, the pathology of the eye is associated with (1) Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1); (2) Usher's-Type 1 and the therapeutic product is Myosin VIIA (MYO7A); (3) Usher's-Type 1 and the therapeutic product is Cadherin Related 23 (CDH23); (4) Usher's-Type 2 and the therapeutic product is Protocadherin Related 15 (PCDH15); (5) Usher's-Type 2 and the therapeutic product is Usherin (USH2A); (6) Usher's-Type 3 and the therapeutic product is Clarin 1 (CLRN1); (7) Stargardt's and the therapeutic product is ATP Binding Cassette Subfamily A Member 4 (ABCA4); (8) Stargardt's and the therapeutic product is ELOVL Fatty Acid Elongase 4 (ELOVL4); (9) red-green color blindness and the therapeutic product is L opsin (OPN1LW); (10) red-green color blindness and the therapeutic product is M opsin (OPN1MW); (11) blue cone monochromacy and the therapeutic product is M opsin (OPN1MW); (12) Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D); (13) Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65); (14) Leber congenital amaurosis-4 (LCA 4) and the therapeutic product is Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1); (15) Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX); (16) Leber congenital amaurosis-8 (LCA 8) and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1); (17) Leber congenital amaurosis-9 (LCA 9) and the therapeutic product is Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1); (18) Leber congenital amaurosis-10 (LCA 10) and the therapeutic product is Centrosomal Protein 290 (CEP290); (19) Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1); (20) Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1); (21) LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4); (22) LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6); (23) choroideremia and the therapeutic product is Rab Escort Protein 1 (CHM); (24) X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1); (25) Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1); (26) Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS); (27) Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10); (28) cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A); (29) optic atrophy and the therapeutic product is OPA1 Mitochondrial Dynamin Like GTPase (OPA1); (30) retinitis pigmentosa 1 and the therapeutic product is RP1 Axonemal Microtubule Associated (RP1); (31) retinitis pigmentosa 2 and the therapeutic product is RP2 Activator of ARL3 GTPase (RP2); (32) retinitis pigmentosa 7 and the therapeutic product is Peripherin 2 (PRPH2); (33) retinitis pigmentosa 11 and the therapeutic product is Pre-mRNA Processing Factor 31(PRPF31); (34) retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8); (35) retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3); (36) retinitis pigmentosa 38 and the therapeutic product is MER Proto-Oncogene, Tyrosine Kinase (MERTK); (37) retinitis pigmentosa 40 and the therapeutic product is Phosphodiesterase 6B (PDE6B); (38) retinitis pigmentosa 41 and the therapeutic product is Prominin 1 (PROM1); (39) retinitis pigmentosa 56 and the therapeutic product is Interphotoreceptor Matrix Proteoglycan 2 (IMPG2); (40) petinitis pigmentosa 62 and the therapeutic product is Male Germ Cell Associated Kinase (MAK); (41) retinitis pigmentosa 80 and the therapeutic product is Intraflagellar Transport 140 (IFT140); or (42) Best disease and the therapeutic product is Bestrophin 1 (BEST1).


In certain embodiments of the methods described herein, the pathology of the eye is associated with X-linked retinitis pigmentosa (XLRP) and the therapeutic product is Retinitis Pigmentosa GTPase Regulator (RPGR). In certain embodiments of any of the foregoing methods, the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Beta 3 (CNGB3); or achromatopsia (for example, a CNGA3-linked achromatopsia) and the therapeutic product is Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3).


In certain embodiments of the method described herein, the recombinant viral vector further comprises a nucleotide sequence encoding a promoter or an enhancer-promoter, which nucleotide sequence encoding the promoter or enhancer-promoter is operably linked to the nucleotide sequence encoding the therapeutic product, and wherein the promoter or enhancer-promoter is a ubiquitous promoter/enhancer-promoter, eye-specific promoter/enhancer-promoter, or retina-specific promoter/enhancer-promoter.


In certain embodiments of the methods described herein, the recombinant viral vector further comprises a nucleotide sequence encoding a promoter or an enhancer-promoter, which nucleotide sequence encoding the promoter or enhancer-promoter is operably linked to the nucleotide sequence encoding the therapeutic product, and wherein the promoter or enhancer-promoter is: (1) a CAG promoter; (2) a CBA promoter; (3) a CMV promoter; (4) a 1.7-kb red cone opsin promoter (PR1.7 promoter); (5) a Rhodopsin Kinase (GRK1) photoreceptor-specific enhancer-promoter (see, e.g., Young et al., 2003, Retinal Cell Biology; 44:4076-4085); (6) an hCARp promoter, which is a human cone arrestin promoter; (7) an hRKp, which is a rhodopsin kinase promoter; (8) a cone photoreceptor specific human arrestin 3 (ARR3) promoter; (9) a rhodopsin promoter; or (10) a U6 promoter (in particular when the therapeutic product is a small RNA such as shRNA and siRNA).


In certain embodiments of the methods described herein, the recombinant viral vector further comprises a nucleotide sequence encoding a cone-specific promoter, which nucleotide sequence encoding the cone-specific promoter is operably linked to the nucleotide sequence encoding the therapeutic product, and wherein: (1) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW); (2) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW); (3) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW); (4) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A); or (5) the pathology of the eye is associated with blue cone monochromacy (BCM) and the therapeutic product is L opsin (OPN1LW).


In certain embodiments of the methods described herein, the administering step delivers a therapeutically effective amount of the therapeutic product to the retina of said human subject.


In certain embodiments of the methods described herein, the therapeutically effective amount of the therapeutic product is produced by human retinal cells of said human subject.


In certain embodiments of the methods described herein, the therapeutically effective amount of the therapeutic product is produced by human photoreceptor cells, horizontal cells, bipolar cells, amacrine cells, retina ganglion cells, and/or retinal pigment epithelial cells in the external limiting membrane of said human subject.


In certain embodiments of the methods described herein, the human photoreceptor cells are cone cells and/or rod cells.


In certain embodiments of the methods described herein, the retina ganglion cells are midget cells, parasol cells, bistratified cells, giant retina ganglion cells, photosensitive ganglion cells, and/or Müller glia.


In certain embodiments of the methods described herein, the recombinant viral vector is an rAAV vector (e.g., an rAAV8, rAAV2, rAAV2tYF, or rAAV5 vector).


In certain embodiments of the methods described herein, wherein the recombinant viral vector is an rAAV8 vector.


In certain embodiments of the methods described herein, the method further comprises, after the administering step, a step of monitoring temperature of the surface of the eye using an infrared thermal camera. In a specific embodiment, the infrared thermal camera is an FLIR T530 infrared thermal camera. In a specific embodiment, the infrared thermal camera is an FLIR T420 infrared thermal camera. In a specific embodiment, the infrared thermal camera is an FLIR T440 infrared thermal camera. In a specific embodiment, the infrared thermal camera is an Fluke Ti400 infrared thermal camera. In a specific embodiment, the infrared thermal camera is an FLIRE60 infrared thermal camera. In a specific embodiment, the infrared resolution of the infrared thermal camera is equal to or greater than 75,000 pixels. In a specific embodiment, the thermal sensitivity of the infrared thermal camera is equal to or smaller than 0.05° C. at 30° C. In a specific embodiment, the field of view (FOV) of the infrared thermal camera is equal to or lower than 25°×25°.


In certain embodiments of the methods described herein, delivering to the eye comprises delivering to the retina, choroid, and/or vitreous humor of the eye.


In certain embodiments, the recombinant vector used for delivering the therapeutic product should have a tropism for cells of the eye, for example, human retinal cells, (e.g., photoreceptor cells). Such vectors can include non-replicating recombinant adeno-associated virus vectors (“rAAV”), particularly those bearing an AAV8 capsid are preferred. However, other recombinant viral vectors may be used, including but not limited to recombinant lentiviral vectors, vaccinia viral vectors, or non-viral expression vectors referred to as “naked DNA” constructs. Preferably, the expression of therapeutic product should be controlled by appropriate expression control elements, for example, (1) a CAG promoter; (2) a CBA promoter; (3) a CMV promoter; (4) PR1.7 promoter; (5) a Rhodopsin Kinase (GRK1) photoreceptor-specific enhancer-promoter (6) an hCARp promoter; (7) an hRKp; (8) a cone photoreceptor specific human arrestin 3 (ARR3) promoter; (9) a rhodopsin promoter; or (10) a U6 promoter, and can include other expression control elements that enhance expression of the therapeutic product driven by the vector (e.g., introns such as the chicken β-actin intron, minute virus of mice (MVM) intron, human factor IX intron (e.g., FIX truncated intron 1), β-globin splice donor/immunoglobulin heavy chain spice acceptor intron, adenovirus splice donor/immunoglobulin splice acceptor intron, SV40 late splice donor/splice acceptor (19S/16S) intron, and hybrid adenovirus splice donor/IgG splice acceptor intron and polyA signals such as the rabbit β-globin polyA signal, human growth hormone (hGH) polyA signal, SV40 late polyA signal, synthetic polyA (SPA) signal, and bovine growth hormone (bGH) polyA signal). See, e.g., Powell and Rivera-Soto, 2015, Discov. Med., 19(102):49-57.


In certain embodiments of the method described herein, therapeutically effective doses of the recombinant vector are administered (1) to the subretinal space without vitrectomy (e.g., via the suprachoroidal space or via peripheral injection), (2) to the suprachoroidal space, (3) to the outer space of the sclera (i.e., juxtascleral administration), (4) to the subretinal space via vitrectomy, or (5) to the vitreous cavity, in a volume ranging from 50-100 μl or 100-500 μl, preferably 100-300 μl, and most preferably, 250 μl, depending on the administration method. In certain embodiments, therapeutically effective doses of the recombinant vector are administered suprachoroidally in a volume of 100 μl or less, for example, in a volume of 50-100 μl. In certain embodiments, therapeutically effective doses of the recombinant vector are administered to the outer surface of the sclera (e.g., by a posterior juxtascleral depot procedure) in a volume of 500 μl or less, for example, in a volume of 10-20 μl, 20-50 μl, 50-100 μl, 100-200 μl, 200-300 μl, 300-400 μl, or 400-500 μl. In certain embodiments, therapeutically effective doses of the recombinant vector are administered to the subretinal space via peripheral injection, in a volume ranging from 50-100 μl or 100-500 μl, preferably 100-300 μl, and most preferably, 250 μl.


In certain embodiments, OptoKinetic Nystagmus (OKN) is assessed to measure visual acuity in patients. In certain embodiments, OKN can be performed using the methods and/or devices described and disclosed for example, in Cetinkaya et al., 2008, Eye, 22:77-81; Hyon et al., 2010, IOVS, 51(2): 752-757, Han et al., 2011, IOVS, 52(10): 7492-7497; Wester et al., 2007, IOVS, 48(10):4542-4548; Palmowski-Wolfe et al., 2019, J. AAPOS, 23(4): e49; Turuwhenua et al., Objective Assessment of Visual Performance Using Optokinetic Nystagmus in Young Children, October 2016, <anzctr.org.au/AnzctrAttachments/371914-OKN %20protocol.pdf; and Objective Acuity and Aier Eye Hospital Group Announce Strategic Cooperation Agreement, Cision PR Newswire, Jul. 25, 2019, retrieved from the Internet <prnewswire.com/news-releases/objective-acuity-and-aier-eye-hospital-group-announce-a-strategic-cooperation-agreement-300891165.html>, each of which is incorporated by reference in its entirety.


Without being bound by theory, this visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN can be used to measure visual acuity in pre-verbal and/or non-verbal patients. In certain embodiments, OKN is used to measure visual acuity in patients that are 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. In certain embodiments, an iPad is used to measure visual acuity through detection of the OKN reflex when a patient is looking at movement on the iPad.


Without being bound by theory, this visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN can be used to measure visual acuity in pre-verbal and/or non-verbal patients. In certain embodiments, OKN is used to measure visual acuity in patients that are less than 1.5 months old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. In another specific embodiment, OKN is used to measure visual acuity in patients that are 1-2 months old, 2-3 months old, 3-4 months old, 4-5 months old, 5-6 months old, 6-7 months old, 7-8 months old, 8-9 months old, 9-10 months old, 10-11 months old, 11 months to 1 year old, 1-1.5 years old, 1.5-2 years old, 2-2.5 years old, 2.5-3 years old, 3-3.5 years old, 3.5-4 years old, 4-4.5 years old, or 4.5-5 years old. In another specific embodiment, OKN is used to measure visual acuity in patients that are 6 months to 5 years old. In certain embodiments, an iPad is used to measure visual acuity through detection of the OKN reflex when a patient is looking at movement on the iPad.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN2-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Tripeptidyl-Peptidase 1(TPP1). Specifically, the patient presenting with Batten-CLN2-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity assessed in a patient up to 5 years old presenting with Batten-CLN2-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Tripeptidyl-Peptidase 1. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN2-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding TPP1. Specifically, the patient presenting with Batten-CLN2-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient up to 5 years old presenting with Batten-CLN2-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Tripeptidyl-Peptidase 1. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN1-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Palmitoyl-Protein Thioesterase 1 (PPT1). Specifically, the patient up to 5 years old presenting with Batten-CLN1-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN1-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding PPT1. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN1-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding PPT1. Specifically, the patient presenting with Batten-CLN1-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient up to 5 years old presenting with Batten-CLN1-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding PPT 1. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN3-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Battenin (CLN3). Specifically, the patient presenting with Batten-CLN3-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient up to 5 years old presenting with Batten-CLN3-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Battenin (CLN3). In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN3-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Battenin (CLN3). Specifically, the patient presenting with Batten-CLN3-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient up to 5 years old presenting with Batten-CLN3-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Battenin (CLN3). In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN6-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding CLN6 Transmembrane ER Protein (CLN6). Specifically, the patient up to 5 years old presenting with Batten-CLN6-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN6-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding CLN6 Transmembrane ER Protein (CLN6). In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN6-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding CLN6 Transmembrane ER Protein (CLN6). Specifically, the patient up to 5 years old presenting with Batten-CLN6-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN6-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding CLN6 Transmembrane ER Protein (CLN6). In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN7-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Major Facilitator Superfamily Domain Containing 8 (MFSD8). Specifically, the patient up to 5 years old presenting with Batten-CLN7-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN7-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding MFSD8. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN7-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding MFSD8. Specifically, the patient presenting with Batten-CLN7-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient up to 5 years old presenting with Batten-CLN7-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding MFSD8. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


Subretinal administration via vitrectomy is a surgical procedure performed by trained retinal surgeons that involves a vitrectomy with the subject under local anesthesia, and subretinal injection of the gene therapy into the retina (see, e.g., Campochiaro et al., 2017, Hum Gen Ther 28(1):99-111, which is incorporated by reference herein in its entirety). Alternatively, subretinal administration can be performed without vitrectomy. In a specific embodiment, the subretinal administration without vitrectomy is performed via the suprachoroidal space using a suprachoroidal catheter which injects drug into the subretinal space, such as a subretinal drug delivery device that comprises a catheter which can be inserted and tunneled through the suprachoroidal space to the posterior pole, where a small needle injects into the subretinal space (see, e.g., Baldassarre et al., 2017, Subretinal Delivery of Cells via the Suprachoroidal Space: Janssen Trial. In: Schwartz et al. (eds) Cellular Therapies for Retinal Disease, Springer, Cham; International Patent Application Publication No. WO 2016/040635 A1; each of which is incorporated by reference herein in its entirety). In another specific embodiment, the subretinal administration without vitrectomy is performed via peripheral injection. In other words, the recombinant vector can be delivered to the subretinal space by peripheral injection into the retina (i.e., peripheral to the optic disc, fovea and macula located in the back of the eye) without performing a vitrectomy. This can be accomplished by transvitreal injection. Suprachoroidal administration procedures involve administration of a drug to the suprachoroidal space of the eye, and are normally performed using a suprachoroidal drug delivery device such as a microinjector with a microneedle (see, e.g., Hariprasad, 2016, Retinal Physician 13: 20-23; Goldstein, 2014, Retina Today 9(5): 82-87; each of which is incorporated by reference herein in its entirety).


The suprachoroidal drug delivery devices that can be used to deposit the recombinant vector in the suprachoroidal space according to the invention described herein include, but are not limited to, suprachoroidal drug delivery devices manufactured by Clearside® Biomedical, Inc. (see, for example, Hariprasad, 2016, Retinal Physician 13: 20-23) and MedOne suprachoroidal catheters. The subretinal drug delivery devices that can be used to deposit the recombinant vector in the subretinal space via the suprachoroidal space according to the invention described herein include, but are not limited to, subretinal drug delivery devices manufactured by Janssen Pharmaceuticals, Inc. (see, for example, International Patent Application Publication No. WO 2016/040635 A1) The subretinal drug delivery devices that can be used to deposit the recombinant vector in the subretinal space via the peripheral injection approach according to the invention described herein include, but are not limited to, sharp needles that can be inserted into the sclera via the superior or inferior side of the eye (e.g., at the 2 or 10 o'clock position) and pass all the way through the vitreous to inject the retina on the other side, and trochars that can be inserted into the sclera to allow a subretinal cannula to be inserted into the eye and through the vitreous to the area of desired injection. In a specific embodiment, administration to the outer surface of the sclera is performed by a juxtascleral drug delivery device comprising a cannula whose tip can be inserted and kept in direct apposition to the scleral surface.


Suprachoroidal, subretinal, juxtascleral, intravitreal, subconjunctival, and/or intraretinal administration should result in delivery of the soluble therapeutic product to the retina, the vitreous humor, and/or the aqueous humor. The expression of the therapeutic product by retinal cells, e.g., rod, cone, retinal pigment epithelial, horizontal, bipolar, amacrine, ganglion, and/or Müller cells, results in delivery and maintenance of the therapeutic product in the retina, the vitreous humor, and/or the aqueous humor. In specific embodiments, because the therapeutic product is continuously produced, maintenance of low concentrations can be effective. The concentration of the therapeutic product can be measured in patient samples of the vitreous humour and/or aqueous from the anterior chamber of the treated eye. Alternatively, vitreous humour concentrations can be estimated and/or monitored by measuring the patient's serum concentrations of the therapeutic product—the ratio of systemic to vitreal exposure to the therapeutic product is about 1:90,000. (E.g., see, vitreous humor and serum concentrations of ranibizumab reported in Xu L, et al., 2013, Invest. Opthal. Vis. Sci. 54: 1616-1624, at p. 1621 and Table 5 at p. 1623, which is incorporated by reference herein in its entirety).


Pharmaceutical compositions suitable for suprachoroidal, subretinal, juxtascleral, intravitreal, subconjunctival, and/or intraretinal administration comprise a suspension of the recombinant vector in a formulation buffer comprising a physiologically compatible aqueous buffer, a surfactant and optional excipients.


The invention has several advantages over standard of care treatments that involve repeated ocular injections of high dose boluses of therapeutic products that dissipate over time resulting in peak and trough levels. Sustained expression of the therapeutic product, as opposed to injecting a therapeutic product repeatedly, allows for a more consistent levels of antibody to be present at the site of action, and is less risky and more convenient for patients, since fewer injections need to be made, resulting in fewer doctor visits. Consistent protein production may leads to better clinical outcomes as edema rebound in the retina is less likely to occur. Furthermore, in certain embodiments, therapeutic products expressed from recombinant vectors are post-translationally modified in a different manner than those that are directly injected because of the different microenvironment present during and after translation. Without being bound by any particular theory, this results in therapeutic products that have different diffusion, bioactivity, distribution, affinity, pharmacokinetic, and immunogenicity characteristics, such that the therapeutic products delivered to the site of action are “biobetters” in comparison with directly injected therapeutic products.


In addition, when the therapeutic products are antibodies, antibodies expressed from recombinant vectors in vivo are not likely to contain degradation products associated with antibodies produced by recombinant technologies, such as protein aggregation and protein oxidation. Aggregation is an issue associated with protein production and storage due to high protein concentration, surface interaction with manufacturing equipment and containers, and purification with certain buffer systems. These conditions, which promote aggregation, do not exist in antibody expression in gene therapy. Oxidation, such as methionine, tryptophan, and histidine oxidation, is also associated with protein production and storage, and is caused by stressed cell culture conditions, metal and air contact, and impurities in buffers and excipients. The proteins expressed from recombinant vectors in vivo may also oxidize in a stressed condition. However, humans, and many other organisms, are equipped with an antioxidation defense system, which not only reduces the oxidation stress, but sometimes also repairs and/or reverses the oxidation. Thus, proteins produced in vivo are not likely to be in an oxidized form. Both aggregation and oxidation could affect the potency, pharmacokinetics (clearance), and immunogenicity.


Unlike small molecule drugs, biologics usually comprise a mixture of many variants with different modifications or forms that have a different potency, pharmacokinetics, and safety profile. For therapeutic products that are post-translationally modified upon expression in cells of the eye, it is not essential that every molecule produced either in the gene therapy or protein therapy approach be fully post-translationally modified. Rather, the population of such therapeutic products that are produced should have sufficient post-translational modification (for example, from about 1% to about 10% of the population, from about 1% to about 20% of the population, from about 1% to about 50% of the population, or from about 10% to about 50% of the population) to demonstrate efficacy. The goal of gene therapy treatment provided herein is to slow or arrest the progression of the pathology of the eye, and to slow or prevent loss of vision with minimal intervention/invasive procedures. Efficacy may be monitored by measuring BCVA (Best-Corrected Visual Acuity), intraocular pressure, slit lamp biomicroscopy, indirect ophthalmoscopy, SD-OCT (SD-Optical Coherence Tomography), electroretinography (ERG). Signs of vision loss, infection, inflammation and other safety events, including retinal detachment may also be monitored. In certain embodiments, retinal thickness may be monitored to determine efficacy of the treatments provided herein. Without being bound by any particular theory, in certain embodiment, thickness of the retina may be used as a clinical readout, wherein the greater reduction in retinal thickness or the longer period of time before thickening of the retina, the more efficacious the treatment. Retinal thickness may be determined, for example, by SD-OCT. SD-OCT is a three-dimensional imaging technology which uses low-coherence interferometry to determine the echo time delay and magnitude of backscattered light reflected off an object of interest. OCT can be used to scan the layers of a tissue sample (e.g., the retina) with 3 to 15 μm axial resolution, and SD-OCT improves axial resolution and scan speed over previous forms of the technology (Schuman, 2008, Trans. Am. Opthamol. Soc. 106:426-458). Retinal function may be determined, for example, by ERG. ERG is a non-invasive electrophysiologic test of retinal function, approved by the FDA for use in humans, which examines the light sensitive cells of the eye (the rods and cones), and their connecting ganglion cells, in particular, their response to a flash stimulation.


4.1 ILLUSTRATIVE EMBODIMENTS

4.1.1 Set 1


1. A method of subretinal administration without vitrectomy for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient.


2. The method of paragraph 1, wherein the administering step comprises administering to the subretinal space in the eye of said human subject the recombinant viral vector therapeutic product via the suprachoroidal space in the eye of said human subject.


3. The method of paragraph 2, wherein the administering step is by the use of a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space toward the posterior pole, where a small needle injects into the subretinal space.


4. The method of paragraph 3, wherein the administering step comprises inserting and tunneling the catheter of the subretinal drug delivery device through the suprachoroidal space.


5. A method of suprachoroidal administration for treating a pathology of the eye, comprising administering to the suprachoroidal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye.


6. The method of paragraph 5, wherein the administering step is by injecting the recombinant viral vector into the suprachoroidal space using a suprachoroidal drug delivery device.


7. The method of paragraph 5 or 6, wherein the suprachoroidal drug delivery device is a microinjector.


8. A method of administration to the outer space of the sclera for treating a pathology of the eye, comprising administering to the outer surface of the sclera in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye.


9. The method of paragraph 8, wherein the administering step is by the use of a juxtascleral drug delivery device that comprises a cannula whose tip can be inserted and kept in direct apposition to the scleral surface.


10. The method of paragraph 9, wherein the administering step comprises inserting and keeping the tip of the cannula in direct apposition to the scleral surface.


11. The method of any one of paragraphs 1-10, wherein the therapeutic product is not an anti-human vascular endothelial growth factor (hVEGF) antibody.


12. The method of any one of paragraphs 1-11, wherein the pathology of the eye is not associated with neovascular age-related macular degeneration (nAMID).


13. A method of subretinal administration accompanied by vitrectomy for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient, and wherein the therapeutic product is not anti-human vascular endothelial growth factor (hVEGF) antibody


14. The method of paragraph 13, wherein the vitrectomy is a partial vitrectomy.


15. A method of subretinal administration for treating a pathology of the eye, comprising administering to the subretinal space peripheral to the optic disc, fovea and macula located in the back of the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient.


16. The method of paragraph 15, wherein the administering step is by transvitreal injection.


17. The method of paragraph 16, wherein the transvitreal injection comprises inserting a sharp needle into the sclera via the superior or inferior side of the eye and passing the sharp needle all the way through the vitreous to inject the recombinant viral vector to the subretinal space on the other side.


18. The method of paragraph 16, wherein the transvitreal injection comprises inserting a trochar into the sclera and inserting a cannula through the trochar and through the vitreous to inject the recombinant viral vector to the subretinal space on the other side


19. The method of any one of paragraphs 15-18, wherein the therapeutic product is an anti-hVEGF antibody.


20. The method of paragraph 19, wherein the anti-hVEGF antibody is an anti-hVEGF antigen-binding fragment.


21. The method of paragraph 20, wherein the anti-hVEGF antigen-binding fragment is a Fab, F(ab′)2, or single chain variable fragment (scFv).


22. The method of any one of paragraphs 19-21, wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4, and a light chain comprising the amino acid sequence of SEQ ID NO:1, or SEQ ID NO:3.


23. The method of any one of paragraphs 19-21, wherein the anti-hVEGF antibody comprises light chain CDRs 1-3 of SEQ ID NOs:14-16 and heavy chain CDRs 1-3 of SEQ ID NOs:17-19 or SEQ ID NOs:20, 18, and 21.


24. The method of any one of paragraphs 19-23, wherein the pathology of the eye is associated with nAMD, dry age-related macular degeneration (dry AMD), retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR).


25. The method of any one of paragraphs 19-23, wherein the pathology of the eye is associated with nAMD.


26. The method of any one of paragraphs 1-11 and 13-18, wherein:

    • (1) the pathology of the eye is associated with Batten-CLN1 and the therapeutic product is Palmitoyl-Protein Thioesterase 1 (PPT1);
    • (2) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1);
    • (3) the pathology of the eye is associated with Batten-CLN3 and the therapeutic product is Battenin (CLN3);
    • (4) the pathology of the eye is associated with Batten-CLN6 and the therapeutic product is CLN6 Transmembrane ER Protein (CLN6);
    • (5) the pathology of the eye is associated with Batten-CLN7 and the therapeutic product is Major Facilitator Superfamily Domain Containing 8 (MFSD8);
    • (6) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Myosin VIIA (MYO7A);
    • (7) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Cadherin Related 23 (CDH23);
    • (8) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Protocadherin Related 15 (PCDH15);
    • (9) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Usherin (USH2A);
    • (10) the pathology of the eye is associated with Usher's-Type 3 and the therapeutic product is Clarin 1 (CLRN1);
    • (11) the pathology of the eye is associated with Stargardt's and the therapeutic product is ATP Binding Cassette Subfamily A Member 4 (ABCA4);
    • (12) the pathology of the eye is associated with Stargardt's and the therapeutic product is ELOVL Fatty Acid Elongase 4 (ELOVL4);
    • (13) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-Interleukin 6 (IL6) monoclonal antibody;
    • (14) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF-alpha (TNF) monoclonal antibody;
    • (15) the pathology of the eye is associated with diabetic macular edema (DME) and the therapeutic product is an anti-IL6 monoclonal antibody;
    • (16) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);
    • (17) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);
    • (18) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);
    • (19) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D);
    • (20) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65);
    • (21) the pathology of the eye is associated with LCA 3 and the therapeutic product is Spermatogenesis Associated 7 (SPATA7);
    • (22) the pathology of the eye is associated with Leber congenital amaurosis-4 (LCA 4) and the therapeutic product is Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1);
    • (23) the pathology of the eye is associated with Leber congenital amaurosis-5 (LCA 5) and the therapeutic product is Lebercilin (LCA5);
    • (24) the pathology of the eye is associated with Leber congenital amaurosis-6 (LCA 6) and the therapeutic product is RPGR Interacting Protein 1 (RPGRIP1);
    • (25) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX);
    • (26) the pathology of the eye is associated with Leber congenital amaurosis-8 (LCA 8) and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);
    • (27) the pathology of the eye is associated with Leber congenital amaurosis-9 (LCA 9) and the therapeutic product is Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1);
    • (28) the pathology of the eye is associated with Leber congenital amaurosis-10 (LCA 10) and the therapeutic product is Centrosomal Protein 290 (CEP290);
    • (29) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1);
    • (30) the pathology of the eye is associated with Leber congenital amaurosis-12 (LCA 12) and the therapeutic product is Retinal Degeneration 3, GUCY2D regulator (RD3);
    • (31) the pathology of the eye is associated with Leber congenital amaurosis-13 (LCA 13) and the therapeutic product is Retinol Dehydrogenase 12 (RDH12);
    • (32) the pathology of the eye is associated with Leber congenital amaurosis-14 (LCA 14) and the therapeutic product is Lecithin Retinol Acyltransferase (LRAT);
    • (33) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1);
    • (34) the pathology of the eye is associated with Leber congenital amaurosis-16 (LCA 16) and the therapeutic product is Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13);
    • (35) the pathology of the eye is associated with Leber's hereditary optic neuropathy (LHON) and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1);
    • (36) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4);
    • (37) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6);
    • (38) the pathology of the eye is associated with neuromyelitis optica (NMO) and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (39) the pathology of the eye is associated with NMO and the therapeutic product is an anti-IL6 monoclonal antibody;
    • (40) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (41) the pathology of the eye is associated with uveitis and the therapeutic product is Angiotensin I Converting Enzyme (ACE);
    • (42) the pathology of the eye is associated with uveitis and the therapeutic product is Interleukin 10 (IL10);
    • (43) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF monoclonal antibody;
    • (44) the pathology of the eye is associated with choroideremia and the therapeutic product is Rab Escort Protein 1 (CHM);
    • (45) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1);
    • (46) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1);
    • (47) the pathology of the eye is associated with Bardet-Biedl syndrome 2 and the therapeutic product is Bardet-Biedl Syndrome 2 (BBS2);
    • (48) the pathology of the eye is associated with Bardet-Biedl syndrome 3 and the therapeutic product is ADP Ribosylation Factor Like GTPase 6 (ARL6);
    • (49) the pathology of the eye is associated with Bardet-Biedl syndrome 4 and the therapeutic product is Bardet-Biedl Syndrome 4 (BBS4);
    • (50) the pathology of the eye is associated with Bardet-Biedl syndrome 5 and the therapeutic product is Bardet-Biedl Syndrome 5 (BBS5);
    • (51) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS);
    • (52) the pathology of the eye is associated with Bardet-Biedl syndrome 7 and the therapeutic product is Bardet-Biedl Syndrome 7 (BBS7);
    • (53) the pathology of the eye is associated with Bardet-Biedl syndrome 8 and the therapeutic product is Tetratricopeptide Repeat Domain 8 (TTC8);
    • (54) the pathology of the eye is associated with Bardet-Biedl syndrome 9 and the therapeutic product is Bardet-Biedl Syndrome 9 (BBS9);
    • (55) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10);
    • (56) the pathology of the eye is associated with Bardet-Biedl syndrome 11 and the therapeutic product is Tripartite Motif Containing 32 (TRIM32);
    • (57) the pathology of the eye is associated with Bardet-Biedl syndrome 12 and the therapeutic product is Bardet-Biedl Syndrome 12 (BBS12);
    • (58) the pathology of the eye is associated with Bardet-Biedl syndrome 13 and the therapeutic product is MKS Transition Zone Complex Subunit 1 (MKS1);
    • (59) the pathology of the eye is associated with Bardet-Biedl syndrome 14 and the therapeutic product is Centrosomal Protein 290 (CEP290);
    • (60) the pathology of the eye is associated with Bardet-Biedl syndrome 15 and the therapeutic product is WD Repeat Containing Planar Cell Polarity Effector (WDPCP);
    • (61) the pathology of the eye is associated with Bardet-Biedl syndrome 16 and the therapeutic product is Serologically Defined Colon Cancer Antigen 8 (SDCCAG8);
    • (62) the pathology of the eye is associated with Bardet-Biedl syndrome 17 and the therapeutic product is Leucine Zipper Transcription Factor Like 1 (LZTFL1);
    • (63) the pathology of the eye is associated with Bardet-Biedl syndrome 18 and the therapeutic product is BBSome Interacting Protein 1 (BBIP1);
    • (64) the pathology of the eye is associated with Bardet-Biedl syndrome 19 and the therapeutic product is Intraflagellar Transport 27 (IFT27);
    • (65) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A);
    • (66) the pathology of the eye is associated with optic atrophy and the therapeutic product is OPA1 Mitochondrial Dynamin Like GTPase (OPA1);
    • (67) the pathology of the eye is associated with retinitis pigmentosa 1 and the therapeutic product is RP1 Axonemal Microtubule Associated (RP1);
    • (68) the pathology of the eye is associated with retinitis pigmentosa 2 and the therapeutic product is RP2 Activator of ARL3 GTPase (RP2);
    • (69) the pathology of the eye is associated with retinitis pigmentosa 7 and the therapeutic product is Peripherin 2 (PRPH2);
    • (70) the pathology of the eye is associated with retinitis pigmentosa 11 and the therapeutic product is Pre-mRNA Processing Factor 31(PRPF31);
    • (71) the pathology of the eye is associated with retinitis pigmentosa 12 and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);
    • (72) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8);
    • (73) the pathology of the eye is associated with retinitis pigmentosa 25 and the therapeutic product is Eyes Shut Homolog (EYS);
    • (74) the pathology of the eye is associated with retinitis pigmentosa 28 and the therapeutic product is FAM161 Centrosomal Protein A (FAM161A);
    • (75) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3);
    • (76) the pathology of the eye is associated with retinitis pigmentosa 38 and the therapeutic product is MER Proto-Oncogene, Tyrosine Kinase (MERTK);
    • (77) the pathology of the eye is associated with retinitis pigmentosa 40 and the therapeutic product is Phosphodiesterase 6B (PDE6B);
    • (78) the pathology of the eye is associated with retinitis pigmentosa 41 and the therapeutic product is Prominin 1 (PROM1);
    • (79) the pathology of the eye is associated with retinitis pigmentosa 43 and the therapeutic product is Phosphodiesterase 6A (PDE6A);
    • (80) the pathology of the eye is associated with retinitis pigmentosa 56 and the therapeutic product is Interphotoreceptor Matrix Proteoglycan 2 (IMPG2);
    • (81) the pathology of the eye is associated with petinitis pigmentosa 62 and the therapeutic product is Male Germ Cell Associated Kinase (MAK);
    • (82) the pathology of the eye is associated with retinitis pigmentosa 80 and the therapeutic product is Intraflagellar Transport 140 (IFT140);
    • (83) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (84) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-membrane attack complex (MAC) monoclonal antibody;
    • (85) the pathology of the eye is associated with dry AMD and the therapeutic product is HtrA Serine Peptidase 1 (HTRA1);
    • (86) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1);
    • (87) the pathology of the eye is associated with dry AMD and the therapeutic product is a complement factor B anti sense oligonucleotide;
    • (88) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-beta-amyloid monoclonal antibody;
    • (89) the pathology of the eye is associated with dry AMD and the therapeutic product is CD59 glycoprotein (CD59);
    • (90) the pathology of the eye is associated with dry AMD and the therapeutic product is Channelrhodopsin-1 (ChR1);
    • (91) the pathology of the eye is associated with dry AMD and the therapeutic product is Channelrhodopsin-2 (ChR2), the light-sensitive protein discovered in Chlamydomonas reinhardtii;
    • (92) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-complement factor C5a aptamer;
    • (93) the pathology of the eye is associated with dry AMD and the therapeutic product is anti-complement factor D monoclonal antibody;
    • (94) the pathology of the eye is associated with age-related retinal ganglion cell (RGC) degeneration and the therapeutic product is DnaJ heat shock protein family (Hsp40) member C3 (DNAJC3);
    • (95) the pathology of the eye is associated with blue cone monochromacy (BCM) and the therapeutic product is L opsin (OPN1LW);
    • (96) the pathology of the eye is associated with glaucoma and the therapeutic product is beta-2 adrenoceptor siRNA;
    • (97) the pathology of the eye is associated with glaucoma and the therapeutic product is Caspase-2 (CASP2);
    • (98) the pathology of the eye is associated with glaucoma and the therapeutic product is Insulin Receptor Substrate 1 (IRS1);
    • (99) the pathology of the eye is associated with glaucoma and the therapeutic product is HIF-1 Responsive Protein RTP801 (RTP801);
    • (100) the pathology of the eye is associated with glaucoma and the therapeutic product is Transforming Growth Factor Beta 2 (TGFB2);
    • (101) the pathology of the eye is associated with glaucoma and the therapeutic product is Brain Derived Neurotrophic Factor (BDNF);
    • (102) the pathology of the eye is associated with glaucoma and the therapeutic product is Ciliary Neurotrophic Factor (CNTF);
    • (103) the pathology of the eye is associated with glaucoma and the therapeutic product is Prostaglandin-Endoperoxide Synthase 2 (PTGS2);
    • (104) the pathology of the eye is associated with glaucoma and the therapeutic product is Prostaglandin F Receptor (PTGFR);
    • (105) the pathology of the eye is associated with glaucoma and the therapeutic product is a hyaluronidase;
    • (106) the pathology of the eye is associated with glaucoma and the therapeutic product is Pigment Epithelium-Derived Factor (PEDF);
    • (107) the pathology of the eye is associated with glaucoma and the therapeutic product is Vascular Endothelial Growth Factor (VEGF);
    • (108) the pathology of the eye is associated with glaucoma and the therapeutic product is Placental Growth Factor (PGF);
    • (109) the pathology of the eye is associated with glaucoma and the therapeutic product is Myocilin (MYOC);
    • (110) the pathology of the eye is associated with NMO and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (111) the pathology of the eye is associated with NMO and the therapeutic product is C-C Motif Chemokine Receptor 5 (CCR5) siRNA;
    • (112) the pathology of the eye is associated with NMO and the therapeutic product is an anti-CD19 monoclonal antibody;
    • (113) the pathology of the eye is associated with retinitis pigmentosa that is associated with rhodopsin mutations and the therapeutic product is Channelrhodopsin-1 (ChR1);
    • (114) the pathology of the eye is associated with retinitis pigmentosa that is associated with rhodopsin mutations and the therapeutic product is Channelrhodopsin-2 (ChR2);
    • (115) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Ciliary Neurotrophic Factor (CNTF);
    • (116) the pathology of the eye is associated with autosomal recessive retinitis pigmentosa and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);
    • (117) the pathology of the eye is associated with autosomal recessive retinitis pigmentosa and the therapeutic product is Crumbs Cell Polarity Complex Component 2 (CRB2);
    • (118) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Histone Deacetylase 4 (HDAC4);
    • (119) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rhodopsin (RHO);
    • (120) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Nerve Growth Factor (NGF);
    • (121) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Nuclear Factor, Erythroid 2 Like 2 (NRF2);
    • (122) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Pigment Epithelium-Derived Factor (PEDF);
    • (123) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Glutathione S-Transferase PI 1 (GSTP1);
    • (124) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rod-Derived Cone Viability Factor (RDCVF);
    • (125) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rhodopsin (RHO);
    • (126) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Retinaldehyde Binding Protein 1 (RLBP1);
    • (127) the pathology of the eye is associated with Stargardt's disease and the therapeutic product is an anti-complement C5 aptamer;
    • (128) the pathology of the eye is associated with uveitis and the therapeutic product is Double Homeobox 4 (DUX4);
    • (129) the pathology of the eye is associated with uveitis and the therapeutic product is NLR Family Pyrin Domain Containing 3 (NLRP3);
    • (130) the pathology of the eye is associated with uveitis and the therapeutic product is Spleen Associated Tyrosine Kinase (SYK);
    • (131) the pathology of the eye is associated with uveitis and the therapeutic product is Adrenocorticotropic Hormone (ACTH);
    • (132) the pathology of the eye is associated with uveitis and the therapeutic product is Caspase 1 (CASP1);
    • (133) the pathology of the eye is associated with uveitis and the therapeutic product is anti-CD59 monoclonal antibody;
    • (134) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement C5 aptamer;
    • (135) the pathology of the eye is associated with corneal neovascularization and the therapeutic product is Insulin Receptor Substrate 1 (IRS1);
    • (136) the pathology of the eye is associated with corneal neovascularization and the therapeutic product is NOTCH Regulated Ankyrin Repeat Protein (NRARP);
    • (137) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is NOTCH Regulated Ankyrin Repeat Protein (NRARP);
    • (138) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Alpha-2-Antiplasmin (A2AP);
    • (139) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Plasminogen (PLG);
    • (140) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is a growth hormone;
    • (141) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Insulin Like Growth Factor 1 (IGF1);
    • (142) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Interleukin 1 Beta (IL1B).
    • (143) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Angiotensin I Converting Enzyme 2 (ACE2);
    • (144) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is IRS1;
    • (145) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is an anti-integrin oligopeptide;
    • (146) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is an anti-Placental Growth Factor (PGF) monoclonal antibody;
    • (147) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-CD40 monoclonal antibody;
    • (148) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-Insulin-Like Growth Factor 1 Receptor (IGF1R) monoclonal antibody;
    • (149) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-Insulin-Like Growth Factor 2 Receptor (IGF2R) monoclonal antibody;
    • (150) the pathology of the eye is associated with DME and the therapeutic product is an anti-integrin oligopeptide;
    • (151) the pathology of the eye is associated with DME and the therapeutic product is an anti-Placental Growth Factor (PGF) monoclonal antibody;
    • (152) the pathology of the eye is associated with DME and the therapeutic product is RTP801 siRNA;
    • (153) the pathology of the eye is associated with multiple sclerosis (MS)-associated vision loss and the therapeutic product is ND1;
    • (154) the pathology of the eye is associated with myopia and the therapeutic product is Matrix Metalloproteinase 2 (MMP2) RNAi;
    • (155) the pathology of the eye is associated with X-linked recessive ocular albinism and the therapeutic product is G-Protein Coupled Receptor 143 (GPR143);
    • (156) the pathology of the eye is associated with oculocutaneous albinism type 1 and the therapeutic product is Tyrosinase (TYR);
    • (157) the pathology of the eye is associated with optic neuritis and the therapeutic product is Caspase 2 (CASP2);
    • (158) the pathology of the eye is associated with optic neuritis and the therapeutic product is an anti-Leucine Rich Repeat And Ig Domain Containing Protein 1 (LINGO1) monoclonal antibody; or
    • (159) the pathology of the eye is associated with polypoidal choroidal vasculopathy and the therapeutic product is an anti-complement C5 aptamer.


27. The method of any one of paragraphs 1-11 and 15-18, wherein:

    • (1) the pathology of the eye is associated with X-linked retinitis pigmentosa (XLRP) and the therapeutic product is Retinitis Pigmentosa GTPase Regulator (RPGR);
    • (2) the pathology of the eye is associated with achromatopsia (ACHM) and the therapeutic product is Cyclic Nucleotide Gated Channel Beta 3 (CNGB3);
    • (3) the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3); or
    • (4) the pathology of the eye is associated with biallelic RPE65 mutation-associated retinal dystrophy and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65).


28. The method of any one of paragraphs 1-11 and 13-18, wherein:

    • (1) the pathology of the eye is associated with Batten-CLN1 and the therapeutic product is Palmitoyl-Protein Thioesterase 1 (PPT1);
    • (2) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1);
    • (3) the pathology of the eye is associated with Batten-CLN3 and the therapeutic product is Battenin (CLN3);
    • (4) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-Interleukin 6 (IL6) monoclonal antibody;
    • (5) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF-alpha (TNF) monoclonal antibody;
    • (6) the pathology of the eye is associated with diabetic macular edema (DME) and the therapeutic product is an anti-IL6 monoclonal antibody;
    • (7) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);
    • (8) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);
    • (9) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);
    • (10) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D);
    • (11) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65);
    • (12) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX);
    • (13) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1);
    • (14) the pathology of the eye is associated with Leber congenital amaurosis-12 (LCA 12) and the therapeutic product is Retinal Degeneration 3, GUCY2D regulator (RD3);
    • (15) the pathology of the eye is associated with Leber congenital amaurosis-13 (LCA 13) and the therapeutic product is Retinol Dehydrogenase 12 (RDH12);
    • (16) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1);
    • (17) the pathology of the eye is associated with Leber congenital amaurosis-16 (LCA 16) and the therapeutic product is Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13);
    • (18) the pathology of the eye is associated with Leber's hereditary optic neuropathy (LHON) and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1);
    • (19) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4);
    • (20) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6);
    • (21) the pathology of the eye is associated with neuromyelitis optica (NMO) and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (22) the pathology of the eye is associated with NMO and the therapeutic product is an anti-IL6 monoclonal antibody;
    • (23) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (24) the pathology of the eye is associated with uveitis and the therapeutic product is Angiotensin I Converting Enzyme (ACE);
    • (25) the pathology of the eye is associated with uveitis and the therapeutic product is Interleukin 10 (IL10);
    • (26) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF monoclonal antibody;
    • (27) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1);
    • (28) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1);
    • (29) the pathology of the eye is associated with Bardet-Biedl syndrome 3 and the therapeutic product is ADP Ribosylation Factor Like GTPase 6 (ARL6);
    • (30) the pathology of the eye is associated with Bardet-Biedl syndrome 5 and the therapeutic product is Bardet-Biedl Syndrome 5 (BBS5);
    • (31) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS);
    • (32) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10);
    • (33) the pathology of the eye is associated with Bardet-Biedl syndrome 11 and the therapeutic product is Tripartite Motif Containing 32 (TRIM32);
    • (34) the pathology of the eye is associated with Bardet-Biedl syndrome 13 and the therapeutic product is MKS Transition Zone Complex Subunit 1 (MKS1);
    • (35) the pathology of the eye is associated with Bardet-Biedl syndrome 18 and the therapeutic product is BBSome Interacting Protein 1 (BBIP1);
    • (36) the pathology of the eye is associated with Bardet-Biedl syndrome 19 and the therapeutic product is Intraflagellar Transport 27 (IFT27);
    • (37) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A);
    • (38) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8);
    • (39) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3); or
    • (40) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1).


29. The method of any one of paragraphs 1-11 and 15-18, wherein:

    • (1) the pathology of the eye is associated with biallelic RPE65 mutation-associated retinal dystrophy and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65).


30. The method of any one of paragraphs 1-11 and 13-18, wherein:

    • (1) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1);
    • (2) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Myosin VIIA (MYO7A);
    • (3) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Cadherin Related 23 (CDH23);
    • (4) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Protocadherin Related 15 (PCDH15);
    • (5) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Usherin (USH2A);
    • (6) the pathology of the eye is associated with Usher's-Type 3 and the therapeutic product is Clarin 1 (CLRN1);
    • (7) the pathology of the eye is associated with Stargardt's and the therapeutic product is ATP Binding Cassette Subfamily A Member 4 (ABCA4);
    • (8) the pathology of the eye is associated with Stargardt's and the therapeutic product is ELOVL Fatty Acid Elongase 4 (ELOVL4);
    • (9) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);
    • (10) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);
    • (11) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);
    • (12) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D);
    • (13) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65);
    • (14) the pathology of the eye is associated with Leber congenital amaurosis-4 (LCA 4) and the therapeutic product is Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1);
    • (15) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX);
    • (16) the pathology of the eye is associated with Leber congenital amaurosis-8 (LCA 8) and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);
    • (17) the pathology of the eye is associated with Leber congenital amaurosis-9 (LCA 9) and the therapeutic product is Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1);
    • (18) the pathology of the eye is associated with Leber congenital amaurosis-10 (LCA 10) and the therapeutic product is Centrosomal Protein 290 (CEP290);
    • (19) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1);
    • (20) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1);
    • (21) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4);
    • (22) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6);
    • (23) the pathology of the eye is associated with choroideremia and the therapeutic product is Rab Escort Protein 1 (CHM);
    • (24) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1);
    • (25) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1);
    • (26) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS);
    • (27) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10);
    • (28) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A);
    • (29) the pathology of the eye is associated with optic atrophy and the therapeutic product is OPA1 Mitochondrial Dynamin Like GTPase (OPA1);
    • (30) the pathology of the eye is associated with retinitis pigmentosa 1 and the therapeutic product is RP1 Axonemal Microtubule Associated (RP1);
    • (31) the pathology of the eye is associated with retinitis pigmentosa 2 and the therapeutic product is RP2 Activator of ARL3 GTPase (RP2);
    • (32) the pathology of the eye is associated with retinitis pigmentosa 7 and the therapeutic product is Peripherin 2 (PRPH2);
    • (33) the pathology of the eye is associated with retinitis pigmentosa 11 and the therapeutic product is Pre-mRNA Processing Factor 31(PRPF31);
    • (34) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8);
    • (35) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3);
    • (36) the pathology of the eye is associated with retinitis pigmentosa 38 and the therapeutic product is MER Proto-Oncogene, Tyrosine Kinase (MERTK);
    • (37) the pathology of the eye is associated with retinitis pigmentosa 40 and the therapeutic product is Phosphodiesterase 6B (PDE6B);
    • (38) the pathology of the eye is associated with retinitis pigmentosa 41 and the therapeutic product is Prominin 1 (PROM1);
    • (39) the pathology of the eye is associated with retinitis pigmentosa 56 and the therapeutic product is Interphotoreceptor Matrix Proteoglycan 2 (IMPG2);
    • (40) the pathology of the eye is associated with petinitis pigmentosa 62 and the therapeutic product is Male Germ Cell Associated Kinase (MAK);
    • (41) the pathology of the eye is associated with retinitis pigmentosa 80 and the therapeutic product is Intraflagellar Transport 140 (IFT140); or (42) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1).


31. The method of any one of paragraphs 1-11 and 15-18, wherein:

    • (1) the pathology of the eye is associated with X-linked retinitis pigmentosa (XLRP) and the therapeutic product is Retinitis Pigmentosa GTPase Regulator (RPGR);
    • (2) the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Beta 3 (CNGB3); or
    • (3) the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3).


32. The method of any one of paragraphs 1-31, wherein the recombinant viral vector further comprises a nucleotide sequence encoding a promoter or an enhancer-promoter, which nucleotide sequence encoding the promoter or enhancer-promoter is operably linked to the nucleotide sequence encoding the therapeutic product, and wherein the promoter or enhancer-promoter is:

    • (1) a CAG promoter;
    • (2) a CBA promoter;
    • (3) a CMV promoter;
    • (4) a PR1.7 promoter;
    • (5) a Rhodopsin Kinase (GRK1) photoreceptor-specific enhancer-promoter;
    • (6) an hCARp promoter;
    • (7) an hRKp;
    • (8) a cone photoreceptor specific human arrestin 3 (ARR3) promoter;
    • (9) a rhodopsin promoter; or
    • (10) a U6 promoter.


33. The method of any one of paragraphs 1-11 and 13-15, wherein the recombinant viral vector further comprises a nucleotide sequence encoding a cone-specific promoter, which nucleotide sequence encoding the cone-specific promoter is operably linked to the nucleotide sequence encoding the therapeutic product, and wherein:

    • (1) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);
    • (2) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);
    • (3) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);
    • (4) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A); or
    • (5) the pathology of the eye is associated with blue cone monochromacy (BCM) and the therapeutic product is L opsin (OPN1LW).


34. The method of any one of paragraphs 1-33, wherein the administering step delivers a therapeutically effective amount of the therapeutic product to the retina of said human subject.


35. The method of paragraph 34, wherein the therapeutically effective amount of the therapeutic product is produced by human retinal cells of said human subject.


36. The method of paragraph 34, wherein the therapeutically effective amount of the therapeutic product is produced by human photoreceptor cells, horizontal cells, bipolar cells, amacrine cells, retina ganglion cells, and/or retinal pigment epithelial cells in the external limiting membrane of said human subject.


37. The method of paragraph 36, wherein the human photoreceptor cells are cone cells and/or rod cells.


38. The method of paragraph 36, wherein the retina ganglion cells are midget cells, parasol cells, bistratified cells, giant retina ganglion cells, photosensitive ganglion cells, and/or Müller glia.


39. The method of any one of paragraphs 1-38, wherein the recombinant viral vector is an rAAV vector.


40. The method of paragraph 39, wherein the recombinant viral vector is an rAAV8 vector.


41. The method of any one of paragraphs 1-40, which further comprises, after the administering step, a step of monitoring the post ocular injection thermal profile of the injected material in the eye using an infrared thermal camera.


42. The method of paragraph 41, wherein the infrared thermal camera is an FLIR T530 infrared thermal camera.


43. The method of any one of paragraphs 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 6.0×1010 genome copies per eye.


44. The method of any one of paragraphs 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 1.6×1011 genome copies per eye.


45. The method of any one of paragraphs 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 2.5×1011 genome copies per eye.


46. The method of any one of paragraphs 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 5.0×1011 genome copies per eye.


47. The method of any one of paragraphs 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 3.0×1012 genome copies per eye.


4.1.2 Set 2


1. A method for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient.


2. The method of paragraph 1, wherein the administering step comprises administering to the subretinal space in the eye of said human subject the recombinant viral vector therapeutic product via the suprachoroidal space in the eye of said human subject.


3. The method of paragraph 2, wherein the administering step is by the use of a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space toward the posterior pole, where a small needle injects into the subretinal space.


4. The method of paragraph 3, wherein the administering step comprises inserting and tunneling the catheter of the subretinal drug delivery device through the suprachoroidal space.


5. A method for treating a pathology of the eye, comprising administering to the suprachoroidal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye.


6. The method of paragraph 5, wherein the administering step is by injecting the recombinant viral vector into the suprachoroidal space using a suprachoroidal drug delivery device.


7. The method of paragraph 5 or 6, wherein the suprachoroidal drug delivery device is a microinjector.


8. A method for treating a pathology of the eye, comprising administering to the outer surface of the sclera in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye.


9. The method of paragraph 8, wherein the administering step is by the use of a juxtascleral drug delivery device that comprises a cannula whose tip can be inserted and kept in direct apposition to the scleral surface.


10. The method of paragraph 9, wherein the administering step comprises inserting and keeping the tip of the cannula in direct apposition to the scleral surface.


11. The method of any one of paragraphs 1-10, wherein the therapeutic product is not an anti-human vascular endothelial growth factor (hVEGF) antibody.


12. The method of any one of paragraphs 1-11, wherein the pathology of the eye is not associated with neovascular age-related macular degeneration (nAMD).


13. A method for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient, and wherein the therapeutic product is not anti-human vascular endothelial growth factor (hVEGF) antibody


14. The method of paragraph 13, wherein the vitrectomy is a partial vitrectomy.


15. A method for treating a pathology of the eye, comprising administering to the subretinal space peripheral to the optic disc, fovea and macula located in the back of the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient.


16. The method of paragraph 15, wherein the administering step is by transvitreal injection.


17. The method of paragraph 16, wherein the transvitreal injection comprises inserting a sharp needle into the sclera via the superior or inferior side of the eye and passing the sharp needle all the way through the vitreous to inject the recombinant viral vector to the subretinal space on the other side.


18. The method of paragraph 16, wherein the transvitreal injection comprises inserting a trochar into the sclera and inserting a cannula through the trochar and through the vitreous to inject the recombinant viral vector to the subretinal space on the other side


19. The method of any one of paragraphs 15-18, wherein the therapeutic product is an anti-hVEGF antibody.


20. The method of paragraph 19, wherein the anti-hVEGF antibody is an anti-hVEGF antigen-binding fragment.


21. The method of paragraph 20, wherein the anti-hVEGF antigen-binding fragment is a Fab, F(ab′)2, or single chain variable fragment (scFv).


22. The method of any one of paragraphs 19-21, wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4, and a light chain comprising the amino acid sequence of SEQ ID NO:1, or SEQ ID NO:3.


23. The method of any one of paragraphs 19-21, wherein the anti-hVEGF antibody comprises light chain CDRs 1-3 of SEQ ID NOs:14-16 and heavy chain CDRs 1-3 of SEQ ID NOs:17-19 or SEQ ID NOs:20, 18, and 21.


24. The method of any one of paragraphs 19-23, wherein the pathology of the eye is associated with nAMD, dry age-related macular degeneration (dry AMD), retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR).


25. The method of any one of paragraphs 19-23, wherein the pathology of the eye is associated with nAMD.


26. The method of any one of paragraphs 1-11 and 13-18, wherein:

    • (1) the pathology of the eye is associated with Batten-CLN1 and the therapeutic product is Palmitoyl-Protein Thioesterase 1 (PPT1);
    • (2) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1);
    • (3) the pathology of the eye is associated with Batten-CLN3 and the therapeutic product is Battenin (CLN3);
    • (4) the pathology of the eye is associated with Batten-CLN6 and the therapeutic product is CLN6 Transmembrane ER Protein (CLN6);
    • (5) the pathology of the eye is associated with Batten-CLN7 and the therapeutic product is Major Facilitator Superfamily Domain Containing 8 (MFSD8);
    • (6) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Myosin VIIA (MYO7A);
    • (7) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Cadherin Related 23 (CDH23);
    • (8) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Protocadherin Related 15 (PCDH15);
    • (9) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Usherin (USH2A);
    • (10) the pathology of the eye is associated with Usher's-Type 3 and the therapeutic product is Clarin 1 (CLRN1);
    • (11) the pathology of the eye is associated with Stargardt's and the therapeutic product is ATP Binding Cassette Subfamily A Member 4 (ABCA4);
    • (12) the pathology of the eye is associated with Stargardt's and the therapeutic product is ELOVL Fatty Acid Elongase 4 (ELOVL4);
    • (13) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-Interleukin 6 (IL6) monoclonal antibody;
    • (14) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF-alpha (TNF) monoclonal antibody;
    • (15) the pathology of the eye is associated with diabetic macular edema (DME) and the therapeutic product is an anti-IL6 monoclonal antibody;
    • (16) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);
    • (17) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);
    • (18) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);
    • (19) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D);
    • (20) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65);
    • (21) the pathology of the eye is associated with LCA 3 and the therapeutic product is Spermatogenesis Associated 7 (SPATA7);
    • (22) the pathology of the eye is associated with Leber congenital amaurosis-4 (LCA 4) and the therapeutic product is Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1);
    • (23) the pathology of the eye is associated with Leber congenital amaurosis-5 (LCA 5) and the therapeutic product is Lebercilin (LCA5);
    • (24) the pathology of the eye is associated with Leber congenital amaurosis-6 (LCA 6) and the therapeutic product is RPGR Interacting Protein 1 (RPGRIP1);
    • (25) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX);
    • (26) the pathology of the eye is associated with Leber congenital amaurosis-8 (LCA 8) and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);
    • (27) the pathology of the eye is associated with Leber congenital amaurosis-9 (LCA 9) and the therapeutic product is Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1);
    • (28) the pathology of the eye is associated with Leber congenital amaurosis-10 (LCA 10) and the therapeutic product is Centrosomal Protein 290 (CEP290);
    • (29) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1);
    • (30) the pathology of the eye is associated with Leber congenital amaurosis-12 (LCA 12) and the therapeutic product is Retinal Degeneration 3, GUCY2D regulator (RD3);
    • (31) the pathology of the eye is associated with Leber congenital amaurosis-13 (LCA 13) and the therapeutic product is Retinol Dehydrogenase 12 (RDH12);
    • (32) the pathology of the eye is associated with Leber congenital amaurosis-14 (LCA 14) and the therapeutic product is Lecithin Retinol Acyltransferase (LRAT);
    • (33) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1);
    • (34) the pathology of the eye is associated with Leber congenital amaurosis-16 (LCA 16) and the therapeutic product is Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13);
    • (35) the pathology of the eye is associated with Leber's hereditary optic neuropathy (LHON) and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1);
    • (36) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4);
    • (37) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6);
    • (38) the pathology of the eye is associated with neuromyelitis optica (NMO) and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (39) the pathology of the eye is associated with NMO and the therapeutic product is an anti-IL6 monoclonal antibody;
    • (40) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (41) the pathology of the eye is associated with uveitis and the therapeutic product is Angiotensin I Converting Enzyme (ACE);
    • (42) the pathology of the eye is associated with uveitis and the therapeutic product is Interleukin 10 (IL10);
    • (43) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF monoclonal antibody;
    • (44) the pathology of the eye is associated with choroideremia and the therapeutic product is Rab Escort Protein 1 (CHM);
    • (45) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1);
    • (46) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1);
    • (47) the pathology of the eye is associated with Bardet-Biedl syndrome 2 and the therapeutic product is Bardet-Biedl Syndrome 2 (BBS2);
    • (48) the pathology of the eye is associated with Bardet-Biedl syndrome 3 and the therapeutic product is ADP Ribosylation Factor Like GTPase 6 (ARL6);
    • (49) the pathology of the eye is associated with Bardet-Biedl syndrome 4 and the therapeutic product is Bardet-Biedl Syndrome 4 (BBS4);
    • (50) the pathology of the eye is associated with Bardet-Biedl syndrome 5 and the therapeutic product is Bardet-Biedl Syndrome 5 (BBS5);
    • (51) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS);
    • (52) the pathology of the eye is associated with Bardet-Biedl syndrome 7 and the therapeutic product is Bardet-Biedl Syndrome 7 (BBS7);
    • (53) the pathology of the eye is associated with Bardet-Biedl syndrome 8 and the therapeutic product is Tetratricopeptide Repeat Domain 8 (TTC8);
    • (54) the pathology of the eye is associated with Bardet-Biedl syndrome 9 and the therapeutic product is Bardet-Biedl Syndrome 9 (BBS9);
    • (55) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10);
    • (56) the pathology of the eye is associated with Bardet-Biedl syndrome 11 and the therapeutic product is Tripartite Motif Containing 32 (TRIM32);
    • (57) the pathology of the eye is associated with Bardet-Biedl syndrome 12 and the therapeutic product is Bardet-Biedl Syndrome 12 (BBS12);
    • (58) the pathology of the eye is associated with Bardet-Biedl syndrome 13 and the therapeutic product is MKS Transition Zone Complex Subunit 1 (MKS1);
    • (59) the pathology of the eye is associated with Bardet-Biedl syndrome 14 and the therapeutic product is Centrosomal Protein 290 (CEP290);
    • (60) the pathology of the eye is associated with Bardet-Biedl syndrome 15 and the therapeutic product is WD Repeat Containing Planar Cell Polarity Effector (WDPCP);
    • (61) the pathology of the eye is associated with Bardet-Biedl syndrome 16 and the therapeutic product is Serologically Defined Colon Cancer Antigen 8 (SDCCAG8);
    • (62) the pathology of the eye is associated with Bardet-Biedl syndrome 17 and the therapeutic product is Leucine Zipper Transcription Factor Like 1 (LZTFL1);
    • (63) the pathology of the eye is associated with Bardet-Biedl syndrome 18 and the therapeutic product is BBSome Interacting Protein 1 (BBIP1);
    • (64) the pathology of the eye is associated with Bardet-Biedl syndrome 19 and the therapeutic product is Intraflagellar Transport 27 (IFT27);
    • (65) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A);
    • (66) the pathology of the eye is associated with optic atrophy and the therapeutic product is OPA1 Mitochondrial Dynamin Like GTPase (OPA1);
    • (67) the pathology of the eye is associated with retinitis pigmentosa 1 and the therapeutic product is RP1 Axonemal Microtubule Associated (RP1);
    • (68) the pathology of the eye is associated with retinitis pigmentosa 2 and the therapeutic product is RP2 Activator of ARL3 GTPase (RP2);
    • (69) the pathology of the eye is associated with retinitis pigmentosa 7 and the therapeutic product is Peripherin 2 (PRPH2);
    • (70) the pathology of the eye is associated with retinitis pigmentosa 11 and the therapeutic product is Pre-mRNA Processing Factor 31(PRPF31);
    • (71) the pathology of the eye is associated with retinitis pigmentosa 12 and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);
    • (72) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8);
    • (73) the pathology of the eye is associated with retinitis pigmentosa 25 and the therapeutic product is Eyes Shut Homolog (EYS);
    • (74) the pathology of the eye is associated with retinitis pigmentosa 28 and the therapeutic product is FAM161 Centrosomal Protein A (FAM161A);
    • (75) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3);
    • (76) the pathology of the eye is associated with retinitis pigmentosa 38 and the therapeutic product is MER Proto-Oncogene, Tyrosine Kinase (MERTK);
    • (77) the pathology of the eye is associated with retinitis pigmentosa 40 and the therapeutic product is Phosphodiesterase 6B (PDE6B);
    • (78) the pathology of the eye is associated with retinitis pigmentosa 41 and the therapeutic product is Prominin 1 (PROM1);
    • (79) the pathology of the eye is associated with retinitis pigmentosa 43 and the therapeutic product is Phosphodiesterase 6A (PDE6A);
    • (80) the pathology of the eye is associated with retinitis pigmentosa 56 and the therapeutic product is Interphotoreceptor Matrix Proteoglycan 2 (IMPG2);
    • (81) the pathology of the eye is associated with petinitis pigmentosa 62 and the therapeutic product is Male Germ Cell Associated Kinase (MAK);
    • (82) the pathology of the eye is associated with retinitis pigmentosa 80 and the therapeutic product is Intraflagellar Transport 140 (IFT140);
    • (83) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (84) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-membrane attack complex (MAC) monoclonal antibody;
    • (85) the pathology of the eye is associated with dry AMD and the therapeutic product is HtrA Serine Peptidase 1 (HTRA1);
    • (86) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1);
    • (87) the pathology of the eye is associated with dry AMD and the therapeutic product is a complement factor B anti sense oligonucleotide;
    • (88) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-beta-amyloid monoclonal antibody;
    • (89) the pathology of the eye is associated with dry AMD and the therapeutic product is CD59 glycoprotein (CD59);
    • (90) the pathology of the eye is associated with dry AMD and the therapeutic product is Channelrhodopsin-1 (ChR1);
    • (91) the pathology of the eye is associated with dry AMD and the therapeutic product is Channelrhodopsin-2 (ChR2), the light-sensitive protein discovered in Chlamydomonas reinhardtii;
    • (92) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-complement factor C5a aptamer;
    • (93) the pathology of the eye is associated with dry AMD and the therapeutic product is anti-complement factor D monoclonal antibody;
    • (94) the pathology of the eye is associated with age-related retinal ganglion cell (RGC) degeneration and the therapeutic product is DnaJ heat shock protein family (Hsp40) member C3 (DNAJC3);
    • (95) the pathology of the eye is associated with blue cone monochromacy (BCM) and the therapeutic product is L opsin (OPN1LW);
    • (96) the pathology of the eye is associated with glaucoma and the therapeutic product is beta-2 adrenoceptor siRNA;
    • (97) the pathology of the eye is associated with glaucoma and the therapeutic product is Caspase-2 (CASP2);
    • (98) the pathology of the eye is associated with glaucoma and the therapeutic product is Insulin Receptor Substrate 1 (IRS1);
    • (99) the pathology of the eye is associated with glaucoma and the therapeutic product is HIF-1 Responsive Protein RTP801 (RTP801);
    • (100) the pathology of the eye is associated with glaucoma and the therapeutic product is Transforming Growth Factor Beta 2 (TGFB2);
    • (101) the pathology of the eye is associated with glaucoma and the therapeutic product is Brain Derived Neurotrophic Factor (BDNF);
    • (102) the pathology of the eye is associated with glaucoma and the therapeutic product is Ciliary Neurotrophic Factor (CNTF);
    • (103) the pathology of the eye is associated with glaucoma and the therapeutic product is Prostaglandin-Endoperoxide Synthase 2 (PTGS2);
    • (104) the pathology of the eye is associated with glaucoma and the therapeutic product is Prostaglandin F Receptor (PTGFR);
    • (105) the pathology of the eye is associated with glaucoma and the therapeutic product is a hyaluronidase;
    • (106) the pathology of the eye is associated with glaucoma and the therapeutic product is Pigment Epithelium-Derived Factor (PEDF);
    • (107) the pathology of the eye is associated with glaucoma and the therapeutic product is Vascular Endothelial Growth Factor (VEGF);
    • (108) the pathology of the eye is associated with glaucoma and the therapeutic product is Placental Growth Factor (PGF);
    • (109) the pathology of the eye is associated with glaucoma and the therapeutic product is Myocilin (MYOC);
    • (110) the pathology of the eye is associated with NMO and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (111) the pathology of the eye is associated with NMO and the therapeutic product is C-C Motif Chemokine Receptor 5 (CCR5) siRNA;
    • (112) the pathology of the eye is associated with NMO and the therapeutic product is an anti-CD19 monoclonal antibody;
    • (113) the pathology of the eye is associated with retinitis pigmentosa that is associated with rhodopsin mutations and the therapeutic product is Channelrhodopsin-1 (ChR1);
    • (114) the pathology of the eye is associated with retinitis pigmentosa that is associated with rhodopsin mutations and the therapeutic product is Channelrhodopsin-2 (ChR2);
    • (115) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Ciliary Neurotrophic Factor (CNTF);
    • (116) the pathology of the eye is associated with autosomal recessive retinitis pigmentosa and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);
    • (117) the pathology of the eye is associated with autosomal recessive retinitis pigmentosa and the therapeutic product is Crumbs Cell Polarity Complex Component 2 (CRB2);
    • (118) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Histone Deacetylase 4 (HDAC4);
    • (119) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rhodopsin (RHO);
    • (120) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Nerve Growth Factor (NGF);
    • (121) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Nuclear Factor, Erythroid 2 Like 2 (NRF2);
    • (122) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Pigment Epithelium-Derived Factor (PEDF);
    • (123) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Glutathione S-Transferase PI 1 (GSTP1);
    • (124) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rod-Derived Cone Viability Factor (RDCVF);
    • (125) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rhodopsin (RHO);
    • (126) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Retinaldehyde Binding Protein 1 (RLBP1);
    • (127) the pathology of the eye is associated with Stargardt's disease and the therapeutic product is an anti-complement C5 aptamer;
    • (128) the pathology of the eye is associated with uveitis and the therapeutic product is Double Homeobox 4 (DUX4);
    • (129) the pathology of the eye is associated with uveitis and the therapeutic product is NLR Family Pyrin Domain Containing 3 (NLRP3);
    • (130) the pathology of the eye is associated with uveitis and the therapeutic product is Spleen Associated Tyrosine Kinase (SYK);
    • (131) the pathology of the eye is associated with uveitis and the therapeutic product is Adrenocorticotropic Hormone (ACTH);
    • (132) the pathology of the eye is associated with uveitis and the therapeutic product is Caspase 1 (CASP1);
    • (133) the pathology of the eye is associated with uveitis and the therapeutic product is anti-CD59 monoclonal antibody;
    • (134) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement C5 aptamer;
    • (135) the pathology of the eye is associated with corneal neovascularization and the therapeutic product is Insulin Receptor Substrate 1 (IRS1);
    • (136) the pathology of the eye is associated with corneal neovascularization and the therapeutic product is NOTCH Regulated Ankyrin Repeat Protein (NRARP);
    • (137) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is NOTCH Regulated Ankyrin Repeat Protein (NRARP);
    • (138) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Alpha-2-Antiplasmin (A2AP);
    • (139) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Plasminogen (PLG);
    • (140) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is a growth hormone;
    • (141) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Insulin Like Growth Factor 1 (IGF1);
    • (142) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Interleukin 1 Beta (IL1B).
    • (143) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Angiotensin I Converting Enzyme 2 (ACE2);
    • (144) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is IRS1;
    • (145) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is an anti-integrin oligopeptide;
    • (146) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is an anti-Placental Growth Factor (PGF) monoclonal antibody;
    • (147) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-CD40 monoclonal antibody;
    • (148) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-Insulin-Like Growth Factor 1 Receptor (IGF1R) monoclonal antibody;
    • (149) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-Insulin-Like Growth Factor 2 Receptor (IGF2R) monoclonal antibody;
    • (150) the pathology of the eye is associated with DME and the therapeutic product is an anti-integrin oligopeptide;
    • (151) the pathology of the eye is associated with DME and the therapeutic product is an anti-Placental Growth Factor (PGF) monoclonal antibody;
    • (152) the pathology of the eye is associated with DME and the therapeutic product is RTP801 siRNA;
    • (153) the pathology of the eye is associated with multiple sclerosis (MS)-associated vision loss and the therapeutic product is ND1;
    • (154) the pathology of the eye is associated with myopia and the therapeutic product is Matrix Metalloproteinase 2 (MMP2) RNAi;
    • (155) the pathology of the eye is associated with X-linked recessive ocular albinism and the therapeutic product is G-Protein Coupled Receptor 143 (GPR143);
    • (156) the pathology of the eye is associated with oculocutaneous albinism type 1 and the therapeutic product is Tyrosinase (TYR);
    • (157) the pathology of the eye is associated with optic neuritis and the therapeutic product is Caspase 2 (CASP2);
    • (158) the pathology of the eye is associated with optic neuritis and the therapeutic product is an anti-Leucine Rich Repeat And Ig Domain Containing Protein 1 (LINGO1) monoclonal antibody; or
    • (159) the pathology of the eye is associated with polypoidal choroidal vasculopathy and the therapeutic product is an anti-complement C5 aptamer.


27. The method of any one of paragraphs 1-11 and 15-18, wherein:

    • (1) the pathology of the eye is associated with X-linked retinitis pigmentosa (XLRP) and the therapeutic product is Retinitis Pigmentosa GTPase Regulator (RPGR);
    • (2) the pathology of the eye is associated with achromatopsia (ACHM) and the therapeutic product is Cyclic Nucleotide Gated Channel Beta 3 (CNGB3);
    • (3) the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3); or
    • (4) the pathology of the eye is associated with biallelic RPE65 mutation-associated retinal dystrophy and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65).


28. The method of any one of paragraphs 1-11 and 13-18, wherein:

    • (1) the pathology of the eye is associated with Batten-CLN1 and the therapeutic product is Palmitoyl-Protein Thioesterase 1 (PPT1);
    • (2) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1);
    • (3) the pathology of the eye is associated with Batten-CLN3 and the therapeutic product is Battenin (CLN3);
    • (4) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-Interleukin 6 (IL6) monoclonal antibody;
    • (5) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF-alpha (TNF) monoclonal antibody;
    • (6) the pathology of the eye is associated with diabetic macular edema (DME) and the therapeutic product is an anti-IL6 monoclonal antibody;
    • (7) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);
    • (8) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);
    • (9) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);
    • (10) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D);
    • (11) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65);
    • (12) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX);
    • (13) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1);
    • (14) the pathology of the eye is associated with Leber congenital amaurosis-12 (LCA 12) and the therapeutic product is Retinal Degeneration 3, GUCY2D regulator (RD3);
    • (15) the pathology of the eye is associated with Leber congenital amaurosis-13 (LCA 13) and the therapeutic product is Retinol Dehydrogenase 12 (RDH12);
    • (16) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1);
    • (17) the pathology of the eye is associated with Leber congenital amaurosis-16 (LCA 16) and the therapeutic product is Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13);
    • (18) the pathology of the eye is associated with Leber's hereditary optic neuropathy (LHON) and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1);
    • (19) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4);
    • (20) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6);
    • (21) the pathology of the eye is associated with neuromyelitis optica (NMO) and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (22) the pathology of the eye is associated with NMO and the therapeutic product is an anti-IL6 monoclonal antibody;
    • (23) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement C5 monoclonal antibody;
    • (24) the pathology of the eye is associated with uveitis and the therapeutic product is Angiotensin I Converting Enzyme (ACE);
    • (25) the pathology of the eye is associated with uveitis and the therapeutic product is Interleukin 10 (IL10);
    • (26) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF monoclonal antibody;
    • (27) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1);
    • (28) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1);
    • (29) the pathology of the eye is associated with Bardet-Biedl syndrome 3 and the therapeutic product is ADP Ribosylation Factor Like GTPase 6 (ARL6);
    • (30) the pathology of the eye is associated with Bardet-Biedl syndrome 5 and the therapeutic product is Bardet-Biedl Syndrome 5 (BBS5);
    • (31) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS);
    • (32) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10);
    • (33) the pathology of the eye is associated with Bardet-Biedl syndrome 11 and the therapeutic product is Tripartite Motif Containing 32 (TRIM32);
    • (34) the pathology of the eye is associated with Bardet-Biedl syndrome 13 and the therapeutic product is MKS Transition Zone Complex Subunit 1 (MKS1);
    • (35) the pathology of the eye is associated with Bardet-Biedl syndrome 18 and the therapeutic product is BBSome Interacting Protein 1 (BBIP1);
    • (36) the pathology of the eye is associated with Bardet-Biedl syndrome 19 and the therapeutic product is Intraflagellar Transport 27 (IFT27);
    • (37) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A);
    • (38) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8);
    • (39) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3); or
    • (40) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1).


29. The method of any one of paragraphs 1-11 and 15-18, wherein:

    • (1) the pathology of the eye is associated with biallelic RPE65 mutation-associated retinal dystrophy and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65).


30. The method of any one of paragraphs 1-11 and 13-18, wherein:

    • (1) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1);
    • (2) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Myosin VIIA (MYO7A);
    • (3) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Cadherin Related 23 (CDH23);
    • (4) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Protocadherin Related 15 (PCDH15);
    • (5) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Usherin (USH2A);
    • (6) the pathology of the eye is associated with Usher's-Type 3 and the therapeutic product is Clarin 1 (CLRN1);
    • (7) the pathology of the eye is associated with Stargardt's and the therapeutic product is ATP Binding Cassette Subfamily A Member 4 (ABCA4);
    • (8) the pathology of the eye is associated with Stargardt's and the therapeutic product is ELOVL Fatty Acid Elongase 4 (ELOVL4);
    • (9) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);
    • (10) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);
    • (11) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);
    • (12) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D);
    • (13) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65);
    • (14) the pathology of the eye is associated with Leber congenital amaurosis-4 (LCA 4) and the therapeutic product is Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1);
    • (15) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX);
    • (16) the pathology of the eye is associated with Leber congenital amaurosis-8 (LCA 8) and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);
    • (17) the pathology of the eye is associated with Leber congenital amaurosis-9 (LCA 9) and the therapeutic product is Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1);
    • (18) the pathology of the eye is associated with Leber congenital amaurosis-10 (LCA 10) and the therapeutic product is Centrosomal Protein 290 (CEP290);
    • (19) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1);
    • (20) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1);
    • (21) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4);
    • (22) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6);
    • (23) the pathology of the eye is associated with choroideremia and the therapeutic product is Rab Escort Protein 1 (CHM);
    • (24) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1);
    • (25) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1);
    • (26) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS);
    • (27) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10);
    • (28) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A);
    • (29) the pathology of the eye is associated with optic atrophy and the therapeutic product is OPA1 Mitochondrial Dynamin Like GTPase (OPA1);
    • (30) the pathology of the eye is associated with retinitis pigmentosa 1 and the therapeutic product is RP1 Axonemal Microtubule Associated (RP1);
    • (31) the pathology of the eye is associated with retinitis pigmentosa 2 and the therapeutic product is RP2 Activator of ARL3 GTPase (RP2);
    • (32) the pathology of the eye is associated with retinitis pigmentosa 7 and the therapeutic product is Peripherin 2 (PRPH2);
    • (33) the pathology of the eye is associated with retinitis pigmentosa 11 and the therapeutic product is Pre-mRNA Processing Factor 31(PRPF31);
    • (34) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8);
    • (35) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3);
    • (36) the pathology of the eye is associated with retinitis pigmentosa 38 and the therapeutic product is MER Proto-Oncogene, Tyrosine Kinase (MERTK);
    • (37) the pathology of the eye is associated with retinitis pigmentosa 40 and the therapeutic product is Phosphodiesterase 6B (PDE6B);
    • (38) the pathology of the eye is associated with retinitis pigmentosa 41 and the therapeutic product is Prominin 1 (PROM1);
    • (39) the pathology of the eye is associated with retinitis pigmentosa 56 and the therapeutic product is Interphotoreceptor Matrix Proteoglycan 2 (IMPG2);
    • (40) the pathology of the eye is associated with petinitis pigmentosa 62 and the therapeutic product is Male Germ Cell Associated Kinase (MAK);
    • (41) the pathology of the eye is associated with retinitis pigmentosa 80 and the therapeutic product is Intraflagellar Transport 140 (IFT140); or
    • (42) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1).


31. The method of any one of paragraphs 1-11 and 15-18, wherein:

    • (1) the pathology of the eye is associated with X-linked retinitis pigmentosa (XLRP) and the therapeutic product is Retinitis Pigmentosa GTPase Regulator (RPGR);
    • (2) the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Beta 3 (CNGB3); or
    • (3) the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3).


32. The method of any one of paragraphs 1-31, wherein the recombinant viral vector further comprises a nucleotide sequence encoding a promoter or an enhancer-promoter, which nucleotide sequence encoding the promoter or enhancer-promoter is operably linked to the nucleotide sequence encoding the therapeutic product, and wherein the promoter or enhancer-promoter is:

    • (1) a CAG promoter;
    • (2) a CBA promoter;
    • (3) a CMV promoter;
    • (4) a PR1.7 promoter;
    • (5) a Rhodopsin Kinase (GRK1) photoreceptor-specific enhancer-promoter;
    • (6) an hCARp promoter;
    • (7) an hRKp;
    • (8) a cone photoreceptor specific human arrestin 3 (ARR3) promoter;
    • (9) a rhodopsin promoter; or
    • (10) a U6 promoter.


33. The method of any one of paragraphs 1-11 and 13-15, wherein the recombinant viral vector further comprises a nucleotide sequence encoding a cone-specific promoter, which nucleotide sequence encoding the cone-specific promoter is operably linked to the nucleotide sequence encoding the therapeutic product, and wherein:

    • (1) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);
    • (2) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);
    • (3) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);
    • (4) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A); or
    • (5) the pathology of the eye is associated with blue cone monochromacy (BCM) and the therapeutic product is L opsin (OPN1LW).


34. The method of any one of paragraphs 1-33, wherein the administering step delivers a therapeutically effective amount of the therapeutic product to the retina of said human subject.


35. The method of paragraph 34, wherein the therapeutically effective amount of the therapeutic product is produced by human retinal cells of said human subject.


36. The method of paragraph 34, wherein the therapeutically effective amount of the therapeutic product is produced by human photoreceptor cells, horizontal cells, bipolar cells, amacrine cells, retina ganglion cells, and/or retinal pigment epithelial cells in the external limiting membrane of said human subject.


37. The method of paragraph 36, wherein the human photoreceptor cells are cone cells and/or rod cells.


38. The method of paragraph 36, wherein the retina ganglion cells are midget cells, parasol cells, bistratified cells, giant retina ganglion cells, photosensitive ganglion cells, and/or Müller glia.


39. The method of any one of paragraphs 1-38, wherein the recombinant viral vector is an rAAV vector.


40. The method of paragraph 39, wherein the recombinant viral vector is an rAAV8 vector.


41. The method of any one of paragraphs 1-40, which further comprises, after the administering step, a step of monitoring the post ocular injection thermal profile of the injected material in the eye using an infrared thermal camera.


42. The method of paragraph 41, wherein the infrared thermal camera is an FLIR T530 infrared thermal camera. 43. The method of any one of paragraphs 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 6.0×1010 genome copies per eye.


44. The method of any one of paragraphs 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 1.6×1011 genome copies per eye.


45. The method of any one of paragraphs 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 2.5×1011 genome copies per eye.


46. The method of any one of paragraphs 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 5.0×1011 genome copies per eye.


47. The method of any one of paragraphs 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 3.0×1012 genome copies per eye.





5. BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1. A suprachoroidal drug delivery device manufactured by Clearside® Biomedical, Inc.



FIG. 2. A subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space toward the posterior pole, where a small needle injects into the subretinal space, manufactured by Janssen Pharmaceuticals, Inc.



FIG. 3. Diagram of the human eye with cross-sectional view.



FIGS. 4A-4D. Illustration of the posterior juxtascleral depot procedure.



FIG. 5. Schematic of AAV8-antiVEGFfab genome.



FIG. 6. Use of an infrared thermal camera to monitor thermal profile post suprachoroidal injection.



FIGS. 7A and 7B. A micro volume injector drug delivery device manufactured by Altaviz.



FIGS. 8A and 8B. A drug delivery device manufactured by Visionisti OY. Specifically, FIG. 8A depicts the injection adapter, which is able to convert 30 g short hypodermic needles into a suprachoroidal/subretinal needles. The device is able to control the length of the needle tip exposed from the distal tip of the adapter. Adjustments can be made at 10 μL. The device has the ability to adjust for suprachoroidal delivery and/or ab-externo subretinal delivery. FIG. 8B depicts a needle adaptor guide which is able to keep the lids open and hold the needle at the optimal angle and depth for delivery. The needle adapter is locked into the stabilizing device. The needle adapter is an all-in-one tool for standardized and optimized in-office suprachoroidal and/or subretinal injections.





6. DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compositions and methods for the delivery of therapeutic products (such as therapeutic proteins (for example, antibodies), therapeutic RNAs (for example, shRNAs, siRNAs, and miRNAs), and therapeutic aptamers) to the retina/vitreal humour in the eyes of human subjects to treat pathologies of the eye, involving, for example, recombinant viral vectors such as recombinant adeno-associated virus (rAAV) vectors.


The therapeutic products can be, for example, therapeutic proteins (for example, antibodies), therapeutic RNAs (for example, shRNAs, siRNAs, and miRNAs), or therapeutic aptamers.


In a specific embodiment, the therapeutic products is a human protein or an antibody against a human protein. Antibodies include, but are not limited to, monoclonal antibodies, polyclonal antibodies, recombinantly produced antibodies, human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-heavy chain pairs, intrabodies, heteroconjugate antibodies, monovalent antibodies, antigen-binding fragments of full-length antibodies, and fusion proteins of the above. Such antigen-binding fragments include, but are not limited to, single-domain antibodies (variable domain of heavy chain antibodies (VHHs) or nanobodies), Fabs, F(ab′)2s, and scFvs (single-chain variable fragments). In certain embodiment, the therapeutic product (for example, a therapeutic protein) is post-translationally modified. In a specific embodiment, the post-translational modification is specific to the cell type, to which the therapeutic product (for example, a therapeutic protein) is delivered using a specific route as described herein. Delivery may be accomplished via gene therapy—e.g., by administering a recombinant viral vector or a recombinant DNA expression construct (collectively, a “recombinant vector”) encoding an therapeutic product to the suprachoroidal space, subretinal space (with vitrectomy, or without vitrectomy (e.g., with a catheter through the suprachoroidal space, or via peripheral injection), intraretinal space, vitreous cavity, and/or outer surface of the sclera (i.e., juxtascleral administration) in the eye(s) of a human patient, to create a permanent depot in the eye that continuously supplies the therapeutic product (e.g., a post-translationally modified therapeutic product).


6.1 Methods for the Delivery of Therapeutic Products


In one aspect, provided herein is a method of subretinal administration without vitrectomy for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient. In certain embodiments, the administering step comprises administering to the subretinal space in the eye of said human subject the recombinant viral vector therapeutic product via the suprachoroidal space in the eye of said human subject. In certain embodiments, the administering step is by the use of a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space toward the posterior pole, where a small needle injects into the subretinal space. In certain embodiments, the administering step comprises inserting and tunneling the catheter of the subretinal drug delivery device through the suprachoroidal space.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient. In certain embodiments, the administering step comprises administering to the subretinal space in the eye of said human subject the recombinant viral vector therapeutic product via the suprachoroidal space in the eye of said human subject. In certain embodiments, the administering step is by the use of a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space toward the posterior pole, where a small needle injects into the subretinal space. In certain embodiments, the administering step comprises inserting and tunneling the catheter of the subretinal drug delivery device through the suprachoroidal space.


In one aspect, provided herein is a method of subretinal administration with vitrectomy for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient. In certain embodiments, the vitrectomy is a partial vitrectomy.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient. In certain embodiments, the vitrectomy is a partial vitrectomy.


In one aspect, provided herein is a method of suprachoroidal administration for treating a pathology of the eye, comprising administering to the suprachoroidal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye. In certain embodiments, the administering step is by injecting the recombinant viral vector into the suprachoroidal space using a suprachoroidal drug delivery device. In certain embodiments, the suprachoroidal drug delivery device is a microinjector.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the suprachoroidal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye. In certain embodiments, the administering step is by injecting the recombinant viral vector into the suprachoroidal space using a suprachoroidal drug delivery device. In certain embodiments, the suprachoroidal drug delivery device is a microinjector.


In certain embodiments, delivery to the subretinal or suprachoroidal space can be performed using the methods and/or devices described and disclosed in International Publication Nos. WO 2016/042162, WO 2017/046358, WO 2017/158365, and WO 2017/158366, each of which is incorporated by reference in its entirety.


In one aspect, provided herein is a method of administration to the outer space of the sclera for treating a pathology of the eye, comprising administering to the outer surface of the sclera in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye. In certain embodiments, the administering step is by the use of a juxtascleral drug delivery device that comprises a cannula whose tip can be inserted and kept in direct apposition to the scleral surface. In certain embodiments, the administering step comprises inserting and keeping the tip of the cannula in direct apposition to the scleral surface.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the outer surface of the sclera in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye. In certain embodiments, the administering step is by the use of a juxtascleral drug delivery device that comprises a cannula whose tip can be inserted and kept in direct apposition to the scleral surface. In certain embodiments, the administering step comprises inserting and keeping the tip of the cannula in direct apposition to the scleral surface


In one aspect, provided herein is a method of intravitreal administration for treating a pathology of the eye, comprising administering to the vitreous cavity in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye. In certain embodiments, the administering step is by injecting the recombinant viral vector into the vitreous cavity using an intravitreal drug delivery device. In certain embodiments, the intravitreal drug delivery device is a microinjector. In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the vitreous cavity in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye. In certain embodiments, the administering step is by injecting the recombinant viral vector into the vitreous cavity using an intravitreal drug delivery device. In certain embodiments, the intravitreal drug delivery device is a microinjector.


In certain embodiments, the therapeutic product is not an anti-human vascular endothelial growth factor (hVEGF) antibody.


In certain embodiments, the pathology of the eye is not associated with neovascular age-related macular degeneration (nAMD) (also known as the “wet,” neovascular form of AMD (“WAMD” or “wet AMD”)).


In certain embodiments, the therapeutic product is an anti-hVEGF antibody.


In certain embodiments, the pathology of the eye is associated with nAMD.


In certain embodiments, the pathology of the eye is associated with nAMD and the therapeutic product is an anti-hVEGF antibody.


In one aspect, provided herein is a method of subretinal administration accompanied by vitrectomy for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient, and wherein the therapeutic product is not anti-human vascular endothelial growth factor (hVEGF) antibody. In certain embodiments, the pathology of the eye is an ocular disease or a disease involving multiple organs including the eye. In certain embodiments, the vitrectomy is a partial vitrectomy.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient, and wherein the therapeutic product is not anti-human vascular endothelial growth factor (hVEGF) antibody. In certain embodiments, the pathology of the eye is an ocular disease or a disease involving multiple organs including the eye. In certain embodiments, the vitrectomy is a partial vitrectomy.


In one aspect, provided herein is a method of subretinal administration for treating a pathology of the eye, comprising administering to the subretinal space peripheral to the optic disc, fovea and macula located in the back of the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient. In certain embodiments, the injecting step is by transvitreal injection. In certain embodiments, the method of transvitreal administration results in uniform expression of the therapeutic product throughout the eye (e.g. the expression level at the site of injection varies by less than 5%, 10%, 20%, 30%, 40%, or 50% as compared to the expression level at other areas of the eye). In certain embodiments, the transvitreal injection comprises inserting a sharp needle into the sclera via the superior or inferior side of the eye and passing the sharp needle all the way through the vitreous to inject the recombinant viral vector to the subretinal space on the other side. In certain embodiments, a needle is inserted at the 2 or 10 o'clock position. In certain embodiments, the transvitreal injection comprises inserting a trochar into the sclera and inserting a cannula through the trochar and through the vitreous to inject the recombinant viral vector to the subretinal space on the other side. In certain embodiments, the therapeutic product is an anti-hVEGF antibody. In certain embodiments, the anti-hVEGF antibody is an anti-hVEGF antigen-binding fragment. In certain embodiments, the anti-hVEGF antigen-binding fragment is a Fab, F(ab′)2, or single chain variable fragment (scFv). In certain embodiments, the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4, and a light chain comprising the amino acid sequence of SEQ ID NO:1, or SEQ ID NO:3. In certain embodiments, wherein the anti-hVEGF antibody comprises light chain CDRs 1-3 of SEQ ID NOs:14-16 and heavy chain CDRs 1-3 of SEQ ID NOs:17-19 or SEQ ID NOs:20, 18, and 21. In certain embodiments, wherein the pathology of the eye is associated with nAMD, dry age-related macular degeneration (dry AMD), retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR). In certain embodiments, the pathology of the eye is associated with nAMD.


In another aspect, provided herein is a method for treating a pathology of the eye, comprising administering to the subretinal space peripheral to the optic disc, fovea and macula located in the back of the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient. In certain embodiments, the injecting step is by transvitreal injection. In certain embodiments, the method of transvitreal administration results in uniform expression of the therapeutic product throughout the eye (e.g. the expression level at the site of injection varies by less than 5%, 10%, 20%, 30%, 40%, or 50% as compared to the expression level at other areas of the eye). In certain embodiments, the transvitreal injection comprises inserting a sharp needle into the sclera via the superior or inferior side of the eye and passing the sharp needle all the way through the vitreous to inject the recombinant viral vector to the subretinal space on the other side. In certain embodiments, a needle is inserted at the 2 or 10 o'clock position. In certain embodiments, the transvitreal injection comprises inserting a trochar into the sclera and inserting a cannula through the trochar and through the vitreous to inject the recombinant viral vector to the subretinal space on the other side. In certain embodiments, the therapeutic product is an anti-hVEGF antibody. In certain embodiments, the anti-hVEGF antibody is an anti-hVEGF antigen-binding fragment. In certain embodiments, the anti-hVEGF antigen-binding fragment is a Fab, F(ab′)2, or single chain variable fragment (scFv). In certain embodiments, the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4, and a light chain comprising the amino acid sequence of SEQ ID NO:1, or SEQ ID NO:3. In certain embodiments, wherein the anti-hVEGF antibody comprises light chain CDRs 1-3 of SEQ ID NOs:14-16 and heavy chain CDRs 1-3 of SEQ ID NOs:17-19 or SEQ ID NOs:20, 18, and 21. In certain embodiments, wherein the pathology of the eye is associated with nAMD, dry age-related macular degeneration (dry AMD), retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR). In certain embodiments, the pathology of the eye is associated with nAMD.


In certain embodiments of the methods described herein, the administering step delivers a therapeutically effective amount of the therapeutic product to the retina of said human subject.


In certain embodiments of the methods described herein, the therapeutically effective amount of the therapeutic product is produced by human retinal cells of said human subject.


In certain embodiments of the methods described herein, the therapeutically effective amount of the therapeutic product is produced by human photoreceptor cells, horizontal cells, bipolar cells, amacrine cells, retina ganglion cells, and/or retinal pigment epithelial cells in the external limiting membrane of said human subject.


In certain embodiments of the methods described herein, the human photoreceptor cells are cone cells and/or rod cells.


In certain embodiments of the methods described herein, the retina ganglion cells are midget cells, parasol cells, bistratified cells, giant retina ganglion cells, photosensitive ganglion cells, and/or Müllner glia.


In certain embodiments of the methods described herein, the recombinant viral vector is an rAAV vector (e.g., an rAAV8, rAAV2, rAAV2tYF, or rAAV5 vector).


In certain embodiments of the methods described herein, wherein the recombinant viral vector is an rAAV8 vector.


In certain embodiments of the methods described herein, delivering to the eye comprises delivering to the retina, choroid, and/or vitreous humor of the eye.


6.1.1 Post-Translational Modification


In certain embodiments, the therapeutic product (for example, a therapeutic protein) is post-translationally modified. In a specific embodiment, the post-translational modification is specific to the cell type, to which the therapeutic product (for example, a therapeutic protein) is delivered using a specific route as described herein.


In a specific embodiment, the post-translational modification is glycosylation. In another specific embodiment, the post-translational modification is tyrosine sulfation. In another specific embodiment, the post-translational modification is a phosphorylation. In another specific embodiment, the post-translational modification is a ADP-ribosylation. In another specific embodiment, the post-translational modification is a prenylation. In another specific embodiment, the post-translational modification is a myristoylation or palmitylation. In another specific embodiment, the post-translational modification is ubiquitination. In another specific embodiment, the post-translational modification is sentrinization. In another specific embodiment, the post-translational modification is a ubiquitination-like protein modification.


In a specific embodiment, the therapeutic product is post-translationally modified upon expression from the recombinant vector in a human immortalized retina-derived cell.


In a specific embodiment, the administration of the recombinant vector results in the formation of a depot that releases the therapeutic product containing a post-translational modification.


In a specific embodiment, the recombinant vector, when used to transduce a retina-derived cell in culture results in production of the therapeutic product containing a post-translational modification.


The post-translational modification can be detected by any method known in the art for detecting post-translational modifications, for example, western blot, chromatography, or flow cytometry.


In a specific embodiment, the post-translation can be detected by in vivo labeling of cellular substrate pools with radioactive substrate or substrate precursor molecules, which result in incorporation of radiolabeled moieties, including, but not limited to, phosphate, fatty acyl (e.g. myristoyl, or palmityl), sentrin, methyl, acetyl, hydroxyl, iodine, flavin, ubiquitin or ADP-ribosyls, to therapeutic product. Analysis of modified proteins is typically performed by electrophoresis and autoradiography, with specificity enhanced by immunoprecipitation of proteins of interest prior to electrophoresis.


In a specific embodiment, the post-translation can be detected by enzymatic incorporation of a labeled moiety (including, but not limited to, radioactive, luminescent, or fluorescent label) into a therapeutic product in vitro to estimate the state of modification in vivo.


In a specific embodiment, the post-translation can be detected by analyzing the alteration in electrophoretic mobility of modified therapeutic product (e.g., glycosylated or ubiquitinated) compared with unmodified therapeutic product.


In a specific embodiment, the post-translation can be detected by thin-layer chromatography of radiolabeled fatty acids extracted from the therapeutic product.


In a specific embodiment, the post-translation can be detected by partitioning of therapeutic product into detergent-rich or detergent layer by phase separation, and the effects of enzyme treatment of the therapeutic product on the partitioning between aqueous and detergent-rich environments.


In a specific embodiment, the post-translation can be detected by antibody recognition of the modified form of the protein, e.g., by western blot, or flow cytometry.


6.1.2 Constructs and Formulations


For use in the methods provided herein are recombinant viral vectors or other recombinant DNA expression constructs (collectively, “recombinant vectors”) encoding an therapeutic product. The recombinant viral vectors and other DNA expression constructs provided herein include any suitable ones for delivery of therapeutic products (such as therapeutic proteins (for example, antibodies), therapeutic RNAs (for example, shRNAs, siRNAs, and miRNAs), and therapeutic aptamers)) to a target cell (e.g., retinal pigment epithelial cells). The means of delivery of a therapeutic product include recombinant viral vectors, liposomes, other lipid-containing complexes, other macromolecular complexes, synthetic modified mRNA, unmodified mRNA, small molecules, non-biologically active molecules (e.g., gold particles), polymerized molecules (e.g., dendrimers), naked DNA, plasmids, phages, transposons, cosmids, or episomes. In some embodiments, the vector is a targeted vector, e.g., a vector targeted to retinal pigment epithelial cells.


In some aspects, the disclosure provides for a nucleic acid for use, wherein the nucleic acid encodes a therapeutic product operatively linked to a promoter or enhancer-promoter described herein.


In certain embodiments, provided herein are recombinant vectors that comprise one or more nucleic acids (e.g. polynucleotides). The nucleic acids may comprise DNA, RNA, or a combination of DNA and RNA. In certain embodiments, the DNA comprises one or more of the sequences selected from the group consisting of promoter sequences, the sequence encoding the therapeutic product of interest, untranslated regions, and termination sequences. In certain embodiments, recombinant vectors provided herein comprise a promoter operably linked to the sequence encoding the therapeutic product of interest.


In certain embodiments, nucleic acids (e.g., polynucleotides) and nucleic acid sequences disclosed herein may be codon-optimized, for example, via any codon-optimization technique known to one of skill in the art (see, e.g., review by Quax et al., 2015, Mol Cell 59:149-161).


(a) mRNA

In certain embodiments, the recombinant vectors provided herein comprise modified mRNA encoding for the therapeutic product of interest. The synthesis of modified and unmodified mRNA for delivery of a therapeutic product to cells of the eye, for example, to retinal pigment epithelial cells, is taught, for example, in Hansson et al., J. Biol. Chem., 2015, 290(9):5661-5672, which is incorporated by reference herein in its entirety. In certain embodiments, provided herein is a modified mRNA encoding for a therapeutic product moiety.


(b) shRNAs, siRNAs, and miRNAs

In certain embodiments, the recombinant vectors provided herein comprise a nucleotide sequence encoding for a therapeutic product that is an shRNA, siRNA, or miRNA.


(c) Recombinant Viral Vectors

Recombinant viral vectors include recombinant adenovirus, adeno-associated virus (AAV, e.g., AAV1, AAV2, AAV2tYF, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, and AAVrh10), lentivirus, helper-dependent adenovirus, herpes simplex virus, poxvirus, hemagglutinin virus of Japan (HVJ), alphavirus, vaccinia virus, and retrovirus vectors. Retroviral vectors include murine leukemia virus (MLV)- and human immunodeficiency virus (HIV)-based vectors. Alphavirus vectors include semliki forest virus (SFV) and sindbis virus (SIN). In certain embodiments, the recombinant viral vectors provided herein are altered such that they are replication-deficient in humans. In certain embodiments, the recombinant viral vectors are hybrid vectors, e.g., an AAV vector placed into a “helpless” adenoviral vector. In certain embodiments, provided herein are recombinant viral vectors comprising a viral capsid from a first virus and viral envelope proteins from a second virus. In specific embodiments, the second virus is vesicular stomatitus virus (VSV). In more specific embodiments, the envelope protein is VSV-G protein.


In certain embodiments, the recombinant viral vectors provided herein are HIV based viral vectors. In certain embodiments, HIV-based vectors provided herein comprise at least two polynucleotides, wherein the gag and pol genes are from an HIV genome and the env gene is from another virus.


In certain embodiments, the recombinant viral vectors provided herein are herpes simplex virus-based viral vectors. In certain embodiments, herpes simplex virus-based vectors provided herein are modified such that they do not comprise one or more immediately early (IE) genes, rendering them non-cytotoxic.


In certain embodiments, the recombinant viral vectors provided herein are MLV based viral vectors. In certain embodiments, MLV-based vectors provided herein comprise up to 8 kb of heterologous DNA in place of the viral genes.


In certain embodiments, the recombinant viral vectors provided herein are lentivirus-based viral vectors. In certain embodiments, lentiviral vectors provided herein are derived from human lentiviruses. In certain embodiments, lentiviral vectors provided herein are derived from non-human lentiviruses. In certain embodiments, lentiviral vectors provided herein are packaged into a lentiviral capsid. In certain embodiments, lentiviral vectors provided herein comprise one or more of the following elements: long terminal repeats, a primer binding site, a polypurine tract, att sites, and an encapsidation site.


In certain embodiments, the recombinant viral vectors provided herein are alphavirus-based viral vectors. In certain embodiments, alphavirus vectors provided herein are recombinant, replication-defective alphaviruses. In certain embodiments, alphavirus replicons in the alphavirus vectors provided herein are targeted to specific cell types by displaying a functional heterologous ligand on their virion surface.


In certain embodiments, the recombinant viral vectors provided herein are AAV based viral vectors. In preferred embodiments, the recombinant viral vectors provided herein are AAV8 based viral vectors. In certain embodiments, the AAV8 based viral vectors provided herein retain tropism for retinal cells. In certain embodiments, the AAV-based vectors provided herein encode the AAV rep gene (required for replication) and/or the AAV cap gene (required for synthesis of the capsid proteins). Multiple AAV serotypes have been identified. In certain embodiments, AAV-based vectors provided herein comprise components from one or more serotypes of AAV. In certain embodiments, AAV based vectors provided herein comprise capsid components from one or more of AAV1, AAV2, AAV2tYF, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, or AAVrh10. In preferred embodiments, AAV based vectors provided herein comprise components from one or more of AAV8, AAV9, AAV10, AAV11, or AAVrh10 serotypes.


Provided in particular embodiments are AAV8 vectors comprising a viral genome comprising an expression cassette for expression of the therapeutic product, under the control of regulatory elements and flanked by ITRs and a viral capsid that has the amino acid sequence of the AAV8 capsid protein or is at least 95%, 96%, 97%, 98%, 99% or 99.9% identical to the amino acid sequence of the AAV8 capsid protein (SEQ ID NO: 48) while retaining the biological function of the AAV8 capsid. In certain embodiments, the encoded AAV8 capsid has the sequence of SEQ ID NO: 48 with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acid substitutions and retaining the biological function of the AAV8 capsid.


In certain embodiments, the AAV that is used in the methods described herein is Anc80 or Anc80L65, as described in Zinn et al., 2015, Cell Rep. 12(6): 1056-1068, which is incorporated by reference in its entirety. In certain embodiments, the AAV that is used in the methods described herein comprises one of the following amino acid insertions: LGETTRP or LALGETTRP, as described in U.S. Pat. Nos. 9,193,956; 9,458,517; and 9,587,282 and US patent application publication no. 2016/0376323, each of which is incorporated herein by reference in its entirety. In certain embodiments, the AAV that is used in the methods described herein is AAV.7m8, as described in U.S. Pat. Nos. 9,193,956; 9,458,517; and 9,587,282 and US patent application publication no. 2016/0376323, each of which is incorporated herein by reference in its entirety. In certain embodiments, the AAV that is used in the methods described herein is any AAV disclosed in U.S. Pat. No. 9,585,971, such as AAV-PHP.B. In certain embodiments, the AAV that is used in the methods described herein is an AAV disclosed in any of the following patents and patent applications, each of which is incorporated herein by reference in its entirety: U.S. Pat. Nos. 7,906,111; 8,524,446; 8,999,678; 8,628,966; 8,927,514; 8,734,809; 9,284,357; 9,409,953; 9,169,299; 9,193,956; 9,458,517; and 9,587,282 US patent application publication nos. 2015/0374803; 2015/0126588; 2017/0067908; 2013/0224836; 2016/0215024; 2017/0051257; and International Patent Application Nos. PCT/US2015/034799; PCT/EP2015/053335.


AAV8-based viral vectors are used in certain embodiments of the methods described herein. Nucleic acid sequences of AAV based viral vectors and methods of making recombinant AAV and AAV capsids are taught, for example, in U.S. Pat. No. 7,282,199 B2, U.S. Pat. No. 7,790,449 B2, U.S. Pat. No. 8,318,480 B2, U.S. Pat. No. 8,962,332 B2 and International Patent Application No. PCT/EP2014/076466, each of which is incorporated herein by reference in its entirety. In one aspect, provided herein are AAV (e.g., AAV8)-based viral vectors encoding a therapeutic product.


In certain embodiments, a single-stranded AAV (ssAAV) may be used supra. In certain embodiments, a self-complementary vector, e.g., scAAV, may be used (see, e.g., Wu, 2007, Human Gene Therapy, 18(2):171-82, McCarty et al, 2001, Gene Therapy, Vol 8, Number 16, Pages 1248-1254; and U.S. Pat. Nos. 6,596,535; 7,125,717; and 7,456,683, each of which is incorporated herein by reference in its entirety).


In certain embodiments, the recombinant viral vectors used in the methods described herein is a recombinant adenovirus vector. The recombinant adenovirus can be a first generation vector, with an E1 deletion, with or without an E3 deletion, and with the expression cassette inserted into either deleted region. The recombinant adenovirus can be a second generation vector, which contains full or partial deletions of the E2 and E4 regions. A helper-dependent adenovirus retains only the adenovirus inverted terminal repeats and the packaging signal (phi). The therapeutic product is inserted between the packaging signal and the 3′ ITR, with or without stuffer sequences to keep the genome close to wild-type size of approx. 36 kb. An exemplary protocol for production of adenoviral vectors may be found in Alba et al., 2005, “Gutless adenovirus: last generation adenovirus for gene therapy,” Gene Therapy 12:S18-S27, which is incorporated by reference herein in its entirety.


In certain embodiments, the recombinant viral vectors used in the methods described herein are lentivirus based viral vectors. Four plasmids are used to make the construct: Gag/pol sequence containing plasmid, Rev sequence containing plasmids, Envelope protein containing plasmid (i.e. VSV-G), and Cis plasmid with the packaging elements and the therapeutic product containing plasmid.


For lentiviral vector production, the four plasmids are co-transfected into cells (i.e., HEK293 based cells), whereby polyethylenimine or calcium phosphate can be used as transfection agents, among others. The lentivirus is then harvested in the supernatant (lentiviruses need to bud from the cells to be active, so no cell harvest needs/should be done). The supernatant is filtered (0.45 μm) and then magnesium chloride and benzonase added. Further downstream processes can vary widely, with using TFF and column chromatography being the most GMP compatible ones. Others use ultracentrifugation with/without column chromatography. Exemplary protocols for production of lentiviral vectors may be found in Lesch et al., 2011, “Production and purification of lentiviral vector generated in 293T suspension cells with baculoviral vectors,” Gene Therapy 18:531-538, and Ausubel et al., 2012, “Production of CGMP-Grade Lentiviral Vectors,” Bioprocess Int. 10(2):32-43, both of which are incorporated by reference herein in their entireties.


(d) Promoters and Modifiers of Gene Expression

In certain embodiments, the recombinant vectors provided herein comprise components that modulate delivery or expression of the therapeutic product (e.g., “expression control elements”). In certain embodiments, the recombinant vectors provided herein comprise components that modulate expression of the therapeutic product. In certain embodiments, the recombinant vectors provided herein comprise components that influence binding or targeting to cells. In certain embodiments, the recombinant vectors provided herein comprise components that influence the localization of the polynucleotide encoding the therapeutic product within the cell after uptake. In certain embodiments, the recombinant vectors provided herein comprise components that can be used as detectable or selectable markers, e.g., to detect or select for cells that have taken up the polynucleotide encoding the therapeutic product.


In certain embodiments, the recombinant vectors provided herein comprise one or more promoters. In certain embodiments, the promoter is a constitutive promoter. In certain embodiments, the promoter is an inducible promoter. Inducible promoters may be preferred so that expression of the therapeutic product may be turned on and off as desired for therapeutic efficacy. Such promoters include, for example, hypoxia-induced promoters and drug inducible promoters, such as promoters induced by rapamycin and related agents. Hypoxia-inducible promoters include promoters with HIF binding sites, see, for example, Schodel, et al., 2011, Blood 117(23):e207-e217 and Kenneth and Rocha, 2008, Biochem J. 414:19-29, each of which is incorporated by reference for teachings of hypoxia-inducible promoters. In addition, hypoxia-inducible promoters that may be used in the constructs include the erythropoietin promoter and N-WASP promoter (see, Tsuchiya, 1993, J. Biochem. 113:395 for disclosure of the erythropoietin promoter and Salvi, 2017, Biochemistry and Biophysics Reports 9:13-21 for disclosure of N-WASP promoter, both of which are incorporated by reference for the teachings of hypoxia-induced promoters). Alternatively, the recombinant vectors may contain drug inducible promoters, for example promoters inducible by administration of rapamycin and related analogs (see, for example, International Patent Application Publication Nos. WO94/18317, WO 96/20951, WO 96/41865, WO 99/10508, WO 99/10510, WO 99/36553, and WO 99/41258, and U.S. Pat. No. 7,067,526 (disclosing rapamycin analogs), which are incorporated by reference herein for their disclosure of drug inducible promoters). In certain embodiments the promoter is a hypoxia-inducible promoter. In certain embodiments, the promoter comprises a hypoxia-inducible factor (HIF) binding site. In certain embodiments, the promoter comprises a HIF-1α binding site. In certain embodiments, the promoter comprises a HIF-2a binding site. In certain embodiments, the HIF binding site comprises an RCGTG motif. For details regarding the location and sequence of HIF binding sites, see, e.g., Schodel, et al., Blood, 2011, 117(23):e207-e217, which is incorporated by reference herein in its entirety. In certain embodiments, the promoter comprises a binding site for a hypoxia induced transcription factor other than a HIF transcription factor. In certain embodiments, the recombinant vectors provided herein comprise one or more IRES sites that is preferentially translated in hypoxia. For teachings regarding hypoxia-inducible gene expression and the factors involved therein, see, e.g., Kenneth and Rocha, Biochem J., 2008, 414:19-29, which is incorporated by reference herein in its entirety.


In certain embodiments, the promoter is a CB7 promoter (see Dinculescu et al., 2005, Hum Gene Ther 16: 649-663, incorporated by reference herein in its entirety). In certain embodiments, the CB7 promoter includes other expression control elements that enhance expression of the therapeutic product driven by the vector, e.g. (1) a CAG promoter; (2) a CBA promoter; (3) a CMV promoter; (4) a 1.7-kb red cone opsin promoter (PR1.7 promoter); (5) a Rhodopsin Kinase (GRK1) photoreceptor-specific enhancer-promoter (Young et al., 2003, Retinal Cell Biology; 44:4076-4085); (6) an hCARp promoter, which is a human cone arrestin promoter; (7) an hRKp, which is a rhodopsin kinase promoter; (8) a cone photoreceptor specific human arrestin 3 (ARR3) promoter; (9) a rhodopsin promoter; and (10) a U6 promoter (in particular when the therapeutic product is a small RNA such as shRNA or siRNA).


In certain embodiments, the other expression control elements include chicken β-actin intron and/or rabbit β-globin polA signal. In certain embodiments, the promoter comprises a TATA box. In certain embodiments, the promoter comprises one or more elements. In certain embodiments, the one or more promoter elements may be inverted or moved relative to one another. In certain embodiments, the elements of the promoter are positioned to function cooperatively. In certain embodiments, the elements of the promoter are positioned to function independently. In certain embodiments, the recombinant vectors provided herein comprise one or more promoters selected from the group consisting of the human CMV immediate early gene promoter, the SV40 early promoter, the Rous sarcoma virus (RS) long terminal repeat, and rat insulin promoter. In certain embodiments, the recombinant vectors provided herein comprise one or more long terminal repeat (LTR) promoters selected from the group consisting of AAV, MLV, MMTV, SV40, RSV, HIV-1, and HIV-2 LTRs. In certain embodiments, the recombinant vectors provided herein comprise one or more tissue specific promoters (e.g., a retinal pigment epithelial cell-specific promoter). In certain embodiments, the recombinant vectors provided herein comprise a RPE65 promoter. In certain embodiments, the recombinant vectors provided herein comprise a VMD2 promoter.


In certain embodiments, the recombinant vectors provided herein comprise one or more regulatory elements other than a promoter. In certain embodiments, the recombinant vectors provided herein comprise an enhancer. In certain embodiments, the recombinant vectors provided herein comprise a repressor. In certain embodiments, the recombinant vectors provided herein comprise an intron or a chimeric intron. In certain embodiments, the recombinant vectors provided herein comprise a polyadenylation sequence.


(e) Signal Peptides

In certain embodiments wherein the therapeutic product is a therapeutic protein, the recombinant vectors provided herein comprise components that modulate protein delivery. In certain embodiments, the recombinant vectors provided herein comprise one or more signal peptides. Signal peptides may also be referred to herein as “leader sequences” or “leader peptides”. In certain embodiments, the signal peptides allow for the therapeutic product to achieve the proper packaging (e.g. glycosylation) in the cell. In certain embodiments, the signal peptides allow for the therapeutic product to achieve the proper localization in the cell. In certain embodiments, the signal peptides allow for the therapeutic product to achieve secretion from the cell. Examples of signal peptides to be used in connection with the recombinant vectors and therapeutic products provided herein may be found in Table 1.









TABLE 1







Signal peptides for use with the vectors provided


herein.









SEQ




ID




NO.
Signal Peptide
Sequence












5
VEGF-A signal peptide
MNFLLSWVHW SLALLLYLHH




AKWSQA





6
Fibulin-1 signal peptide
MERAAPSRRV PLPLLLLGGL




ALLAAGVDA





7
Vitronectin signal
MAPLRPLLIL ALLAWVALA



peptide






8
Complement Factor H
MRLLAKIICLMLWAICVA



signal peptide






9
Opticin signal peptide
MRLLAFLSLL ALVLQETGT





22
Albumin signal peptide
MKWVTFISLLFLFSSAYS





23
Chymotrypsinogen signal
MAFLWLLSCWALLGTTFG



peptide






24
Interleukin-2 signal
MYRMQLLSCIALILALVTNS



peptide






25
Trypsinogen-2 signal
MNLLLILTFVAAAVA



peptide









(f) Polycistronic Messages—IRES and F2A Linkers

Internal ribosome entry sites. A single construct can be engineered to encode two peptides (for example, both the heavy and light chains of an antibody) separated by a cleavable linker or IRES so that the two peptides (for example, separate heavy and light chain polypeptides) are expressed by the transduced cells. In certain embodiments, the recombinant vectors provided herein provide polycistronic (e.g., bicistronic) messages. For example, the recombinant vector can comprise a nucleotide sequence encoding two peptides (for example, the heavy and light chains of an antibody) separated by an internal ribosome entry site (IRES) elements (for example, the use of IRES elements to create bicistronic vectors see, e.g., Gurtu et al., 1996, Biochem. Biophys. Res. Comm. 229(1):295-8, which is herein incorporated by reference in its entirety). IRES elements bypass the ribosome scanning model and begin translation at internal sites. The use of IRES in AAV is described, for example, in Furling et al., 2001, Gene Ther 8(11): 854-73, which is herein incorporated by reference in its entirety. In certain embodiments, the bicistronic message is contained within a recombinant vector with a restraint on the size of the polynucleotide(s) therein. In certain embodiments, the bicistronic message is contained within an AAV virus-based vector (e.g., an AAV8-based vector).


Furin-F2A linkers. In other embodiments, the recombinant vectors provided herein comprise a nucleotide sequence encoding two peptides (for example, the heavy and light chains of an antibody) separated by a cleavable linker such as the self-cleaving furin/F2A (F/F2A) linkers (Fang et al., 2005, Nature Biotechnology 23: 584-590, and Fang, 2007, Mol Ther 15: 1153-9, each of which is incorporated by reference herein in its entirety).


For example, a furin-F2A linker may be incorporated into an expression cassette to separate the coding sequences of the two peptides (for example, the heavy and light chain coding sequences), resulting in a construct with the structure:


Leader—Peptide A (for example, Heavy chain of an antibody)—Furin site—F2A site—Leader—Peptide B (for example, Light chain of an antibody)—PolyA.


The F2A site, with the amino acid sequence LLNFDLLKLAGDVESNPGP (SEQ ID NO: 26) is self-processing, resulting in “cleavage” between the final G and P amino acid residues. Additional linkers that could be used include but are not limited to:









(SEQ ID NO: 27)


T2A: (GSG)E G R G S L L T C G D V E E N P GP;





(SEQ ID NO: 28)


P2A: (GSG)A T N F S L L K Q A G D V E E N P GP;





(SEQ ID NO: 29)


E2A: (GSG)Q C T N Y A L L K L A G D V E S N P GP;





(SEQ ID NO: 30)


F2A: (GSG)V K Q T L N F D L L K L A G D V E S N P






GP.







A peptide bond is skipped when the ribosome encounters the F2A sequence in the open reading frame, resulting in the termination of translation, or continued translation of the downstream sequence (the second peptide). This self-processing sequence results in a string of additional amino acids at the end of the C-terminus of the first peptide. However, such additional amino acids are then cleaved by host cell Furin at the furin sites, located immediately prior to the F2A site and after the sequence of the first peptide, and further cleaved by carboxypeptidases. The resultant first peptide may have one, two, three, or more additional amino acids included at the C-terminus, or it may not have such additional amino acids, depending on the sequence of the Furin linker used and the carboxypeptidase that cleaves the linker in vivo (See, e.g., Fang et al., 17 Apr. 2005, Nature Biotechnol. Advance Online Publication; Fang et al., 2007, Molecular Therapy 15(6):1153-1159; Luke, 2012, Innovations in Biotechnology, Ch. 8, 161-186). Furin linkers that may be used comprise a series of four basic amino acids, for example, RKRR, RRRR, RRKR, or RKKR. Once this linker is cleaved by a carboxypeptidase, additional amino acids may remain, such that an additional zero, one, two, three or four amino acids may remain on the C-terminus of the first peptide, for example, R, RR, RK, RKR, RRR, RRK, RKK, RKRR, RRRR, RRKR, or RKKR. In certain embodiments, one the linker is cleaved by an carboxypeptidase, no additional amino acids remain. In certain embodiments, the furin linker has the sequence R-X-K/R-R, such that the additional amino acids on the C-terminus of the first peptide are R, RX, RXK, RXR, RXKR, or RXRR, where X is any amino acid, for example, alanine (A). In certain embodiments, no additional amino acids may remain on the C-terminus of the first peptide.


In certain embodiments, an expression cassette described herein is contained within a recombinant vector with a restraint on the size of the polynucleotide(s) therein. In certain embodiments, the expression cassette is contained within an AAV virus-based vector (e.g., an AAV8-based vector).


(g) Untranslated Regions

In certain embodiments wherein the therapeutic product is a therapeutic protein, the recombinant vectors provided herein comprise one or more untranslated regions (UTRs), e.g., 3′ and/or 5′ UTRs. In certain embodiments, the UTRs are optimized for the desired level of protein expression. In certain embodiments, the UTRs are optimized for the half-life of the mRNA encoding the therapeutic protein. In certain embodiments, the UTRs are optimized for the stability of the mRNA encoding the therapeutic protein. In certain embodiments, the UTRs are optimized for the secondary structure of the mRNA encoding the therapeutic protein.


(h) Inverted Terminal Repeats

In certain embodiments, the recombinant viral vectors provided herein comprise one or more inverted terminal repeat (ITR) sequences. ITR sequences may be used for packaging the recombinant therapeutic product expression cassette into the virion of the recombinant viral vector. In certain embodiments, the ITR is from an AAV, e.g., AAV8 or AAV2 (see, e.g., Yan et al., 2005, J. Virol., 79(1):364-379; U.S. Pat. No. 7,282,199 B2, U.S. Pat. No. 7,790,449 B2, U.S. Pat. No. 8,318,480 B2, U.S. Pat. No. 8,962,332 B2 and International Patent Application No. PCT/EP2014/076466, each of which is incorporated herein by reference in its entirety).


(i) Therapeutic Product

The therapeutic products can be, for example, therapeutic proteins (for example, antibodies), therapeutic RNAs (for example, shRNAs, siRNAs, and miRNAs), or therapeutic aptamers. Antibodies include, but are not limited to, monoclonal antibodies, polyclonal antibodies, recombinantly produced antibodies, human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-heavy chain pairs, intrabodies, heteroconjugate antibodies, monovalent antibodies, antigen-binding fragments of full-length antibodies, and fusion proteins of the above. Such antigen-binding fragments include, but are not limited to, single-domain antibodies (variable domain of heavy chain antibodies (VHHs) or nanobodies), Fabs, F(ab′)2s, and scFvs (single-chain variable fragments).


In certain embodiments of the methods described herein, the therapeutic product is: (1) anti-human vascular endothelial growth factor (hVEGF) antibody or aptamer; (2) an anti-hVEGF antigen-binding fragment; (3) anti-hVEGF antigen-binding fragment is a Fab, F(ab′)2, or single chain variable fragment (scFv); (4) Palmitoyl-Protein Thioesterase 1 (PPT1); (5) Tripeptidyl-Peptidase 1 (TPP1); (6) Battenin (CLN3); (7) CLN6 Transmembrane ER Protein (CLN6); (8) Major Facilitator Superfamily Domain Containing 8 (MFSD8); (9) Myosin VIIA (MYO7A); (1) Cadherin Related 23 (CDH23); (11) Protocadherin Related 15 (PCDH15); (12) Usherin (USH2A); (13) Clarin 1 (CLRN1); (14) ATP Binding Cassette Subfamily A Member 4 (ABCA4); (15) ELOVL Fatty Acid Elongase 4 (ELOVL4); anti-Interleukin 6 (IL6) monoclonal antibody/aptamer; (16) anti-TNF-alpha (TNF) monoclonal antibody or aptamers; (17) L opsin (OPN1LW); (18) M opsin (OPN1MW); (19) Guanylate Cyclase 2D, Retinal (GUCY2D); (20) Retinoid Isomerohydrolase RPE65 (RPE65); (21) Spermatogenesis Associated 7 (SPATA7); (22) Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1); (23) Lebercilin (LCA5); (24) RPGR Interacting Protein 1 (RPGRIP1); (25) Cone-Rod Homeobox (CRX); (26) Crumbs Cell Polarity Complex Component 1 (CRB1); (27) Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1); (28) Centrosomal Protein 290 (CEP290); (29) Inosine Monophosphate Dehydrogenase 1 (IMPDH1); (3) Retinal Degeneration 3, GUCY2D regulator (RD3); (31) Retinol Dehydrogenase 12 (RDH12); (32) Lecithin Retinol Acyltransferase (LRAT); (33) Tubby Like Protein 1 (TULP1); (34) Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13); (35) Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1); (36) Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4); (37) Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6); (38) anti-complement monoclonal antibody or aptamers, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamer, or preferably an anti-complement C5 antibody and the pathology of the eye is associated with neuromyelitis optica (NMO); (39) an anti-IL6 monoclonal antibody or aptamer and the pathology of the eye is associated with NMO; (40) anti-complement monoclonal antibody or aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (41) Angiotensin I Converting Enzyme (ACE); (42) Interleukin 10 (IL10); (43) anti-TNF monoclonal antibody; (43) Rab Escort Protein 1 (CHM); (44) Retinoschisin (RS1); (45) Bardet-Biedl Syndrome 1 (BBS1); (46) Bardet-Biedl Syndrome 2 (BBS2); (47) ADP Ribosylation Factor Like GTPase 6 (ARL6); (48) Bardet-Biedl Syndrome 4 (BBS4); (49) Bardet-Biedl Syndrome 5 (BBS5); (50) McKusick-Kaufman Syndrome (MKKS); (51) Bardet-Biedl Syndrome 7 (BBS7); (52) Tetratricopeptide Repeat Domain 8 (TTC8); (53) Bardet-Biedl Syndrome 9 (BBS9); (54) Bardet-Biedl Syndrome 10 (BBS10); (55) Tripartite Motif Containing 32 (TRIM32); (56) Bardet-Biedl Syndrome 12 (BBS12); (57) MKS Transition Zone Complex Subunit 1 (MKS1); (58) WD Repeat Containing Planar Cell Polarity Effector (WDPCP); (59) Serologically Defined Colon Cancer Antigen 8 (SDCCAG8); (6) Leucine Zipper Transcription Factor Like 1 (LZTFL1); (61) BBSome Interacting Protein 1 (BBIP1); (62) Intraflagellar Transport 27 (IFT27); (63) Guanylate Cyclase Activator 1A (GUCA1A); (64) OPA1 Mitochondrial Dynamin Like GTPase (OPA1); (65) RP1 Axonemal Microtubule Associated (RP1); (66) RP2 Activator of ARL3 GTPase (RP2); (67) Peripherin 2 (PRPH2); (68) Pre-mRNA Processing Factor 31(PRPF31); (69) Pre-mRNA Processing Factor 8 (PRPF8); (70) Eyes Shut Homolog (EYS); (71) FAM161 Centrosomal Protein A (FAM161A); (72) Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3); (73) MER Proto-Oncogene, Tyrosine Kinase (MERTK); (74) Phosphodiesterase 6B (PDE6B); (75) Prominin 1 (PROM1); (76) Phosphodiesterase 6A (PDE6A); (77) Interphotoreceptor Matrix Proteoglycan 2 (IMPG2); (78) Male Germ Cell Associated Kinase (MAK); (79) Intraflagellar Transport 140 (IFT140); (80) anti-membrane attack complex (MAC) monoclonal antibody; (81) HtrA Serine Peptidase 1 (HTRA1); (82) Bestrophin 1 (BEST1); (83) complement factor B antisense oligonucleotide; (84) anti-beta-amyloid monoclonal antibody; (85) CD59 glycoprotein (CD59); (86) Channelrhodopsin-1 (ChR1); (87) Channelrhodopsin-2 (ChR2), (88) anti-complement factor C5a aptamer or monoclonal antibody; (89) anti-complement factor D monoclonal antibody or aptamers; (90) DnaJ heat shock protein family (Hsp40) member C3 (DNAJC3); (91) beta-2 adrenoceptor siRNA; (92) Caspase-2 (CASP2); (93) Insulin Receptor Substrate 1 (IRS1); (94) HIF-1 Responsive Protein RTP801 (RTP801); (95) Transforming Growth Factor Beta 2 (TGFB2); (96) Brain Derived Neurotrophic Factor (BDNF); (97) Ciliary Neurotrophic Factor (CNTF); (98) Prostaglandin-Endoperoxide Synthase 2 (PTGS2); (99) Prostaglandin F Receptor (PTGFR); (100) hyaluronidase; (101) Pigment Epithelium-Derived Factor (PEDF); (102) Vascular Endothelial Growth Factor (VEGF); (103) Placental Growth Factor (PGF); (104) Myocilin (MYOC); (105) C-C Motif Chemokine Receptor 5 (CCR5) siRNA; (106) anti-CD19 monoclonal antibody or aptamers; (107) Crumbs Cell Polarity Complex Component 2 (CRB2); (108) Histone Deacetylase 4 (HDAC4); (109) Rhodopsin (RHO); (110) Nerve Growth Factor (NGF); (111) Nuclear Factor, Erythroid 2 Like 2 (NRF2); (112) Glutathione S-Transferase PI 1 (GSTP1); (113) Rod-Derived Cone Viability Factor (RDCVF); (114) Retinaldehyde Binding Protein 1 (RLBP1); (115) Double Homeobox 4 (DUX4); (116) NLR Family Pyrin Domain Containing 3 (NLRP3); (117) Spleen Associated Tyrosine Kinase (SYK); (118) Adrenocorticotropic Hormone (ACTH); (119) anti-CD59 monoclonal antibody or aptamers; (120) NOTCH Regulated Ankyrin Repeat Protein (NRARP); (121) Alpha-2-Antiplasmin (A2AP); (122) Plasminogen (PLG); (123) growth hormone; (124) Insulin Like Growth Factor 1 (IGF1); (125) Interleukin 1 Beta (IL1B); (126) Angiotensin I Converting Enzyme 2 (ACE2); (127) anti-integrin oligopeptide; (128) anti-Placental Growth Factor (PGF) monoclonal antibody or aptamer; (129) anti-Insulin-Like Growth Factor 1 Receptor (IGF1R) monoclonal antibody or aptamer; (130) anti-Insulin-Like Growth Factor 2 Receptor (IGF2R) monoclonal antibody or aptamer; (131) RTP801 siRNA; (132) Matrix Metalloproteinase 2 (MMP2) RNAi; (133) G-Protein Coupled Receptor 143 (GPR143); (134) Tyrosinase (TYR); (135) anti-Leucine Rich Repeat And Ig Domain Containing Protein 1 (LINGO1) monoclonal antibody or aptamers; (136) Retinitis Pigmentosa GTPase Regulator (RPGR); (137) Cyclic Nucleotide Gated Channel Beta 3 (CNGB3); (138) Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3); (139) Retinoid Isomerohydrolase RPE65 (RPE65); (14) anti-TNF-alpha (TNF) monoclonal antibody; or (140) Interleukin 10 (IL10).


In certain embodiments of the methods described herein, (1) the pathology of the eye is associated with Batten-CLN1 and the therapeutic product is Palmitoyl-Protein Thioesterase 1 (PPT1); (2) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1); (3) the pathology of the eye is associated with Batten-CLN3 and the therapeutic product is Battenin (CLN3); (4) the pathology of the eye is associated with Batten-CLN6 and the therapeutic product is CLN6 Transmembrane ER Protein (CLN6); (5) the pathology of the eye is associated with Batten-CLN7 and the therapeutic product is Major Facilitator Superfamily Domain Containing 8 (MFSD8); (6) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Myosin VIIA (MYO7A); (7) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Cadherin Related 23 (CDH23); (8) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Protocadherin Related 15 (PCDH15); (9) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Usherin (USH2A); (10) the pathology of the eye is associated with Usher's-Type 3 and the therapeutic product is Clarin 1 (CLRN1); (11) the pathology of the eye is associated with Stargardt's and the therapeutic product is ATP Binding Cassette Subfamily A Member 4 (ABCA4); (12) the pathology of the eye is associated with Stargardt's and the therapeutic product is ELOVL Fatty Acid Elongase 4 (ELOVL4); (13) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-Interleukin 6 (IL6) monoclonal antibody; (14) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF-alpha (TNF) monoclonal antibody; (15) the pathology of the eye is associated with diabetic macular edema (DME) and the therapeutic product is an anti-IL6 monoclonal antibody; (16) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW); (17) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW); (18) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW); (19) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D); (20) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65); (21) the pathology of the eye is associated with LCA 3 and the therapeutic product is Spermatogenesis Associated 7 (SPATA7); (22) the pathology of the eye is associated with Leber congenital amaurosis-4 (LCA 4) and the therapeutic product is Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1); (23) the pathology of the eye is associated with Leber congenital amaurosis-5 (LCA 5) and the therapeutic product is Lebercilin (LCA5); (24) the pathology of the eye is associated with Leber congenital amaurosis-6 (LCA 6) and the therapeutic product is RPGR Interacting Protein 1 (RPGRIP1); (25) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX); (26) the pathology of the eye is associated with Leber congenital amaurosis-8 (LCA 8) and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1) (also known as LCA8); (27) the pathology of the eye is associated with Leber congenital amaurosis-9 (LCA 9) and the therapeutic product is Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1); (28) the pathology of the eye is associated with Leber congenital amaurosis-10 (LCA 10) and the therapeutic product is Centrosomal Protein 290 (CEP290); (29) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1); (30) the pathology of the eye is associated with Leber congenital amaurosis-12 (LCA 12) and the therapeutic product is Retinal Degeneration 3, GUCY2D regulator (RD3); (31) the pathology of the eye is associated with Leber congenital amaurosis-13 (LCA 13) and the therapeutic product is Retinol Dehydrogenase 12 (RDH12); (32) the pathology of the eye is associated with Leber congenital amaurosis-14 (LCA 14) and the therapeutic product is Lecithin Retinol Acyltransferase (LRAT); (33) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1); (34) the pathology of the eye is associated with Leber congenital amaurosis-16 (LCA 16) and the therapeutic product is Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13); (35) the pathology of the eye is associated with Leber's hereditary optic neuropathy (LHON) and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1); (36) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4); (37) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6); (38) the pathology of the eye is associated with neuromyelitis optica (NMO) and the therapeutic product is an anti-complement antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamer, or preferably an anti-complement C5 antibody; (39) the pathology of the eye is associated with NMO and the therapeutic product is an anti-IL6 monoclonal antibody or aptamer; (40) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement monoclonal antibody or aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (41) the pathology of the eye is associated with uveitis and the therapeutic product is Angiotensin I Converting Enzyme (ACE); (42) the pathology of the eye is associated with uveitis and the therapeutic product is Interleukin 10 (IL10); (43) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF monoclonal antibody; (44) the pathology of the eye is associated with choroideremia and the therapeutic product is Rab Escort Protein 1 (CHM); (45) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1); (46) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1); (47) the pathology of the eye is associated with Bardet-Biedl syndrome 2 and the therapeutic product is Bardet-Biedl Syndrome 2 (BBS2); (48) the pathology of the eye is associated with Bardet-Biedl syndrome 3 and the therapeutic product is ADP Ribosylation Factor Like GTPase 6 (ARL6) (also known as BBS3); (49) the pathology of the eye is associated with Bardet-Biedl syndrome 4 and the therapeutic product is Bardet-Biedl Syndrome 4 (BBS4); (50) the pathology of the eye is associated with Bardet-Biedl syndrome 5 and the therapeutic product is Bardet-Biedl Syndrome 5 (BBS5); (51) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS), also known as BBS6; (52) the pathology of the eye is associated with Bardet-Biedl syndrome 7 and the therapeutic product is Bardet-Biedl Syndrome 7 (BBS7); (53) the pathology of the eye is associated with Bardet-Biedl syndrome 8 and the therapeutic product is Tetratricopeptide Repeat Domain 8 (TTC8), also known as BBS8; (54) the pathology of the eye is associated with Bardet-Biedl syndrome 9 and the therapeutic product is Bardet-Biedl Syndrome 9 (BBS9); (55) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10); (56) the pathology of the eye is associated with Bardet-Biedl syndrome 11 and the therapeutic product is Tripartite Motif Containing 32 (TRIM32), also known as BBS11; (57) the pathology of the eye is associated with Bardet-Biedl syndrome 12 and the therapeutic product is Bardet-Biedl Syndrome 12 (BBS12); (58) the pathology of the eye is associated with Bardet-Biedl syndrome 13 and the therapeutic product is MKS Transition Zone Complex Subunit 1 (MKS1), also known as BBS13; (59) the pathology of the eye is associated with Bardet-Biedl syndrome 14 and the therapeutic product is Centrosomal Protein 290 (CEP290), also known as BBS14 and LCA10; (60) the pathology of the eye is associated with Bardet-Biedl syndrome 15 and the therapeutic product is WD Repeat Containing Planar Cell Polarity Effector (WDPCP), also known as BBS15; (61) the pathology of the eye is associated with Bardet-Biedl syndrome 16 and the therapeutic product is Serologically Defined Colon Cancer Antigen 8 (SDCCAG8), also known as BBS16; (62) the pathology of the eye is associated with Bardet-Biedl syndrome 17 and the therapeutic product is Leucine Zipper Transcription Factor Like 1 (LZTFL1), also known as BBS17; (63) the pathology of the eye is associated with Bardet-Biedl syndrome 18 and the therapeutic product is BBSome Interacting Protein 1 (BBIP1), also known as BBS18; (64) the pathology of the eye is associated with Bardet-Biedl syndrome 19 and the therapeutic product is Intraflagellar Transport 27 (IFT27), also known as BBS19; (65) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A); (66) the pathology of the eye is associated with optic atrophy and the therapeutic product is OPA1 Mitochondrial Dynamin Like GTPase (OPA1); (67) the pathology of the eye is associated with retinitis pigmentosa 1 and the therapeutic product is RP1 Axonemal Microtubule Associated (RP1); (68) the pathology of the eye is associated with retinitis pigmentosa 2 and the therapeutic product is RP2 Activator of ARL3 GTPase (RP2); (69) the pathology of the eye is associated with retinitis pigmentosa 7 and the therapeutic product is Peripherin 2 (PRPH2); (70) the pathology of the eye is associated with retinitis pigmentosa 11 and the therapeutic product is Pre-mRNA Processing Factor 31(PRPF31); (71) the pathology of the eye is associated with retinitis pigmentosa 12 and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1), also known as LCA8; (72) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8); (73) the pathology of the eye is associated with retinitis pigmentosa 25 and the therapeutic product is Eyes Shut Homolog (EYS); (74) the pathology of the eye is associated with retinitis pigmentosa 28 and the therapeutic product is FAM161 Centrosomal Protein A (FAM161A); (75) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3); (76) the pathology of the eye is associated with retinitis pigmentosa 38 and the therapeutic product is MER Proto-Oncogene, Tyrosine Kinase (MERTK); (77) the pathology of the eye is associated with retinitis pigmentosa 40 and the therapeutic product is Phosphodiesterase 6B (PDE6B); (78) the pathology of the eye is associated with retinitis pigmentosa 41 and the therapeutic product is Prominin 1 (PROM1); (79) the pathology of the eye is associated with retinitis pigmentosa 43 and the therapeutic product is Phosphodiesterase 6A (PDE6A); (80) the pathology of the eye is associated with retinitis pigmentosa 56 and the therapeutic product is Interphotoreceptor Matrix Proteoglycan 2 (IMPG2); (81) the pathology of the eye is associated with petinitis pigmentosa 62 and the therapeutic product is Male Germ Cell Associated Kinase (MAK); (82) the pathology of the eye is associated with retinitis pigmentosa 80 and the therapeutic product is Intraflagellar Transport 140 (IFT140); (83) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-complement monoclonal antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or an anti-complement aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (84) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-membrane attack complex (MAC) therapeutic product, preferably the anti-MAC therapeutic product is an anti-MAC monoclonal antibody, which is a monoclonal antibody against a human protein of the membrane attack complex, which is composed of four complement proteins C5b (SEQ ID NOs. 314-316), C6 (SEQ ID NO. 317), C7 (SEQ ID NO. 318), and C8 (SEQ ID NOs. 319-321); (85) the pathology of the eye is associated with dry AMD and the therapeutic product is HtrA Serine Peptidase 1 (HTRA1); (86) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1); (87) the pathology of the eye is associated with dry AMD and the therapeutic product is a complement factor B antisense oligonucleotide; (88) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-beta-amyloid monoclonal antibody; (89) the pathology of the eye is associated with dry AMD and the therapeutic product is CD59 glycoprotein (CD59); (90) the pathology of the eye is associated with dry AMD and the therapeutic product is Channelrhodopsin-1 (ChR1), which includes the human homolog of ChR1; (91) the pathology of the eye is associated with dry AMD and the therapeutic product is Channelrhodopsin-2 (ChR2), which includes the human homolog of ChR2; (92) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-complement monoclonal antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or an anti-complement aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (93) the pathology of the eye is associated with dry AMD and the therapeutic product is anti-complement factor D therapeutic product, including but not limited to an anti-complement factor D monoclonal antibody, or an anti-complement factor D aptamer; (94) the pathology of the eye is associated with age-related retinal ganglion cell (RGC) degeneration and the therapeutic product is DnaJ heat shock protein family (Hsp40) member C3 (DNAJC3), also known as P58IPK; (95) the pathology of the eye is associated with blue cone monochromacy (BCM) and the therapeutic product is L opsin (OPN1LW); (96) the pathology of the eye is associated with glaucoma and the therapeutic product is beta-2 adrenoceptor siRNA; (97) the pathology of the eye is associated with glaucoma and the therapeutic product is Caspase-2 (CASP2); (98) the pathology of the eye is associated with glaucoma and the therapeutic product is Insulin Receptor Substrate 1 (IRS1); (99) the pathology of the eye is associated with glaucoma and the therapeutic product is HIF-1 Responsive Protein RTP801 (RTP801); (100) the pathology of the eye is associated with glaucoma and the therapeutic product is Transforming Growth Factor Beta 2 (TGFB2); (101) the pathology of the eye is associated with glaucoma and the therapeutic product is Brain Derived Neurotrophic Factor (BDNF); (102) the pathology of the eye is associated with glaucoma and the therapeutic product is Ciliary Neurotrophic Factor (CNTF); (103) the pathology of the eye is associated with glaucoma and the therapeutic product is Prostaglandin-Endoperoxide Synthase 2 (PTGS2); (104) the pathology of the eye is associated with glaucoma and the therapeutic product is Prostaglandin F Receptor (PTGFR) (when the pathology of the eye is associated with glaucoma, in a specific embodiment, a recombinant viral vector comprising a nucleotide sequence encoding PTGFR can be administered to the human subject in combination with a recombinant viral vector comprising a nucleotide sequence encoding PTGS2; in another specific embodiment, a recombinant viral vector comprising a nucleotide sequence encoding PTGFR and a nucleotide sequence encoding PTGS2 can be administered to the human subject); (105) the pathology of the eye is associated with glaucoma and the therapeutic product is a hyaluronidase, e.g. HYAL1, HYAL2, HYAL3, HYAL4, and HYAL5; (106) the pathology of the eye is associated with glaucoma and the therapeutic product is Pigment Epithelium-Derived Factor (PEDF); (107) the pathology of the eye is associated with glaucoma and the therapeutic product is Vascular Endothelial Growth Factor (VEGF); (108) the pathology of the eye is associated with glaucoma and the therapeutic product is Placental Growth Factor (PGF), wherein PGF can be used in combo with VEGF; (109) the pathology of the eye is associated with glaucoma (e.g., a congenital glaucoma or juvenile glaucoma) and the therapeutic product is Myocilin (MYOC); (110) the pathology of the eye is associated with NMO and the therapeutic product is an anti-complement C5 monoclonal antibody; (111) the pathology of the eye is associated with NMO and the therapeutic product is C-C Motif Chemokine Receptor 5 (CCR5) siRNA, CCR5 shRNA, siRNA or CCR5 miRNA (preferably, a CCR5 miRNA); (112) the pathology of the eye is associated with NMO and the therapeutic product is an anti-CD19 monoclonal antibody; (113) the pathology of the eye is associated with retinitis pigmentosa that is associated with rhodopsin mutations and the therapeutic product is Channelrhodopsin-1 (ChR1), which includes the human homolog of ChR1; (114) the pathology of the eye is associated with retinitis pigmentosa that is associated with rhodopsin mutations and the therapeutic product is Channelrhodopsin-2 (ChR2), which includes the human homolog of ChR2; (115) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Ciliary Neurotrophic Factor (CNTF); (116) the pathology of the eye is associated with autosomal recessive retinitis pigmentosa and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1); (117) the pathology of the eye is associated with autosomal recessive retinitis pigmentosa and the therapeutic product is Crumbs Cell Polarity Complex Component 2 (CRB2); (118) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Histone Deacetylase 4 (HDAC4); (119) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rhodopsin (RHO); (120) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Nerve Growth Factor (NGF); (121) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Nuclear Factor, Erythroid 2 Like 2 (NRF2); (122) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Pigment Epithelium-Derived Factor (PEDF); (123) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Glutathione S-Transferase PI 1 (GSTP1), also known as PI; (124) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rod-Derived Cone Viability Factor (RDCVF); (125) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rhodopsin (RHO); (126) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Retinaldehyde Binding Protein 1 (RLBP1); (127) the pathology of the eye is associated with Stargardt's disease and the therapeutic product is an anti-complement C5 aptamer; (128) the pathology of the eye is associated with uveitis and the therapeutic product is Double Homeobox 4 (DUX4); (129) the pathology of the eye is associated with uveitis and the therapeutic product is NLR Family Pyrin Domain Containing 3 (NLRP3); (130) the pathology of the eye is associated with uveitis and the therapeutic product is Spleen Associated Tyrosine Kinase (SYK); (131) the pathology of the eye is associated with uveitis and the therapeutic product is Adrenocorticotropic Hormone (ACTH); (132) the pathology of the eye is associated with uveitis and the therapeutic product is Caspase 1 (CASP1); (133) the pathology of the eye is associated with uveitis and the therapeutic product is anti-CD59 therapeutic product (such as an anti-CD59 therapeutic protein (for example, an anti-CD59 monoclonal antibody), or an anti-CD59 therapeutic RNA (for example, an anti-CD59 shRNA, anti-CD59 siRNA, or anti-CD59 miRNA), preferably an anti-CD59 monoclonal antibody); (134) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement monoclonal antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (135) the pathology of the eye is associated with corneal neovascularization and the therapeutic product is Insulin Receptor Substrate 1 (IRS1); (136) the pathology of the eye is associated with corneal neovascularization and the therapeutic product is NOTCH Regulated Ankyrin Repeat Protein (NRARP); (137) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is NOTCH Regulated Ankyrin Repeat Protein (NRARP); (138) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Alpha-2-Antiplasmin (A2AP); (139) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Plasminogen (PLG); (140) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product can be a growth hormone; (141) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Insulin Like Growth Factor 1 (IGF1), wherein IGF1 can be used in combo with growth hormone; (142) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Interleukin 1 Beta (IL1B). (143) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Angiotensin I Converting Enzyme 2 (ACE2), wherein ACE2 can be used in combo with IL1B; (144) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is IRS1; (145) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is an anti-integrin oligopeptide; (146) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is an anti-Placental Growth Factor (PGF) monoclonal antibody; (147) the pathology of the eye is associated with Graves' ophthalmopathy (also known as Graves' orbitopathy) and the therapeutic product is an anti-CD40 monoclonal antibody; (148) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-Insulin-Like Growth Factor 1 Receptor (IGF1R) monoclonal antibody; (149) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-Insulin-Like Growth Factor 2 Receptor (IGF2R) monoclonal antibody; (150) the pathology of the eye is associated with DME and the therapeutic product is an anti-integrin oligopeptide; (151) the pathology of the eye is associated with DME and the therapeutic product is an anti-Placental Growth Factor (PGF) monoclonal antibody; (152) the pathology of the eye is associated with DME and the therapeutic product is RTP801 siRNA; (153) the pathology of the eye is associated with multiple sclerosis (MS)-associated vision loss and the therapeutic product is ND1; (154) the pathology of the eye is associated with myopia and the therapeutic product is Matrix Metalloproteinase 2 (MMP2) RNAi; (155) the pathology of the eye is associated with X-linked recessive ocular albinism and the therapeutic product is G-Protein Coupled Receptor 143 (GPR143); (156) the pathology of the eye is associated with oculocutaneous albinism type 1 and the therapeutic product is Tyrosinase (TYR); (157) the pathology of the eye is associated with optic neuritis and the therapeutic product is Caspase 2 (CASP2); (158) the pathology of the eye is associated with optic neuritis and the therapeutic product is an anti-Leucine Rich Repeat And Ig Domain Containing Protein 1 (LINGO1) monoclonal antibody; or (159) the pathology of the eye is associated with polypoidal choroidal vasculopathy and the therapeutic product is anti-complement monoclonal antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody/aptamer, an anti-complement C1s monoclonal antibody/aptamer, an anti-complement C2 monoclonal antibody/aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody.


In certain embodiments of the methods described herein, the pathology of the eye is associated with X-linked retinitis pigmentosa (XLRP) and the therapeutic product is Retinitis Pigmentosa GTPase Regulator (RPGR). In certain embodiments of any of the foregoing methods, the pathology of the eye is associated with achromatopsia (ACHM) and the therapeutic product is Cyclic Nucleotide Gated Channel Beta 3 (CNGB3). In certain embodiments of any of the foregoing methods, the pathology of the eye is associated with achromatopsia (for example, a CNGA3-linked achromatopsia) and the therapeutic product is Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3). In certain embodiments of any of the foregoing methods, the pathology of the eye is associated with biallelic RPE65 mutation-associated retinal dystrophy and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65).


In certain embodiments of the methods described herein, (1) the pathology of the eye is associated with Batten-CLN1 and the therapeutic product is Palmitoyl-Protein Thioesterase 1 (PPT1); (2) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1); (3) the pathology of the eye is associated with Batten-CLN3 and the therapeutic product is Battenin (CLN3); (4) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-Interleukin 6 (IL6) monoclonal antibody; (5) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF-alpha (TNF) monoclonal antibody; (6) the pathology of the eye is associated with diabetic macular edema (DME) and the therapeutic product is an anti-IL6 monoclonal antibody; (7) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW); (8) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW); (9) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW); (10) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D); (11) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65); (12) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX); (13) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1); (14) the pathology of the eye is associated with Leber congenital amaurosis-12 (LCA 12) and the therapeutic product is Retinal Degeneration 3, GUCY2D regulator (RD3); (15) the pathology of the eye is associated with Leber congenital amaurosis-13 (LCA 13) and the therapeutic product is Retinol Dehydrogenase 12 (RDH12); (16) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1); (17) the pathology of the eye is associated with Leber congenital amaurosis-16 (LCA 16) and the therapeutic product is Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13); (18) the pathology of the eye is associated with Leber's hereditary optic neuropathy (LHON) and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1); (19) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4); (20) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6); (21) the pathology of the eye is associated with neuromyelitis optica (NMO) and the therapeutic product is an anti-complement monoclonal antibody or an anti-complement aptamer, wherein the anti-complement monoclonal antibody or aptamer is an anti-complement C1 monoclonal antibody or aptamer, an anti-complement C1q monoclonal antibody or aptamer, an anti-complement C1s monoclonal antibody or aptamer, an anti-complement C2 monoclonal antibody or aptamer, an anti-complement C2a monoclonal antibody or aptamer, an anti-complement C2b monoclonal antibody or aptamer, an anti-complement C3 monoclonal antibody or aptamer, an anti-complement C3a monoclonal antibody or aptamer, an anti-complement C3b monoclonal antibody or aptamer, an anti-complement C4 monoclonal antibody or aptamer, an anti-complement C4a monoclonal antibody or aptamer, an anti-complement C4b monoclonal antibody or aptamer, an anti-complement C5 monoclonal antibody or aptamer, an anti-complement C5a monoclonal antibody or aptamer, an anti-complement C5b monoclonal antibody or aptamer, an anti-complement C6 monoclonal antibody or aptamer, an anti-complement C7 monoclonal antibody or aptamer, an anti-complement C8 monoclonal antibody or aptamer, or an anti-complement C9 monoclonal antibody or aptamers, or preferably an anti-complement C5 antibody; (22) the pathology of the eye is associated with NMO and the therapeutic product is an anti-IL6 monoclonal antibody; (23) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement C5 monoclonal antibody; (24) the pathology of the eye is associated with uveitis and the therapeutic product is Angiotensin I Converting Enzyme (ACE); (25) the pathology of the eye is associated with uveitis and the therapeutic product is Interleukin 10 (IL10); (26) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF monoclonal antibody; (27) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1); (28) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1); (29) the pathology of the eye is associated with Bardet-Biedl syndrome 3 and the therapeutic product is ADP Ribosylation Factor Like GTPase 6 (ARL6); (30) the pathology of the eye is associated with Bardet-Biedl syndrome 5 and the therapeutic product is Bardet-Biedl Syndrome 5 (BBS5); (31) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS); (32) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10); (33) the pathology of the eye is associated with Bardet-Biedl syndrome 11 and the therapeutic product is Tripartite Motif Containing 32 (TRIM32); (34) the pathology of the eye is associated with Bardet-Biedl syndrome 13 and the therapeutic product is MKS Transition Zone Complex Subunit 1 (MKS1); (35) the pathology of the eye is associated with Bardet-Biedl syndrome 18 and the therapeutic product is BBSome Interacting Protein 1 (BBIP1); (36) the pathology of the eye is associated with Bardet-Biedl syndrome 19 and the therapeutic product is Intraflagellar Transport 27 (IFT27); (37) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A); (38) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8); (39) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3); or (40) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1).


In certain embodiments of the methods described herein, the pathology of the eye is associated with biallelic RPE65 mutation-associated retinal dystrophy and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65).


In certain embodiments of the methods described herein, (1) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1); (2) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Myosin VIIA (MYO7A); (3) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Cadherin Related 23 (CDH23); (4) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Protocadherin Related 15 (PCDH15); (5) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Usherin (USH2A); (6) the pathology of the eye is associated with Usher's-Type 3 and the therapeutic product is Clarin 1 (CLRN1); (7) the pathology of the eye is associated with Stargardt's and the therapeutic product is ATP Binding Cassette Subfamily A Member 4 (ABCA4); (8) the pathology of the eye is associated with Stargardt's and the therapeutic product is ELOVL Fatty Acid Elongase 4 (ELOVL4); (9) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW); (10) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW); (11) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW); (12) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D); (13) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65); (14) the pathology of the eye is associated with Leber congenital amaurosis-4 (LCA 4) and the therapeutic product is Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1); (15) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX); (16) the pathology of the eye is associated with Leber congenital amaurosis-8 (LCA 8) and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1); (17) the pathology of the eye is associated with Leber congenital amaurosis-9 (LCA 9) and the therapeutic product is Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1); (18) the pathology of the eye is associated with Leber congenital amaurosis-10 (LCA 10) and the therapeutic product is Centrosomal Protein 290 (CEP290); (19) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1); (20) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1); (21) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4); (22) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6); (23) the pathology of the eye is associated with choroideremia and the therapeutic product is Rab Escort Protein 1 (CHM); (24) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1); (25) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1); (26) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS); (27) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10); (28) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A); (29) the pathology of the eye is associated with optic atrophy and the therapeutic product is OPA1 Mitochondrial Dynamin Like GTPase (OPA1); (30) the pathology of the eye is associated with retinitis pigmentosa 1 and the therapeutic product is RP1 Axonemal Microtubule Associated (RP1); (31) the pathology of the eye is associated with retinitis pigmentosa 2 and the therapeutic product is RP2 Activator of ARL3 GTPase (RP2); (32) the pathology of the eye is associated with retinitis pigmentosa 7 and the therapeutic product is Peripherin 2 (PRPH2); (33) the pathology of the eye is associated with retinitis pigmentosa 11 and the therapeutic product is Pre-mRNA Processing Factor 31(PRPF31); (34) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8); (35) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3); (36) the pathology of the eye is associated with retinitis pigmentosa 38 and the therapeutic product is MER Proto-Oncogene, Tyrosine Kinase (MERTK); (37) the pathology of the eye is associated with retinitis pigmentosa 40 and the therapeutic product is Phosphodiesterase 6B (PDE6B); (38) the pathology of the eye is associated with retinitis pigmentosa 41 and the therapeutic product is Prominin 1 (PROM1); (39) the pathology of the eye is associated with retinitis pigmentosa 56 and the therapeutic product is Interphotoreceptor Matrix Proteoglycan 2 (IMPG2); (40) the pathology of the eye is associated with petinitis pigmentosa 62 and the therapeutic product is Male Germ Cell Associated Kinase (MAK); (41) the pathology of the eye is associated with retinitis pigmentosa 80 and the therapeutic product is Intraflagellar Transport 140 (IFT140); or (42) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1).


In certain embodiments of the methods described herein, the pathology of the eye is associated with X-linked retinitis pigmentosa (XLRP) and the therapeutic product is Retinitis Pigmentosa GTPase Regulator (RPGR). In certain embodiments of any of the foregoing methods, the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Beta 3 (CNGB3); or achromatopsia (for example, a CNGA3-linked achromatopsia) and the therapeutic product is Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3).


In certain embodiments of the methods described herein, the therapeutic product is a protein, or the therapeutic product is an antibody against a protein, which protein has at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 52-321 provided in Section 7. In a specific embodiment of the methods described herein, the therapeutic product is a protein, or the therapeutic product is an antibody against a protein, which protein has 100% sequence identity to an amino acid sequence selected from SEQ ID NOs: 52-321 provided in Section 7.


(j) Constructs

In certain embodiments of the methods described herein, the recombinant vectors provided herein comprise the following elements in the following order: a) a constitutive or a hypoxia-inducible promoter sequence, and b) a sequence encoding the therapeutic product. In certain embodiments, the sequence encoding the therapeutic product comprises multiple ORFs separated by IRES elements. In certain embodiments, the sequence encoding the therapeutic product comprises multiple subunits in one ORF separated by F/F2A sequences.


In certain embodiments of the methods described herein, the recombinant vectors provided herein comprise the following elements in the following order: a) a first ITR sequence, b) a first linker sequence, c) a constitutive or a hypoxia-inducible promoter sequence, d) a second linker sequence, e) an intron sequence, f) a third linker sequence, g) a first UTR sequence, h) a sequence encoding the therapeutic product, i) a second UTR sequence, j) a fourth linker sequence, k) a poly A sequence, 1) a fifth linker sequence, and m) a second ITR sequence.


(k) Manufacture and Testing of Vectors

The recombinant vectors (for example, recombinant viral vectors) provided herein may be manufactured using host cells. The recombinant vectors provided herein may be manufactured using mammalian host cells, for example, A549, WEHI, 10T1/2, BHK, MDCK, COS 1, COST, BSC 1, BSC 40, BMT 10, VERO, W138, HeLa, 293, Saos, C2C12, L, HT1080, HepG2, primary fibroblast, hepatocyte, and myoblast cells. The recombinant vectors provided herein may be manufactured using host cells from human, monkey, mouse, rat, rabbit, or hamster.


For recombinant viral vectors, the host cells are stably transformed with the sequences encoding the therapeutic product and associated elements (i.e., the vector genome), and the means of producing viruses in the host cells, for example, the replication and capsid genes (e.g., the rep and cap genes of AAV). For a method of producing recombinant AAV vectors with AAV8 capsids, see Section IV of the Detailed Description of U.S. Pat. No. 7,282,199 B2, which is incorporated herein by reference in its entirety. Genome copy titers of said vectors may be determined, for example, by TAQMAN® analysis. Virions may be recovered, for example, by CsCl2 sedimentation.


In vitro assays, e.g., cell culture assays, can be used to measure therapeutic product expression from a vector described herein, thus indicating, e.g., potency of the vector. For example, the PER.C6® Cell Line (Lonza), a cell line derived from human embryonic retinal cells, or retinal pigment epithelial cells, e.g., the retinal pigment epithelial cell line hTERT RPE-1 (available from ATCC®), can be used to assess therapeutic product expression. Once expressed, characteristics of the expressed therapeutic product can be determined, including determination of the post-translational modification patterns. In addition, benefits resulting from post-translational modification of the cell-expressed therapeutic product can be determined using assays known in the art.


(l) Compositions

Compositions are described comprising a recombinant vector encoding a therapeutic product described herein and a suitable carrier. A suitable carrier (e.g., for suprachoroidal, subretinal, juxtascleral, intravitreal, subconjunctival, and/or intraretinal administration) would be readily selected by one of skill in the art.


6.1.3 Gene Therapy


Methods are described for the administration of a therapeutically effective amount of a recombinant vector (i.e., a recombinant viral vector or a DNA expression construct) to human subjects having pathology of the eye. In particular, methods are described for the administration of a therapeutically effective amount of a recombinant vector (i.e., a recombinant viral vector or a DNA expression construct) to human subjects via one of the following approaches: (1) subretinal administration without vitrectomy (for example, administration to subretinal space via the suprachoroidal space or via peripheral injection), (2) suprachoroidal administration, (3) administration to the outer space of the sclera (i.e., juxtascleral administration); (4) subretinal administration accompanied by vitrectomy; (5) intravitreal administration, and (6) subconjunctival administration.


In certain embodiments, delivery to the subretinal or suprachoroidal space can be performed using the methods and/or devices described and disclosed in International Publication Nos. WO 2016/042162, WO 2017/046358, WO 2017/158365, and WO 2017/158366, each of which is incorporated by reference in its entirety.


(a) Target Patient Populations

In certain embodiments of the methods described herein, the methods provided herein are for the administration to patients having a pathology of the eye associated with: (1) neovascular age-related macular degeneration (nAMD); (2) dry age-related macular degeneration (dry AMD); (3) retinal vein occlusion (RVO) diabetic macular edema (DME); (4) diabetic retinopathy (DR); (5) Batten-CLN1; (6) Batten-CLN2; (7) Batten-CLN3; (8) Batten-CLN6; (8) Batten-CLN7; (9) Usher's-Type 1; (10) Usher's-Type 2; (11) Usher's-Type 3; (12) Stargardt's disease; (13) uveitis; (14) red-green color blindness; (15) blue cone monochromacy; (16) Leber congenital amaurosis-1 (LCA 1); (17) Leber congenital amaurosis-2 (LCA 2); (18)) Leber congenital amaurosis-3 (LCA 3); (19) Leber congenital amaurosis-4 (LCA 4); (20) Leber congenital amaurosis-5 (LCA 5); (21) Leber congenital amaurosis-6 (LCA 6); (22) Leber congenital amaurosis-7 (LCA 7); (23) Leber congenital amaurosis-8 (LCA 8); (24) Leber congenital amaurosis-9 (LCA 9); (25) Leber congenital amaurosis-10 (LCA 10); (26) Leber congenital amaurosis-11 (LCA 11); (27) Leber congenital amaurosis-12 (LCA 12); (28) Leber congenital amaurosis-13 (LCA 13); (29) Leber congenital amaurosis-14 (LCA 14); (30) Leber congenital amaurosis-15 (LCA 15); (30) Leber congenital amaurosis-16 (LCA 16); (31) Leber's hereditary optic neuropathy (LHON); (31) neuromyelitis optica (WO); (32) choroideremia; (33) X-linked retinoschisis (XLRS); (34) Bardet-Biedl syndrome 1; (35) Bardet-Biedl syndrome 2; (36) Bardet-Biedl syndrome 3; (37) Bardet-Biedl syndrome 4; (38) Bardet-Biedl syndrome 5; (39) Bardet-Biedl syndrome 6; (40) Bardet-Biedl syndrome 7; (41) Bardet-Biedl syndrome 8; (42) Bardet-Biedl syndrome 9; (43) Bardet-Biedl syndrome 10; (44) Bardet-Biedl syndrome 11; (45) Bardet-Biedl syndrome 12; (46) Bardet-Biedl syndrome 13; (47) Bardet-Biedl syndrome 14; (48) Bardet-Biedl syndrome 15; (49) Bardet-Biedl syndrome 16; (50) Bardet-Biedl syndrome 17; (51) Bardet-Biedl syndrome 18; (52) Bardet-Biedl syndrome 19; (53) cone dystrophy; (54) optic atrophy; (55) retinitis pigmentosa 1; (56) retinitis pigmentosa 2; (57) retinitis pigmentosa 7; (58) retinitis pigmentosa 11; (58) retinitis pigmentosa 12; (59) retinitis pigmentosa 13; (60) retinitis pigmentosa 25; (61) retinitis pigmentosa 28; (62) retinitis pigmentosa 37; (63) retinitis pigmentosa 38; (64) retinitis pigmentosa 40; (65) retinitis pigmentosa 41 (66) retinitis pigmentosa 43; (67) retinitis pigmentosa 56; (68) petinitis pigmentosa 62; (69) retinitis pigmentosa 80; (70) age-related retinal ganglion cell (RGC) degeneration; (71) Best disease; (72) glaucoma; (73) retinitis pigmentosa that is associated with rhodopsin mutations; (74) retinitis pigmentosa; (75) autosomal recessive retinitis pigmentosa; (76) corneal neovascularization; (77) diabetic retinopathy; (78) Graves' ophthalmopathy; (79) multiple sclerosis (MS)-associated vision loss; (80) myopia; (81) X-linked recessive ocular albinism; (82) oculocutaneous albinism type 1; (83) optic neuritis; (84) polypoidal choroidal vasculopathy; (85) X-linked retinitis pigmentosa (XLRP); (86) achromatopsia (ACHM); or (87) biallelic RPE65 mutation-associated retinal dystrophy.


In certain embodiments of the methods described herein, the human subject has a BCVA that is ≤20/20 and ≥20/400. In another specific embodiment, the human subject has a BCVA that is ≤20/63 and ≥20/400. [00152] In certain embodiments, the subject treated in accordance with the methods described herein is female. In certain embodiments, the subject treated in accordance with the methods described herein is male. In certain embodiments, the subject treated in accordance with the methods described herein is a child. In certain embodiments, the subject treated in accordance with the methods described herein is 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. In certain embodiments, the subject treated in accordance with the methods described herein is less than 1.5 months old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or less than 5 years old. In another specific embodiment, the subject treated in accordance with the methods described herein is 1-2 months old, 2-3 months old, 3-4 months old, 4-5 months old, 5-6 months old, 6-7 months old, 7-8 months old, 8-9 months old, 9-10 months old, 10-11 months old, 11 months to 1 year old, 1-1.5 years old, 1.5-2 years old, 2-2.5 years old, 2.5-3 years old, 3-3.5 years old, 3.5-4 years old, 4-4.5 years old, or 4.5-5 years old. In another specific embodiment, the subject treated in accordance with the methods described herein is 6 months to 5 years old.


(b) Dosage and Mode of Administration

In certain embodiments of the method described herein, therapeutically effective doses of the recombinant vector are administered (1) to the subretinal space without vitrectomy (e.g., via the suprachoroidal space or via peripheral injection), (2) to the suprachoroidal space, (3) to the outer space of the sclera (i.e., juxtascleral administration), (4) to the subretinal space via vitrectomy, or (5) to the vitreous cavity, in a volume ranging from 50-100 μl or 100-500 μl, preferably 100-300 μl, and most preferably, 250 μl, depending on the administration method. In certain embodiments, therapeutically effective doses of the recombinant vector are administered suprachoroidally in a volume of 100 μl or less, for example, in a volume of 50-100 μl. In certain embodiments, therapeutically effective doses of the recombinant vector are administered to the outer surface of the sclera (e.g., by a posterior juxtascleral depot procedure) in a volume of 500 μl or less, for example, in a volume of 10-20 μl 20-50 μl 50-100 μl 100-200 μl 200-300 μl, 300-400 μl, or 400-500 μl. In certain embodiments, therapeutically effective doses of the recombinant vector are administered to the subretinal space via peripheral injection in a volume of 50-100 μl or 100-500 preferably 100-300 μl and most preferably, 250 μl.


In certain embodiment, described herein is an micro volume injector delivery system, which is manufactured by Altaviz (see FIGS. 7A and 7B) (see, e.g. International Patent Application Publication No. WO 2013/177215, United States Patent Application Publication No. 2019/0175825, and United States Patent Application Publication No. 2019/0167906) that can be used for any administration route described herein for eye administration. The micro volume injector delivery system may include a gas-powered module providing high force delivery and improved precision, as described in United States Patent Application Publication No. 2019/0175825 and United States Patent Application Publication No. 2019/0167906. In addition, the micro volume injector delivery system may include a hydraulic drive for providing a consistent dose rate, and a low-force activation lever for controlling the gas-powered module and, in turn, the fluid delivery.


In certain embodiment, the micro volume injector delivery system can be used for micro volume injector is a micro volume injector with dose guidance and can be used with, for example, a suprachoroidal needle (for example, the Clearside® needle), a subretinal needle, an intravitreal needle, a juxtascleral needle, a subconjunctival needle, and/or intraretinal needle. The benefits of using micro volume injector include: (a) more controlled delivery (for example, due to having precision injection flow rate control and dose guidance), (b) single surgeon, single hand, one finger operation; (c) pneumatic drive with 10 μL increment dosage; (d) divorced from the vitrectomy machine; (e) 400 μL syringe dose; (f) digitally guided delivery; (g) digitally recorded delivery; and (h) agnostic tip (for example, the MedOne 38 g needle and the Dorc 41 g needle can be used for subretinal delivery, while the Clearside® needle and the Visionisti OY adaptor can be used for subretinal delivery).


In certain embodiments of the methods described herein, the recombinant vector is administered suprachoroidally (e.g., by suprachoroidal injection). In a specific embodiment, suprachoroidal administration (e.g., an injection into the suprachoroidal space) is performed using a suprachoroidal drug delivery device. Suprachoroidal drug delivery devices are often used in suprachoroidal administration procedures, which involve administration of a drug to the suprachoroidal space of the eye (see, e.g., Hariprasad, 2016, Retinal Physician 13: 20-23; Goldstein, 2014, Retina Today 9(5): 82-87; Baldassarre et al., 2017; each of which is incorporated by reference herein in its entirety). The suprachoroidal drug delivery devices that can be used to deposit the recombinant vector in the suprachoroidal space according to the invention described herein include, but are not limited to, suprachoroidal drug delivery devices manufactured by Clearside® Biomedical, Inc. (see, for example, Hariprasad, 2016, Retinal Physician 13: 20-23) and MedOne suprachoroidal catheters. In another embodiment, the suprachoroidal drug delivery device that can be used in accordance with the methods described herein comprises the micro volume injector delivery system, which is manufactured by Altaviz (see FIGS. 7A and 7B) (see, e.g. International Patent Application Publication No. WO 2013/177215, United States Patent Application Publication No. 2019/0175825, and United States Patent Application Publication No. 2019/0167906) that can be used for any administration route described herein for eye administration. The micro volume injector delivery system may include a gas-powered module providing high force delivery and improved precision, as described in United States Patent Application Publication No. 2019/0175825 and United States Patent Application Publication No. 2019/0167906. In addition, the micro volume injector delivery system may include a hydraulic drive for providing a consistent dose rate, and a low-force activation lever for controlling the gas-powered module and, in turn, the fluid delivery.


The micro volume injector is a micro volume injector with dose guidance and can be used with, for example, a suprachoroidal needle (for example, the Clearside® needle) or a subretinal needle. The benefits of using micro volume injector include: (a) more controlled delivery (for example, due to having precision injection flow rate control and dose guidance), (b) single surgeon, single hand, one finger operation; (c) pneumatic drive with 10 μL increment dosage; (d) divorced from the vitrectomy machine; (e) 400 μL syringe dose; (f) digitally guided delivery; (g) digitally recorded delivery; and (h) agnostic tip (for example, the MedOne 38 g needle and the Dorc 41 g needle can be used for subretinal delivery, while the Clearside® needle and the Visionisti OY adaptor can be used for suprachoroidal delivery). In another embodiment, the suprachoroidal drug delivery device that can be used in accordance with the methods described herein is a tool that comprises a normal length hypodermic needle with an adaptor (and preferably also a needle guide) manufactured by Visionisti OY, which adaptor turns the normal length hypodermic needle into a suprachoroidal needle by controlling the length of the needle tip exposing from the adapter (see FIG. 8) (see, for example, U.S. Design Pat. No. D878,575; and International Patent Application. Publication No. WO/2016/083669) In a specific embodiment, the suprachoroidal drug delivery device is a syringe with a 1 millimeter 30 gauge needle (see FIG. 1). During an injection using this device, the needle pierces to the base of the sclera and fluid containing drug enters the suprachoroidal space, leading to expansion of the suprachoroidal space. As a result, there is tactile and visual feedback during the injection. Following the injection, the fluid flows posteriorly and absorbs dominantly in the choroid and retina. This results in the production of therapeutic product from all retinal cell layers and choroidal cells. Using this type of device and procedure allows for a quick and easy in-office procedure with low risk of complications. A max volume of 100 μl can be injected into the suprachoroidal space.


In certain embodiments of the methods described herein, the recombinant vector is administered subretinally via vitrectomy. Subretinal administration via vitrectomy is a surgical procedure performed by trained retinal surgeons that involves a vitrectomy with the subject under local anesthesia, and subretinal injection of the gene therapy into the retina (see, e.g., Campochiaro et al., 2017, Hum Gen Ther 28(1):99-111, which is incorporated by reference herein in its entirety).


In certain embodiments of the methods described herein, the recombinant vector is administered subretinally without vitrectomy.


In certain embodiments of the methods described herein, the subretinal administration without vitrectomy is performed via the suprachoroidal space by use of a subretinal drug delivery device. In certain embodiments, the subretinal drug delivery device is a catheter which is inserted and tunneled through the suprachoroidal space around to the back of the eye during a surgical procedure to deliver drug to the subretinal space (see FIG. 2). This procedure allows the vitreous to remain intact and thus, there are fewer complication risks (less risk of gene therapy egress, and complications such as retinal detachments and macular holes), and without a vitrectomy, the resulting bleb may spread more diffusely allowing more of the surface area of the retina to be transduced with a smaller volume. The risk of induced cataract following this procedure is minimized, which is desirable for younger patients. Moreover, this procedure can deliver bleb under the fovea more safely than the standard transvitreal approach, which is desirable for patients with inherited retinal diseases effecting central vision where the target cells for transduction are in the macula. This procedure is also favorable for patients that have neutralizing antibodies (Nabs) to AAVs present in the systemic circulation which may impact other routes of delivery (such as suprachoroidal and intravitreal). Additionally, this method has shown to create blebs with less egress out the retinotomy site than the standard transvitreal approach. The subretinal drug delivery device originally manufactured by Janssen Pharmaceuticals, Inc. now by Orbit Biomedical Inc. (see, for example, Subretinal Delivery of Cells via the Suprachoroidal Space: Janssen Trial. In: Schwartz et al. (eds) Cellular Therapies for Retinal Disease, Springer, Cham; International Patent Application Publication No. WO 2016/040635 A1) can be used for such purpose.


In another specific embodiment, the subretinal administration without vitrectomy is performed via peripheral injection into the retina (i.e., peripheral to the optic disc, fovea and macula located in the back of the eye, see FIG. 3). This can be accomplished by transvitreal injection.


In one embodiment, a sharp needle is inserted into the sclera via the superior or inferior side of the eye (e.g., at the 2 or 10 o'clock position) so that the needle passes all the way through the vitreous to inject the retina on the other side. In another embodiment, a trochar is inserted into the sclera to allow a subretinal cannula to be inserted into the eye. The cannula is inserted through the trochar and through the vitreous to the area of desired injection. In either embodiment, the recombinant vector is injected in the subretinal space, forming a bleb containing the recombinant vector on the opposite inner surface of the eye. Successful injection is confirmed by the appearance of a dome shaped retinal detachment/retinal bleb.


A self-illuminating lens may be used as a light source for the transvitreal administration (see e.g., Chalam et al., 2004, Ophthalmic Surgery and Lasers 35: 76-77, which is incorporated by reference herein in its entirety). Alternatively, one or more trochar(s) can be placed for light (or infusion) if desired. In yet another embodiment, an optic fiber chandelier can be utilized via a trocar for visualizing the subretinal injection.


One, two, or more peripheral injections can be performed to administer the recombinant vector. In this way, one, two, or more blebs containing recombinant vector can be made in the subretinal space peripheral to the optic disc, fovea and macula. Surprisingly, while administration of the recombinant vector is confined to the peripherally injected blebs, expression of the therapeutic product throughout the retina can be detected when using this approach.


In a specific embodiment, the intravitreal administration is performed with a intravitreal drug delivery device that comprises the micro volume injector delivery system, which is manufactured by Altaviz (see FIGS. 7A and 7B) (see, e.g. International Patent Application Publication No. WO 2013/177215), United States Patent Application Publication No. 2019/0175825, and United States Patent Application Publication No. 2019/0167906) that can be used for any administration route described herein for eye administration. The micro volume injector delivery system may include a gas-powered module providing high force delivery and improved precision, as described in United States Patent Application Publication No. 2019/0175825 and United States Patent Application Publication No. 2019/0167906. In addition, the micro volume injector delivery system may include a hydraulic drive for providing a consistent dose rate, and a low-force activation lever for controlling the gas-powered module and, in turn, the fluid delivery. The micro volume injector is a micro volume injector with dose guidance and can be used with, for example, a intravitreal needle. The benefits of using micro volume injector include: (a) more controlled delivery (for example, due to having precision injection flow rate control and dose guidance), (b) single surgeon, single hand, one finger operation; (c) pneumatic drive with 10 μL increment dosage; (d) divorced from the vitrectomy machine; (e) 400 μL syringe dose; (f) digitally guided delivery; (g) digitally recorded delivery; and (h) agnostic tip (for example, the MedOne 38 g needle and the Dorc 41 g needle can be used for subretinal delivery, while the Clearside® needle and the Visionisti OY adaptor can be used for subretinal delivery).


In certain embodiments, the peripheral injection results in uniform expression of the therapeutic product throughout the eye (e.g. the expression level at the site of injection varies by less than 5%, 10%, 20%, 30%, 40%, or 50% as compared to the expression level at other areas of the eye). The expression of the therapeutic product throughout the eye can be measured by any method known in the art for such a purpose, for example, by whole mount immunofluorescent staining of the eye or retina, or by immunofluorescent staining on frozen ocular sections.


In the event that a transvitreal injection results in loss of the recombinant vector in the vitreous instead of the subretinal space, an optional vitrectomy can be performed to remove the recombinant vector that was injected into the vitreous. A subretinal injection with vitrectomy can then be performed to deliver the 250 μl of recombinant vector into the subretinal space. Alternatively, if some of the injected recombinant vector is deposited into the vitreous and a vitrectomy is not performed to remove the recombinant vector from the vitreous, a catheter lined with immobilized (e.g., covalently bound) anti-AAV antibodies (e.g., anti AAV8 antibodies), can be inserted into the vitreous to capture and remove excess recombinant vector from the vitreous.


In a specific embodiment, the subretinal administration is performed with a subretinal drug delivery device that comprises the micro volume injector delivery system, which is manufactured by Altaviz (see FIGS. 7A and 7B) (see, e.g. International Patent Application Publication No. WO 2013/177215, United States Patent Application Publication No. 2019/0175825, and United States Patent Application Publication No. 2019/0167906) that can be used for any administration route described herein for eye administration. The micro volume injector delivery system may include a gas-powered module providing high force delivery and improved precision, as described in United States Patent Application Publication No. 2019/0175825 and United States Patent Application Publication No. 2019/0167906. In addition, the micro volume injector delivery system may include a hydraulic drive for providing a consistent dose rate, and a low-force activation lever for controlling the gas-powered module and, in turn, the fluid delivery. Micro volume injector is a micro volume injector with dose guidance and can be used with, for example, a subretinal needle. The benefits of using micro volume injector include: (a) more controlled delivery (for example, due to having precision injection flow rate control and dose guidance), (b) single surgeon, single hand, one finger operation; (c) pneumatic drive with 10 μL increment dosage; (d) divorced from the vitrectomy machine; (e) 400 μL syringe dose; (f) digitally guided delivery; (g) digitally recorded delivery; and (h) agnostic tip (for example, the MedOne 38 g needle and the Dorc 41 g needle can be used for subretinal delivery, while the Clearside® needle and the Visionisti OY adaptor can be used for suprachoroidal delivery).


In certain embodiments, the recombinant vector is administered to the outer surface of the sclera (for example, by the use of a juxtascleral drug delivery device that comprises a cannula, whose tip can be inserted and kept in direct apposition to the scleral surface). In a specific embodiment, administration to the outer surface of the sclera is performed using a posterior juxtascleral depot procedure, which involves drug being drawn into a blunt-tipped curved cannula and then delivered in direct contact with the outer surface of the sclera without puncturing the eyeball. In particular, following the creation of a small incision to bare sclera, the cannula tip is inserted (see FIG. 4A). The curved portion of the cannula shaft is inserted, keeping the cannula tip in direct apposition to the scleral surface (see FIGS. 4B-4D). After complete insertion of the cannula (FIG. 4D), the drug is slowly injected while gentle pressure is maintained along the top and sides of the cannula shaft with sterile cotton swabs. This method of delivery avoids the risk of intraocular infection and retinal detachment, side effects commonly associated with injecting therapeutic agents directly into the eye.


In a specific embodiment, the juxtascleral administration is performed with a juxtascleral drug delivery device that comprises the micro volume injector delivery system, which is manufactured by Altaviz (see FIGS. 7A and 7B) (see, e.g. International Patent Application Publication No. WO 2013/177215, United States Patent Application Publication No. 2019/0175825, and United States Patent Application Publication No. 2019/0167906) that can be used for any administration route described herein for eye administration. The micro volume injector delivery system may include a gas-powered module providing high force delivery and improved precision, as described in United States Patent Application Publication No. 2019/0175825 and United States Patent Application Publication No. 2019/0167906. In addition, the micro volume injector delivery system may include a hydraulic drive for providing a consistent dose rate, and a low-force activation lever for controlling the gas-powered module and, in turn, the fluid delivery. Micro Volume Injector is a micro volume injector with dose guidance and can be used with, for example, a juxtascleral needle. The benefits of using micro volume injector include: (a) more controlled delivery (for example, due to having precision injection flow rate control and dose guidance), (b) single surgeon, single hand, one finger operation; (c) pneumatic drive with 10 μL increment dosage; (d) divorced from the vitrectomy machine; (e) 400 μL syringe dose; (f) digitally guided delivery; (g) digitally recorded delivery; and (h) agnostic tip.


In certain embodiments, an infrared thermal camera can be used to detect changes in the thermal profile of the ocular surface after the administering of a solution which is cooler than body temperature to detect changes in the thermal profile of the ocular surface that allows for visualization of the spread of the solution, e.g., within the SCS, and can potentially determine whether the administration was successfully completed. This is because in certain embodiments the formulation containing the recombinant vector to be administered is initially frozen, brought to room temperature (68-72° F.), and thawed for a short period of time (e.g., at least 30 minutes) before administration, and thus the formulation is colder than the human eye (about 92° F.) (and sometimes even colder than room temperature) at the time of injection. The drug product is typically used within 4 hours of thaw and the warmest the solution would be is room temperature. In a preferred embodiment, the procedure is videoed with infrared video.


Infrared thermal cameras can detect small changes in temperature. They capture infrared energy through a lens and convert the energy into an electronic signal. The infrared light is focused onto an infrared sensor array which converts the energy into a thermal image. The infrared thermal camera can be used for any method of administration to the eye, including any administration route described herein, for example, suprachoroidal administration, subretinal administration, subconjunctival administration, intravitreal administration, or administration with the use of a slow infusion catheter in to the suprachoroidal space. In a specific embodiment, the infrared thermal camera is an FLIR T530 infrared thermal camera. The FLIR T530 infrared thermal camera can capture slight temperature differences with an accuracy of ±3.6° F. The camera has an infrared resolution of 76,800 pixels. The camera also utilizes a 24° lens capturing a smaller field of view. A smaller field of view in combination with a high infrared resolution contributes to more detailed thermal profiles of what the operator is imaging. However, other infrared camera can be used that have different abilities and accuracy for capturing slight temperature changes, with different infrared resolutions, and/or with different degrees of lens.


In a specific embodiment, the infrared thermal camera is an FLIR T420 infrared thermal camera. In a specific embodiment, the infrared thermal camera is an FLIR T440 infrared thermal camera. In a specific embodiment, the infrared thermal camera is an Fluke Ti400 infrared thermal camera. In a specific embodiment, the infrared thermal camera is an FLIRE60 infrared thermal camera. In a specific embodiment, the infrared resolution of the infrared thermal camera is equal to or greater than 75,000 pixels. In a specific embodiment, the thermal sensitivity of the infrared thermal camera is equal to or smaller than 0.05° C. at 30° C. In a specific embodiment, the field of view (FOV) of the infrared thermal camera is equal to or lower than 25°×25°.


In certain embodiments, an iron filer is used with the infrared thermal camera to detect changes in the thermal profile of the ocular surface. In a preferred embodiment, the use of an iron filter is able to a generate pseudo-color image, wherein the warmest or high temperature parts are colored white, intermediate temperatures are reds and yellows, and the coolest or low temperature parts are black. In certain embodiments, other types of filters can also be used to generate pseudo-color images of the thermal profile.


The thermal profile for each administration method can be different. For example, in one embodiment, a successful suprachoroidal injection can be characterized by: (a) a slow, wide radial spread of the dark color, (b) very dark color at the beginning, and (c) a gradual change of injectate to lighter color, i.e., a temperature gradient noted by a lighter color. In one embodiment, an unsuccessful suprachoroidal injection can be characterized by: (a) no spread of the dark color, and (b) a minor change in color localized to the injection site without any distribution. In certain embodiments, the small localized temperature drop is result from cannula (low temperature) touching the ocular tissues (high temperature). In one embodiment, a successful intravitreal injection can be characterized by: (a) no spread of the dark color, (b) an initial change to very dark color localized to the injection site, and (c) a gradual and uniform change of the entire eye to darker color. In one embodiment, an extraocular efflux can be characterized by: (a) quick flowing streams on outside on the exterior surface of the eye, (b) very dark color at the beginning, and (c) a quick change to lighter color.


Because the therapeutic product is continuously produced (under the control of a constitutive promoter or induced by hypoxic conditions when using an hypoxia-inducible promoter), maintenance of lower concentrations can be effective. Vitreous humour concentrations can be measured directly in patient samples of fluid collected from the vitreous humour or the anterior chamber, or estimated and/or monitored by measuring the patient's serum concentrations of the therapeutic product—the ratio of systemic to vitreal exposure to the therapeutic product is about 1:90,000. (E.g., see, vitreous humor and serum concentrations of ranibizumab reported in Xu L, et al., 2013, Invest. Opthal. Vis. Sci. 54: 1616-1624, at p. 1621 and Table 5 at p. 1623, which is incorporated by reference herein in its entirety).


In certain embodiments, dosages are measured by genome copies per ml or the number of genome copies administered to the eye of the patient (e.g., administered suprachoroidally, subretinally, intravitreally, juxtasclerally, subconjunctivally, and/or intraretinally. In certain embodiments, 1×109 genome copies per ml to 1×1015 genome copies per ml are administered. In a specific embodiment, 1×109 genome copies per ml to 1×1010 genome copies per ml are administered. In another specific embodiment, 1×1010 genome copies per ml to 1×1011 genome copies per ml are administered. In another specific embodiment, 1×1010 to 5×1011 genome copies are administered. In another specific embodiment, 1×1011 genome copies per ml to 1×1012 genome copies per ml are administered. In another specific embodiment, 1×1012 genome copies per ml to 1×1013 genome copies per ml are administered. In another specific embodiment, 1×1013 genome copies per ml to 1×1014 genome copies per ml are administered. In another specific embodiment, 1×1014 genome copies per ml to 1×1015 genome copies per ml are administered. In another specific embodiment, about 1×109 genome copies per ml are administered. In another specific embodiment, about 1×1010 genome copies per ml are administered. In another specific embodiment, about 1×1011 genome copies per ml are administered. In another specific embodiment, about 1×1012 genome copies per ml are administered. In another specific embodiment, about 1×1013 genome copies per ml are administered. In another specific embodiment, about 1×1014 genome copies per ml are administered. In another specific embodiment, about 1×1015 genome copies per ml are administered. In certain embodiments, 1×109 to 1×1015 genome copies are administered. In a specific embodiment, 1×109 to 1×1010 genome copies are administered. In another specific embodiment, 1×1010 to 1×1011 genome copies are administered. In another specific embodiment, 1×1010 to 5×1011 genome copies are administered. In another specific embodiment, 1×1011 to 1×1012 genome copies are administered. In another specific embodiment, 1×1012 to 1×1013 genome copies are administered. In another specific embodiment, 1×1013 to 1×1014 genome copies are administered. In another specific embodiment, 1×1013 to 1×1014 genome copies are administered. In another specific embodiment, 1×1014 to 1×1015 genome copies are administered. In another specific embodiment, about 1×109 genome copies are administered. In another specific embodiment, about 1×1010 genome copies are administered. In another specific embodiment, about 1×1011 genome copies are administered. In another specific embodiment, about 1×1012 genome copies are administered. In another specific embodiment, about 1×1013 genome copies are administered. In another specific embodiment, about 1×1014 genome copies are administered. In another specific embodiment, about 1×1015 genome copies are administered. In certain embodiments, about 3.0×1013 genome copies per eye are administered. In certain embodiments, up to 3.0×1013 genome copies per eye are administered.


In certain embodiments, about 6.0×1010 genome copies per eye are administered. In certain embodiments, about 1.6×1011 genome copies per eye are administered. In certain embodiments, about 2.5×1011 genome copies per eye are administered. In certain embodiments, about 5.0×1011 genome copies per eye are administered. In certain embodiments, about 3×1012 genome copies per eye are administered. In certain embodiments, about 1.0×1012 genome copies per ml per eye are administered. In certain embodiments, about 2.5×1012 genome copies per ml per eye are administered.


In certain embodiments, about 6.0×1010 genome copies per eye are administered by subretinal injection. In certain embodiments, about 1.6×1011 genome copies per eye are administered by subretinal injection. In certain embodiments, about 2.5×1011 genome copies per eye are administered by subretinal injection. In certain embodiments, about 3.0×1013 genome copies per eye are administered by subretinal injection. In certain embodiments, up to 3.0×1013 genome copies per eye are administered by subretinal injection.


In certain embodiments, about 2.5×1011 genome copies per eye are administered by suprachoroidal injection. In certain embodiments, about 5.0×1011 genome copies per eye are administered by suprachoroidal injection. In certain embodiments, about 3×1012 genome copies per eye are administered by suprachoroidal injection. In certain embodiments, about 2.5×1011 genome copies per eye are administered by a single suprachoroidal injection. In certain embodiments, about 5.0×1011 genome copies per eye are administered by double suprachoroidal injections. In certain embodiments, about 3.0×1013 genome copies per eye are administered by suprachoroidal injection. In certain embodiments, up to 3.0×1013 genome copies per eye are administered by suprachoroidal injection. In certain embodiments, about 2.5×1012 genome copies per ml per eye are administered by a single suprachoroidal injection in a volume of 100 μl. In certain embodiments, about 2.5×1012 genome copies per ml per eye are administered by double suprachoroidal injections, wherein each injection is in a volume of 100 μl.


As used herein and unless otherwise specified, the term “about” means within plus or minus 10% of a given value or range. In certain embodiments, the term “about” encompasses the exact number recited.


(c) Sampling and Monitoring of Efficacy

In certain embodiments, when the human subject has disease manifestations in both the CNS and the eye (for example, when the human subject has a Batten disease), the method provided herein comprises administering a recombinant vector described herein (i.e., a recombinant viral vector or a DNA expression construct) to the human subject via both a central nervous system (CNS) delivery route and an ocular delivery route (for example, an ocular delivery route described herein). In certain embodiments, the ocular delivery route is selected from one of the following: (1) subretinal administration without vitrectomy (for example, administration to subretinal space via the suprachoroidal space or via peripheral injection), (2) suprachoroidal administration, (3) administration to the outer space of the sclera (i.e., juxtascleral administration); (4) subretinal administration accompanied by vitrectomy; (5) intravitreal administration, and (6) intravitreal administration. In certain embodiments, the CNS delivery route is selected from one of the following: intracerebroventricular (ICV) delivery, intracisternal (IC) delivery, or intrathecal-lumbar (IT-L) delivery.


Effects of the methods provided herein on visual deficits may be measured by BCVA (Best-Corrected Visual Acuity), intraocular pressure, slit lamp biomicroscopy, and/or indirect ophthalmoscopy.


In specific embodiments, effects of the methods provided herein on visual deficits may be measured by whether the human patient's eye that is treated by a method described herein achieves BCVA of greater than 43 letters post-treatment (e.g., 46-50 weeks or 98-102 weeks post-treatment). A BCVA of 43 letters corresponds to 20/160 approximate Snellen equivalent. In a specific embodiment, the human patient's eye that is treated by a method described herein achieves BCVA of greater than 43 letters post-treatment (e.g., 46-50 weeks or 98-102 weeks post-treatment).


In specific embodiments, effects of the methods provided herein on visual deficits may be measured by whether the human patient's eye that is treated by a method described herein achieves BCVA of greater than 84 letters post-treatment (e.g., 46-50 weeks or 98-102 weeks post-treatment). A BCVA of 84 letters corresponds to 20/20 approximate Snellen equivalent. In a specific embodiment, the human patient's eye that is treated by a method described herein achieves BCVA of greater than 84 letters post-treatment (e.g., 46-50 weeks or 98-102 weeks post-treatment).


Effects of the methods provided herein on physical changes to eye/retina may be measured by SD-OCT (SD-Optical Coherence Tomography).


Efficacy may be monitored as measured by electroretinography (ERG).


Effects of the methods provided herein may be monitored by measuring signs of vision loss, infection, inflammation and other safety events, including retinal detachment.


Retinal thickness may be monitored to determine efficacy of the methods provided herein. Without being bound by any particular theory, thickness of the retina may be used as a clinical readout, wherein the greater reduction in retinal thickness or the longer period of time before thickening of the retina, the more efficacious the treatment. Retinal function may be determined, for example, by ERG. ERG is a non-invasive electrophysiologic test of retinal function, approved by the FDA for use in humans, which examines the light sensitive cells of the eye (the rods and cones), and their connecting ganglion cells, in particular, their response to a flash stimulation. Retinal thickness may be determined, for example, by SD-OCT. SD-OCT is a three-dimensional imaging technology which uses low-coherence interferometry to determine the echo time delay and magnitude of backscattered light reflected off an object of interest. OCT can be used to scan the layers of a tissue sample (e.g., the retina) with 3 to 15 μm axial resolution, and SD-OCT improves axial resolution and scan speed over previous forms of the technology (Schuman, 2008, Trans. Am. Opthamol. Soc. 106:426-458).


Effects of the methods provided herein may also be measured by a change from baseline in National Eye Institute Visual Functioning Questionnaire, the Rasch-scored version (NEI-VFQ-28-R) (composite score; activity limitation domain score; and socio-emotional functioning domain score). Effects of the methods provided herein may also be measured by a change from baseline in National Eye Institute Visual Functioning Questionnaire 25-item version (NEI-VFQ-25) (composite score and mental health subscale score). Effects of the methods provided herein may also be measured by a change from baseline in Macular Disease Treatment Satisfaction Questionnaire (MacTSQ) (composite score; safety, efficacy, and discomfort domain score; and information provision and convenience domain score).


In specific embodiments, the efficacy of a method described herein is reflected by an improvement in vision at about 4 weeks, 12 weeks, 6 months, 12 months, 24 months, 36 months, or at other desired timepoints. In a specific embodiment, the improvement in vision is characterized by an increase in BCVA, for example, an increase by 1 letter, 2 letters, 3 letters, 4 letters, 5 letters, 6 letters, 7 letters, 8 letters, 9 letters, 10 letters, 11 letters, or 12 letters, or more. In a specific embodiment, the improvement in vision is characterized by a 5%, 10%, 15%, 20%, 30%, 40%, 50% or more increase in visual acuity from baseline.


In specific embodiments, the efficacy of a method described herein is reflected by an reduction in central retinal thickness (CRT) at about 4 weeks, 12 weeks, 6 months, 12 months, 24 months, 36 months, or at other desired timepoint, for example, a 5%, 10%, 15%, 20%, 30%, 40%, 50% or more decrease in central retinal thickness from baseline.


In s specific embodiments, there is no inflammation in the eye after treatment or little inflammation in the eye after treatment (for example, an increase in the level of inflammation by 10%, 5%, 2%, 1% or less from baseline).


Effects of the methods provided herein on visual deficits may be measured by OptoKinetic Nystagmus (OKN).


Without being bound by theory, this visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN can be used to measure visual acuity in pre-verbal and/or non-verbal patients. In certain embodiments, OKN is used to measure visual acuity in patients that are 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. In certain embodiments, an iPad is used to measure visual acuity through detection of the OKN reflex when a patient is looking at movement on the iPad.


Without being bound by theory, this visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN can be used to measure visual acuity in pre-verbal and/or non-verbal patients. In certain embodiments, OKN is used to measure visual acuity in patients that are less than 1.5 months old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. In another specific embodiment, OKN is used to measure visual acuity in patients that are 1-2 months old, 2-3 months old, 3-4 months old, 4-5 months old, 5-6 months old, 6-7 months old, 7-8 months old, 8-9 months old, 9-10 months old, 10-11 months old, 11 months to 1 year old, 1-1.5 years old, 1.5-2 years old, 2-2.5 years old, 2.5-3 years old, 3-3.5 years old, 3.5-4 years old, 4-4.5 years old, or 4.5-5 years old. In another specific embodiment, OKN is used to measure visual acuity in patients that are 6 months to 5 years old. In certain embodiments, an iPad is used to measure visual acuity through detection of the OKN reflex when a patient is looking at movement on the iPad.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN2-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Tripeptidyl-Peptidase 1(TPP1). Specifically, the patient presenting with Batten-CLN2-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity assessed in a patient up to 5 years old presenting with Batten-CLN2-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Tripeptidyl-Peptidase 1. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN2-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding TPP1. Specifically, the patient presenting with Batten-CLN2-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient up to 5 years old presenting with Batten-CLN2-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Tripeptidyl-Peptidase 1. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN1-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Palmitoyl-Protein Thioesterase 1 (PPT1). Specifically, the patient up to 5 years old presenting with Batten-CLN1-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN1-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding PPT1. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN1-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding PPT1. Specifically, the patient presenting with Batten-CLN1-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient up to 5 years old presenting with Batten-CLN1-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding PPT1. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN3-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Battenin (CLN3). Specifically, the patient presenting with Batten-CLN3-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient up to 5 years old presenting with Batten-CLN3-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Battenin (CLN3). In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN3-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Battenin (CLN3). Specifically, the patient presenting with Batten-CLN3-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient up to 5 years old presenting with Batten-CLN3-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Battenin (CLN3). In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN6-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding CLN6 Transmembrane ER Protein (CLN6). Specifically, the patient up to 5 years old presenting with Batten-CLN6-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN6-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding CLN6 Transmembrane ER Protein (CLN6). In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN6-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding CLN6 Transmembrane ER Protein (CLN6). Specifically, the patient up to 5 years old presenting with Batten-CLN6-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN6-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding CLN6 Transmembrane ER Protein (CLN6). In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN7-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding Major Facilitator Superfamily Domain Containing 8 (MFSD8). Specifically, the patient up to 5 years old presenting with Batten-CLN7-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN7-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding MFSD8. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


In certain embodiments, visual acuity is assessed in a patient presenting with Batten-CLN7-associated vision loss by measuring OKN before the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding MFSD8. Specifically, the patient presenting with Batten-CLN7-associated vision loss is at the age, and/or within the age range described above. In certain embodiments, visual acuity is assessed in a patient up to 5 years old presenting with Batten-CLN7-associated vision loss by measuring OKN after the patient has been treated with an AAV, preferably AAV8 or AAV9, encoding MFSD8. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not decrease after treatment with AAV gene therapy. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity improves in a patient after treatment with AAV gene therapy by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In certain embodiments, a visual acuity assessment based on OKN determines that visual acuity does not further deteriorate in a patient after treatment with AAV gene therapy.


If the human patient is a child, visual function can be assessed using an optokinetic nystagmus (OKN)-based approach or a modified OKN-based approach.


6.2 Treatment System, Device, or Apparatus to be Used for a Treatment Method Described Herein


Also provided herein are treatment system, devices, and apparatuses to be used for a treatment method described herein, which may comprise one or more of the following: bottles, tubes, light source, microinjector, and foot pedal. In certain embodiments, the light source is a self-illuminating contact lens, which can be used to deposit vector in the back of the eye and in particular and to avoid damaging the optic disc, fovea and/or macula (see, e.g., Chalam et al., 2004, Ophthalmic surgery and lasers. 35. 76-77, which is incorporated by reference herein in its entirety). In certain embodiments, a self-illuminating contact lens is utilized during peripheral injection for visualizing the subretinal injection (see, e.g., Chalam et al., 2004, Ophthalmic surgery and lasers. 35. 76-77, which is incorporated by reference herein in its entirety). In certain embodiments, an optic fiber chandelier is utilized via a second trocar for visualizing the subretinal injection.


6.3 Delivery of Anti-VEGF Antibody or Antigen-Binding Fragment


In certain embodiments, the therapeutic product is a fully human post-translationally modified (HuPTM) antibody against VEGF. In a specific embodiment, the pathology of the eye is associated with an ocular disease caused by increased neovascularization, for example, nAMD (also known as “wet” AMD), dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) (in particular, wet AMD). The embodiments/aspects described in other sections of this disclosure are incorporated herein in this section to the extent they are applicable to the delivery of anti-VEGF antibodies or antigen-binding fragments. Described below are certain additional embodiments applicable to the delivery of anti-VEGF antibodies or antigen-binding fragments.


In a preferred embodiment, the fully human post-translationally modified antibody against VEGF is a fully human post-translationally modified antigen-binding fragment of a monoclonal antibody (mAb) against VEGF (“HuPTMFabVEGFi”). In a further preferred embodiment, the HuPTMFabVEGFi is a fully human glycosylated antigen-binding fragment of an anti-VEGF mAb (“HuGlyFabVEGFi”). See, also, International Patent Application Publication No. WO/2017/180936 (International Patent Application No. PCT/US2017/027529, filed Apr. 14, 2017), and International Patent Application Publication No. WO/2017/181021 (International Patent Application No. PCT/US2017/027650, filed Apr. 14, 2017), each of which is incorporated by reference herein in its entirety, for compositions and methods that can be used according to the invention described herein. In an alternative embodiment, full-length mAbs can be used.


Subjects to whom such gene therapy is administered should be those responsive to anti-VEGF therapy. In particular embodiments, the methods encompass treating patients who have been diagnosed with wet AMD, dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) (in particular, wet AMD) and identified as responsive to treatment with an anti-VEGF antibody. In more specific embodiments, the patients are responsive to treatment with an anti-VEGF antigen-binding fragment. In certain embodiments, the patients have been shown to be responsive to treatment with an anti-VEGF antigen-binding fragment injected intravitreally prior to treatment with gene therapy. In specific embodiments, the patients have previously been treated with LUCENTIS® (ranibizumab), EYLEA® (aflibercept), and/or AVASTIN® (bevacizumab), and have been found to be responsive to one or more of said LUCENTIS (ranibizumab), EYLEA® (aflibercept), and/or AVASTIN® (bevacizumab).


Subjects to whom such recombinant viral vector or other DNA expression construct is delivered should be responsive to the anti-VEGF antigen-binding fragment encoded by the transgene in the recombinant viral vector or expression construct. To determine responsiveness, the anti-hVEGF antigen-binding fragment transgene product (e.g., produced in cell culture, bioreactors, etc.) may be administered directly to the subject, such as by intravitreal injection.


The HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, encoded by the transgene can include, but is not limited to an antigen-binding fragment of an antibody that binds to hVEGF, such as bevacizumab; an anti-hVEGF Fab moiety such as ranibizumab; or such bevacizumab or ranibizumab Fab moieties engineered to contain additional glycosylation sites on the Fab domain (e.g., see Courtois et al., 2016, mAbs 8: 99-112 which is incorporated by reference herein in its entirety for it description of derivatives of bevacizumab that are hyperglycosylated on the Fab domain of the full length antibody).


The recombinant vector used for delivering the transgene should have a tropism for human retinal cells or photoreceptor cells. Such vectors can include non-replicating recombinant adeno-associated virus vectors (“rAAV”), particularly those bearing an AAV8 capsid are preferred. However, other recombinant viral vectors may be used, including but not limited to recombinant lentiviral vectors, vaccinia viral vectors, or non-viral expression vectors referred to as “naked DNA” constructs. Preferably, the HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, transgene should be controlled by appropriate expression control elements, for example, the CB7 promoter (a chicken β-actin promoter and CMV enhancer), the RPE65 promoter, or opsin promoter to name a few, and can include other expression control elements that enhance expression of the transgene driven by the vector (e.g., introns such as the chicken β-actin intron, minute virus of mice (MVM) intron, human factor IX intron (e.g., FIX truncated intron 1), β-globin splice donor/immunoglobulin heavy chain spice acceptor intron, adenovirus splice donor/immunoglobulin splice acceptor intron, SV40 late splice donor/splice acceptor (19S/16S) intron, and hybrid adenovirus splice donor/IgG splice acceptor intron and polyA signals such as the rabbit β-globin polyA signal, human growth hormone (hGH) polyA signal, SV40 late polyA signal, synthetic polyA (SPA) signal, and bovine growth hormone (bGH) polyA signal). See, e.g., Powell and Rivera-Soto, 2015, Discov. Med., 19(102):49-57.


In preferred embodiments, gene therapy constructs are designed such that both the heavy and light chains are expressed. More specifically, the heavy and light chains should be expressed at about equal amounts, in other words, the heavy and light chains are expressed at approximately a 1:1 ratio of heavy chains to light chains. The coding sequences for the heavy and light chains can be engineered in a single construct in which the heavy and light chains are separated by a cleavable linker or IRES so that separate heavy and light chain polypeptides are expressed. See, e.g., Section 6.1.2 for specific leader sequences and specific IRES, 2A, and other linker sequences that can be used with the methods and compositions provided herein.


Without being bound by theory, in certain embodiments, the methods and compositions provided herein for the delivery of anti-VEGF antibodies or antigen-binding fragments are based, in part, on the following principles:

    • (i) Human retinal cells are secretory cells that possess the cellular machinery for post-translational processing of secreted proteins—including glycosylation and tyrosine-O-sulfation, a robust process in retinal cells. (See, e.g., Wang et al., 2013, Analytical Biochem. 427: 20-28 and Adamis et al., 1993, BBRC 193: 631-638 reporting the production of glycoproteins by retinal cells; and Kanan et al., 2009, Exp. Eye Res. 89: 559-567 and Kanan & Al-Ubaidi, 2015, Exp. Eye Res. 133: 126-131 reporting the production of tyrosine-sulfated glycoproteins secreted by retinal cells, each of which is incorporated by reference in its entirety for post-translational modifications made by human retinal cells).
    • (ii) Contrary to the state of the art understanding, anti-VEGF antigen-binding fragments, such as ranibizumab (and the Fab domain of full length anti-VEGF mAbs such as bevacizumab) do indeed possess N-linked glycosylation sites. For example, see FIG. 1 which identifies non-consensus asparaginal (“N”) glycosylation sites in the CH domain (TVSWN165SGAL) and in the CL domain (QSGN158SQE), as well as glutamine (“Q”) residues that are glycosylation sites in the VH domain (Q115GT) and VL domain (TFQ100GT) of ranibizumab (and corresponding sites in the Fab of bevacizumab). (See, e.g., Valliere-Douglass et al., 2009, J. Biol. Chem. 284: 32493-32506, and Valliere-Douglass et al., 2010, J. Biol. Chem. 285: 16012-16022, each of which is incorporated by reference in its entirety for the identification of N-linked glycosylation sites in antibodies).
    • (iii) While such non-canonical sites usually result in low level glycosylation (e.g., about 1-5%) of the antibody population, the functional benefits may be significant in immunoprivileged organs, such as the eye (See, e.g., van de Bovenkamp et al., 2016, J. Immunol. 196:1435-1441). For example, Fab glycosylation may affect the stability, half-life, and binding characteristics of an antibody. To determine the effects of Fab glycosylation on the affinity of the antibody for its target, any technique known to one of skill in the art may be used, for example, enzyme linked immunosorbent assay (ELISA), or surface plasmon resonance (SPR). To determine the effects of Fab glycosylation on the half-life of the antibody, any technique known to one of skill in the art may be used, for example, by measurement of the levels of radioactivity in the blood or organs (e.g., the eye) in a subject to whom a radiolabelled antibody has been administered. To determine the effects of Fab glycosylation on the stability, for example, levels of aggregation or protein unfolding, of the antibody, any technique known to one of skill in the art may be used, for example, differential scanning calorimetry (DSC), high performance liquid chromatography (HPLC), e.g., size exclusion high performance liquid chromatography (SEC-HPLC), capillary electrophoresis, mass spectrometry, or turbidity measurement. Provided herein, the HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, transgene results in production of a Fab which is 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% or more glycosylated at non-canonical sites. In certain embodiments, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% or more Fabs from a population of Fabs are glycosylated at non-canonical sites. In certain embodiments, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% or more non-canonical sites are glycosylated. In certain embodiments, the glycosylation of the Fab at these non-canonical sites is 25%, 50%, 100%, 200%, 300%, 400%, 500%, or more greater than the amount of glycosylation of these non-canonical sites in a Fab produced in HEK293 cells.
    • (iv) In addition to the glycosylation sites, anti-VEGF Fabs such as ranibizumab (and the Fab of bevacizumab) contain tyrosine (“Y”) sulfation sites in or near the CDRs; see FIG. 1 which identifies tyrosine-O-sulfation sites in the VH (EDTAVY94Y95) and VL (EDFATY86) domains of ranibizumab (and corresponding sites in the Fab of bevacizumab). (See, e.g., Yang et al., 2015, Molecules 20:2138-2164, esp. at p. 2154 which is incorporated by reference in its entirety for the analysis of amino acids surrounding tyrosine residues subjected to protein tyrosine sulfation. The “rules” can be summarized as follows: Y residues with E or D within +5 to −5 position of Y, and where position −1 of Y is a neutral or acidic charged amino acid—but not a basic amino acid, e.g., R, K, or H that abolishes sulfation). Human IgG antibodies can manifest a number of other post-translational modifications, such as N-terminal modifications, C-terminal modifications, degradation or oxidation of amino acid residues, cysteine related variants, and glycation (See, e.g., Liu et al., 2014, mAbs 6(5):1145-1154).
    • (v) Glycosylation of anti-VEGF Fabs, such as ranibizumab or the Fab fragment of bevacizumab by human retinal cells will result in the addition of glycans that can improve stability, half-life and reduce unwanted aggregation and/or immunogenicity of the transgene product. (See, e.g., Bovenkamp et al., 2016, J. Immunol. 196: 1435-1441 for a review of the emerging importance of Fab glycosylation). Significantly, glycans that can be added to HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, provided herein, are highly processed complex-type biantennary N-glycans that contain 2,6-sialic acid (e.g., see FIG. 2 depicting the glycans that may be incorporated into HuPTMFabVEGFi, e.g., HuGlyFabVEGFi) and bisecting GlcNAc, but not NGNA (N-Glycolylneuraminic acid, Neu5Gc). Such glycans are not present in ranibizumab (which is made in E. coli and is not glycosylated at all) or in bevacizumab (which is made in CHO cells that do not have the 2,6-sialyltransferase required to make this post-translational modification, nor do CHO cells product bisecting GlcNAc, although they do add Neu5Gc (NGNA) as sialic acid not typical (and potentially immunogenic) to humans instead of Neu5Ac (NANA)). See, e.g., Dumont et al., 2015, Crit. Rev. Biotechnol. (Early Online, published online Sep. 18, 2015, pp. 1-13 at p. 5). Moreover, CHO cells can also produce an immunogenic glycan, the α-Gal antigen, which reacts with anti-α-Gal antibodies present in most individuals, and at high concentrations can trigger anaphylaxis. See, e.g., Bosques, 2010, Nat Biotech 28: 1153-1156. The human glycosylation pattern of the HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, provided herein, should reduce immunogenicity of the transgene product and improve efficacy.
    • (vi) Tyrosine-sulfation of anti-VEGF Fabs, such as ranibizumab or the Fab fragment of bevacizumab—a robust post-translational process in human retinal cells—could result in transgene products with increased avidity for VEGF. Indeed, tyrosine-sulfation of the Fab of therapeutic antibodies against other targets has been shown to dramatically increase avidity for antigen and activity. (See, e.g., Loos et al., 2015, PNAS 112: 12675-12680, and Choe et al., 2003, Cell 114: 161-170). Such post-translational modifications are not present on ranibizumab (which is made in E. coli a host that does not possess the enzymes required for tyrosine-sulfation), and at best is under-represented in bevacizumab—a CHO cell product. Unlike human retinal cells, CHO cells are not secretory cells and have a limited capacity for post-translational tyrosine-sulfation. (See, e.g., Mikkelsen & Ezban, 1991, Biochemistry 30: 1533-1537, esp. discussion at p. 1537).


For the foregoing reasons, the production of HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, should result in a “biobetter” molecule for the treatment of wet AMD, dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) (in particular, wet AMD) accomplished via gene therapy—e.g., by administering a recombinant viral vector or a recombinant DNA expression construct encoding HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, to the suprachoroidal space, subretinal space, or outer surface of the sclera in the eye(s) of patients (human subjects) diagnosed with wet AMD, dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) (in particular, wet AMD), to create a permanent depot in the eye that continuously supplies the fully-human post-translationally modified, e.g., human-glycosylated, sulfated transgene product produced by transduced retinal cells. The cDNA construct for the FabVEGFi should include a signal peptide that ensures proper co- and post-translational processing (glycosylation and protein sulfation) by the transduced retinal cells. Such signal sequences used by retinal cells may include but are not limited to:









MNFLLSWVHW SLALLLYLHH AKWSQA (VEGF-A signal





peptide)





MERAAPSRRV PLPLLLLGGL ALLAAGVDA (Fibulin-1 signal





peptide)





MAPLRPLLIL ALLAWVALA (Vitronectin signal peptide)





MRLLAKIICLMLWAICVA (Complement Factor H signal





peptide)





MRLLAFLSLL ALVLQETGT (Opticin signal peptide)





MKWVTFISLLFLFSSAYS (Albumin signal peptide)





MAFLWLLSCWALLGTTFG (Chymotrypsinogen signal





peptide)





MYRMQLLSCIALILALVTNS (Interleukin-2 signal





peptide)





MNLLLILTFVAAAVA (Trypsinogen-2 signal peptide).





See, e.g., Stern et al., 2007, Trends Cell. Mol.





Biol., 2: 1-17 and Dalton & Barton, 2014, Protein





Sci, 23: 517-525, each of which is incorporated by





reference herein in its entirety for the signal





peptides that can be used.






As an alternative, or an additional treatment to gene therapy, the HuPTMFabVEGFi product, e.g., HuGlyFabVEGFi glycoprotein, can be produced in human cell lines by recombinant DNA technology, and administered to patients diagnosed with wet AMD, dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) (in particular, wet AMD) by intravitreal injection. The HuPTMFabVEGFi product, e.g., glycoprotein, may also be administered to patients with wet AMD, dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) (in particular, wet AMD). Human cell lines that can be used for such recombinant glycoprotein production include but are not limited to human embryonic kidney 293 cells (HEK293), fibrosarcoma HT-1080, HKB-11, CAP, HuH-7, and retinal cell lines, PER.C6, or RPE to name a few (e.g., see Dumont et al., 2015, Crit. Rev. Biotechnol. (Early Online, published online Sep. 18, 2015, pp. 1-13) “Human cell lines for biopharmaceutical manufacturing: history, status, and future perspectives” which is incorporated by reference in its entirety for a review of the human cell lines that could be used for the recombinant production of the HuPTMFabVEGFi product, e.g., HuGlyFabVEGFi glycoprotein). To ensure complete glycosylation, especially sialylation, and tyrosine-sulfation, the cell line used for production can be enhanced by engineering the host cells to co-express α-2,6-sialyltransferase (or both α-2,3- and α-2,6-sialyltransferases) and/or TPST-1 and TPST-2 enzymes responsible for tyrosine-O-sulfation in retinal cells.


Combinations of delivery of the HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, to the eye/retina accompanied by delivery of other available treatments are encompassed by the methods provided herein. The additional treatments may be administered before, concurrently or subsequent to the gene therapy treatment. Available treatments for wet AMD, dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) (in particular, wet AMD) that could be combined with the gene therapy provided herein include but are not limited to laser photocoagulation, photodynamic therapy with verteporfin, and intravitreal (IVT) injections with anti-VEGF agents, including but not limited to pegaptanib, ranibizumab, aflibercept, or bevacizumab. Additional treatments with anti-VEGF agents, such as biologics, may be referred to as “rescue” therapy.


6.3.1 N-Glycosylation, Tyrosine Sulfation, and O-Glycosylation


The amino acid sequence (primary sequence) of the anti-VEGF antigen-binding fragment of a HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, used in the methods described herein comprises at least one site at which N-glycosylation or tyrosine sulfation takes place. In certain embodiments, the amino acid sequence of the anti-VEGF antigen-binding fragment comprises at least one N-glycosylation site and at least one tyrosine sulfation site. Such sites are described in detail below. In certain embodiments, the amino acid sequence of the anti-VEGF antigen-binding fragment comprises at least one O-glycosylation site, which can be in addition to one or more N-glycosylation sites and/or tyrosine sulfation sites present in said amino acid sequence.


(a) N-Glycosylation

Reverse Glycosylation Sites


The canonical N-glycosylation sequence is known in the art to be Asn-X-Ser (or Thr), wherein X can be any amino acid except Pro. However, it recently has been demonstrated that asparagine (Asn) residues of human antibodies can be glycosylated in the context of a reverse consensus motif, Ser(or Thr)-X-Asn, wherein X can be any amino acid except Pro. See Valliere-Douglass et al., 2009, J. Biol. Chem. 284:32493-32506; and Valliere-Douglass et al., 2010, J. Biol. Chem. 285:16012-16022. As disclosed herein, and contrary to the state of the art understanding, anti-VEGF antigen-binding fragments for use in accordance with the methods described herein, e.g., ranibizumab, comprise several of such reverse consensus sequences. Accordingly, the methods described herein comprise use of anti-VEGF antigen-binding fragments that comprise at least one N-glycosylation site comprising the sequence Ser(or Thr)-X-Asn, wherein X can be any amino acid except Pro (also referred to herein as a “reverse N-glycosylation site”).


In certain embodiments, the methods described herein comprise use of an anti-VEGF antigen-binding fragment that comprises one, two, three, four, five, six, seven, eight, nine, ten, or more than ten N-glycosylation sites comprising the sequence Ser(or Thr)-X-Asn, wherein X can be any amino acid except Pro. In certain embodiments, the methods described herein comprise use of an anti-VEGF antigen-binding fragment that comprises one, two, three, four, five, six, seven, eight, nine, ten, or more than ten reverse N-glycosylation sites, as well as one, two, three, four, five, six, seven, eight, nine, ten, or more than ten non-consensus N-glycosylation sites (as defined herein, below).


In a specific embodiment, the anti-VEGF antigen-binding fragment comprising one or more reverse N-glycosylation sites used in the methods described herein is ranibizumab, comprising a light chain and a heavy chain of SEQ ID NOs. 1 and 2, respectively. In another specific embodiment, the anti-VEGF antigen-binding fragment comprising one or more reverse N-glycosylation sites used in the methods comprises the Fab of bevacizumab, comprising a light chain and a heavy chain of SEQ ID NOs. 3 and 4, respectively.


Non-Consensus Glycosylation Sites


In addition to reverse N-glycosylation sites, it recently has been demonstrated that glutamine (Gln) residues of human antibodies can be glycosylated in the context of a non-consensus motif, Gln-Gly-Thr. See Valliere-Douglass et al., 2010, J. Biol. Chem. 285:16012-16022. Surprisingly, anti-VEGF antigen-binding fragments for use in accordance with the methods described herein, e.g., ranibizumab, comprise several of such non-consensus sequences. Accordingly, the methods described herein comprise use of anti-VEGF antigen-binding fragments that comprise at least one N-glycosylation site comprising the sequence Gln-Gly-Thr (also referred to herein as a “non-consensus N-glycosylation site”).


In certain embodiments, the methods described herein comprise use of an anti-VEGF antigen-binding fragment that comprises one, two, three, four, five, six, seven, eight, nine, ten, or more than ten N-glycosylation sites comprising the sequence Gln-Gly-Thr.


In a specific embodiment, the anti-VEGF antigen-binding fragment comprising one or more non-consensus N-glycosylation sites used in the methods described herein is ranibizumab (comprising a light chain and a heavy chain of SEQ ID NOs. 1 and 2, respectively). In another specific embodiment, the anti-VEGF antigen-binding fragment comprising one or more non-consensus N-glycosylation sites used in the methods comprises the Fab of bevacizumab (comprising a light chain and a heavy chain of SEQ ID NOs. 3 and 4, respectively).


Engineered N-Glycosylation Sites


In certain embodiments, a nucleic acid encoding an anti-VEGF antigen-binding fragment is modified to include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more N-glycosylation sites (including the canonical N-glycosylation consensus sequence, reverse N-glycosylation site, and non-consensus N-glycosylation sites) than would normally be associated with the HuGlyFabVEGFi (e.g., relative to the number of N-glycosylation sites associated with the anti-VEGF antigen-binding fragment in its unmodified state). In specific embodiments, introduction of glycosylation sites is accomplished by insertion of N-glycosylation sites (including the canonical N-glycosylation consensus sequence, reverse N-glycosylation site, and non-consensus N-glycosylation sites) anywhere in the primary structure of the antigen-binding fragment, so long as said introduction does not impact binding of the antigen-binding fragment to its antigen, VEGF. Introduction of glycosylation sites can be accomplished by, e.g., adding new amino acids to the primary structure of the antigen-binding fragment, or the antibody from which the antigen-binding fragment is derived (i.e., the glycosylation sites are added, in full or in part), or by mutating existing amino acids in the antigen-binding fragment, or the antibody from which the antigen-binding fragment is derived, in order to generate the N-glycosylation sites (i.e., amino acids are not added to the antigen-binding fragment/antibody, but selected amino acids of the antigen-binding fragment/antibody are mutated so as to form N-glycosylation sites). Those of skill in the art will recognize that the amino acid sequence of a protein can be readily modified using approaches known in the art, e.g., recombinant approaches that include modification of the nucleic acid sequence encoding the protein.


In a specific embodiment, an anti-VEGF antigen-binding fragment used in the method described herein is modified such that, when expressed in retinal cells, it can be hyperglycosylated. See Courtois et al., 2016, mAbs 8:99-112 which is incorporated by reference herein in its entirety. In a specific embodiment, said anti-VEGF antigen-binding fragment is ranibizumab (comprising a light chain and a heavy chain of SEQ ID NOs. 1 and 2, respectively). In another specific embodiment, said anti-VEGF antigen-binding fragment comprises the Fab of bevacizumab (comprising a light chain and a heavy chain of SEQ ID NOs. 3 and 4, respectively).


N-Glycosylation of Anti-VEGF Antigen-Binding Fragments


Unlike small molecule drugs, biologics usually comprise a mixture of many variants with different modifications or forms that have a different potency, pharmacokinetics, and safety profile. It is not essential that every molecule produced either in the gene therapy or protein therapy approach be fully glycosylated and sulfated. Rather, the population of glycoproteins produced should have sufficient glycosylation (including 2,6-sialylation) and sulfation to demonstrate efficacy. The goal of gene therapy treatment provided herein is to slow or arrest the progression of retinal degeneration, and to slow or prevent loss of vision with minimal intervention/invasive procedures.


In a specific embodiment, an anti-VEGF antigen-binding fragment, e.g., ranibizumab, used in accordance with the methods described herein, when expressed in a retinal cell, could be glycosylated at 100% of its N-glycosylation sites. However, one of skill in the art will appreciate that not every N-glycosylation site of an anti-VEGF antigen-binding fragment need be N-glycosylated in order for benefits of glycosylation to be attained. Rather, benefits of glycosylation can be realized when only a percentage of N-glycosylation sites are glycosylated, and/or when only a percentage of expressed antigen-binding fragments are glycosylated. Accordingly, in certain embodiments, an anti-VEGF antigen-binding fragment used in accordance with the methods described herein, when expressed in a retinal cell, is glycosylated at 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% of it available N-glycosylation sites. In certain embodiments, when expressed in a retinal cell, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% of the an anti-VEGF antigen-binding fragments used in accordance with the methods described herein are glycosylated at least one of their available N-glycosylation sites.


In a specific embodiment, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the N-glycosylation sites present in an anti-VEGF antigen-binding fragment used in accordance with the methods described herein are glycosylated at an Asn residue (or other relevant residue) present in an N-glycosylation site, when the anti-VEGF antigen-binding fragment is expressed in a retinal cell. That is, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the N-glycosylation sites of the resultant HuGlyFabVEGFi are glycosylated.


In another specific embodiment, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the N-glycosylation sites present in an anti-VEGF antigen-binding fragment used in accordance with the methods described herein are glycosylated with an identical attached glycan linked to the Asn residue (or other relevant residue) present in an N-glycosylation site, when the anti-VEGF antigen-binding fragment is expressed in a retinal cell. That is, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the N-glycosylation sites of the resultant HuGlyFabVEGFi an identical attached glycan.


When an anti-VEGF antigen-binding fragment, e.g., ranibizumab, used in accordance with the methods described herein is expressed in a retinal cell, the N-glycosylation sites of the of the antigen-binding fragment can be glycosylated with various different glycans. N-glycans of antigen-binding fragments have been characterized in the art. For example, Bondt et al., 2014, Mol. & Cell. Proteomics 13.11:3029-3039 (incorporated by reference herein in its entirety for it disclosure of Fab-associated N-glycans) characterizes glycans associated with Fabs, and demonstrates that Fab and Fc portions of antibodies comprise distinct glycosylation patterns, with Fab glycans being high in galactosylation, sialylation, and bisection (e.g., with bisecting GlcNAc) but low in fucosylation with respect to Fc glycans. Like Bondt, Huang et al., 2006, Anal. Biochem. 349:197-207 (incorporated by reference herein in its entirety for it disclosure of Fab-associated N-glycans) found that most glycans of Fabs are sialylated. However, in the Fab of the antibody examined by Huang (which was produced in a murine cell background), the identified sialic residues were N-Glycolylneuraminic acid (“Neu5Gc” or “NeuGc”) (which is not natural to humans) instead of N-acetylneuraminic acid (“Neu5Ac,” the predominant human sialic acid). In addition, Song et al., 2014, Anal. Chem. 86:5661-5666 (incorporated by reference herein in its entirety for it disclosure of Fab-associated N-glycans) describes a library of N-glycans associated with commercially available antibodies.


Importantly, when the anti-VEGF antigen-binding fragments, e.g., ranibizumab, used in accordance with the methods described herein are expressed in human retinal cells, the need for in vitro production in prokaryotic host cells (e.g., E. coli) or eukaryotic host cells (e.g., CHO cells) is circumvented. Instead, as a result of the methods described herein (e.g., use of retinal cells to express anti-hVEGF antigen-binding fragments), N-glycosylation sites of the anti-VEGF antigen-binding fragments are advantageously decorated with glycans relevant to and beneficial to treatment of humans. Such an advantage is unattainable when CHO cells or E. coli are utilized in antibody/antigen-binding fragment production, because e.g., CHO cells (1) do not express 2,6 sialyltransferase and thus cannot add 2,6 sialic acid during N-glycosylation and (2) can add Neu5Gc as sialic acid instead of Neu5Ac; and because E. coli does not naturally contain components needed for N-glycosylation. Accordingly, in one embodiment, an anti-VEGF antigen-binding fragment expressed in a retinal cell to give rise to a HuGlyFabVEGFi used in the methods of treatment described herein is glycosylated in the manner in which a protein is N-glycosylated in human retinal cells, e.g., retinal pigment cells, but is not glycosylated in the manner in which proteins are glycosylated in CHO cells. In another embodiment, an anti-VEGF antigen-binding fragment expressed in a retinal cell to give rise to a HuGlyFabVEGFi used in the methods of treatment described herein is glycosylated in the manner in which a protein is N-glycosylated in human retinal cells, e.g., retinal pigment cells, wherein such glycosylation is not naturally possible using a prokaryotic host cell, e.g., using E. coli.


In certain embodiments, a HuGlyFabVEGFi, e.g., ranibizumab, used in accordance with the methods described herein comprises one, two, three, four, five or more distinct N-glycans associated with Fabs of human antibodies. In a specific embodiment, said N-glycans associated with Fabs of human antibodies are those described in Bondt et al., 2014, Mol. & Cell. Proteomics 13.11:3029-3039, Huang et al., 2006, Anal. Biochem. 349:197-207, and/or Song et al., 2014, Anal. Chem. 86:5661-5666. In certain embodiments, a HuGlyFabVEGFi, e.g., ranibizumab, used in accordance with the methods described herein does not comprise detectable NeuGc and/or α-Gal antigen.


In a specific embodiment, the HuGlyFabVEGFi, e.g., ranibizumab, used in accordance with the methods described herein are predominantly glycosylated with a glycan comprising 2,6-linked sialic acid. In certain embodiments, HuGlyFabVEGFi comprising 2,6-linked sialic acid is polysialylated, i.e., contains more than one sialic acid. In certain embodiments, each N-glycosylation site of said HuGlyFabVEGFi comprises a glycan comprising 2,6-linked sialic acid, i.e., 100% of the N-glycosylation site of said HuGlyFabVEGFi comprise a glycan comprising 2,6-linked sialic acid. In another specific embodiment, at least 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the N-glycosylation sites of a HuGlyFabVEGFi used in accordance with the methods described herein are glycosylated with a glycan comprising 2,6-linked sialic acid. In another specific embodiment, at least 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80% 90%, or 90%-99% of the N-glycosylation sites of a HuGlyFabVEGFi used in accordance with the methods described herein are glycosylated with a glycan comprising 2,6-linked sialic acid. In another specific embodiment, at least 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the antigen-binding fragments expressed in a retinal cell in accordance with methods described herein (i.e., the antigen-binding fragments that give rise to HuGlyFabVEGFi, e.g., ranibizumab) are glycosylated with a glycan comprising 2,6-linked sialic acid. In another specific embodiment, at least 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-99% of the antigen-binding fragments expressed in a retinal cell in accordance with methods described herein (i.e., the Fabs that give rise to HuGlyFabVEGFi, e.g., ranibizumab) are glycosylated with a glycan comprising 2,6-linked sialic acid. In another specific embodiment, said sialic acid is Neu5Ac. In accordance with such embodiments, when only a percentage of the N-glycosylation sites of a HuGlyFabVEGFi are 2,6 sialylated or polysialylated, the remaining N-glycosylation can comprise a distinct N-glycan, or no N-glycan at all (i.e., remain non-glycosylated).


When a HuGlyFabVEGFi is 2,6 polysialylated, it comprises multiple sialic acid residues, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10 sialic acid residues. In certain embodiments, when a HuGlyFabVEGFi is polysialylated, it comprises 2-5, 5-10, 10-20, 20-30, 30-40, or 40-50 sialic acid residues. In certain embodiments, when a HuGlyFabVEGFi is polysialylated, it comprises 2,6-linked (sialic acid)n, wherein n can be any number from 1-100.


In a specific embodiment, the HuGlyFabVEGFi, e.g., ranibizumab, used in accordance with the methods described herein are predominantly glycosylated with a glycan comprising a bisecting GlcNAc. In certain embodiments, each N-glycosylation site of said HuGlyFabVEGFi comprises a glycan comprising a bisecting GlcNAc, i.e., 100% of the N-glycosylation site of said HuGlyFabVEGFi comprise a glycan comprising a bisecting GlcNAc. In another specific embodiment, at least 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the N-glycosylation sites of a HuGlyFabVEGFi used in accordance with the methods described herein are glycosylated with a glycan comprising a bisecting GlcNAc. In another specific embodiment, at least 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-99% of the N-glycosylation sites of a HuGlyFabVEGFi used in accordance with the methods described herein are glycosylated with a glycan comprising a bisecting GlcNAc. In another specific embodiment, at least 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the antigen-binding fragments expressed in a retinal cell in accordance with methods described herein (i.e., the antigen-binding fragments that give rise to HuGlyFabVEGFi, e.g., ranibizumab) are glycosylated with a glycan comprising a bisecting GlcNAc. In another specific embodiment, at least 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-99% of the antigen-binding fragments expressed in a retinal cell in accordance with methods described herein (i.e., the antigen-binding fragments that give rise to HuGlyFabVEGFi, e.g., ranibizumab) are glycosylated with a glycan comprising a bisecting GlcNAc.


In certain embodiments, the HuGlyFabVEGFi, e.g., ranibizumab, used in accordance with the methods described herein are hyperglycosylated, i.e., in addition to the N-glycosylation resultant from the naturally occurring N-glycosylation sites, said HuGlyFabVEGFi comprise glycans at N-glycosylation sites engineered to be present in the amino acid sequence of the antigen-binding fragment giving rise to HuGlyFabVEGFi. In certain embodiments, the HuGlyFabVEGFi, e.g., ranibizumab, used in accordance with the methods described herein is hyperglycosylated but does not comprise detectable NeuGc and/or α-Gal antigen.


Assays for determining the glycosylation pattern of antibodies, including antigen-binding fragments are known in the art. For example, hydrazinolysis can be used to analyze glycans. First, polysaccharides are released from their associated protein by incubation with hydrazine (the Ludger Liberate Hydrazinolysis Glycan Release Kit, Oxfordshire, UK can be used). The nucleophile hydrazine attacks the glycosidic bond between the polysaccharide and the carrier protein and allows release of the attached glycans. N-acetyl groups are lost during this treatment and have to be reconstituted by re-N-acetylation. Glycans may also be released using enzymes such as glycosidases or endoglycosidases, such as PNGase F and Endo H, which cleave cleanly and with fewer side reactions than hydrazines. The free glycans can be purified on carbon columns and subsequently labeled at the reducing end with the fluorophor 2-amino benzamide. The labeled polysaccharides can be separated on a GlycoSep-N column (GL Sciences) according to the HPLC protocol of Royle et al, Anal Biochem 2002, 304(1):70-90. The resulting fluorescence chromatogram indicates the polysaccharide length and number of repeating units. Structural information can be gathered by collecting individual peaks and subsequently performing MS/MS analysis. Thereby the monosaccharide composition and sequence of the repeating unit can be confirmed and additionally in homogeneity of the polysaccharide composition can be identified. Specific peaks of low or high molecular weight can be analyzed by MALDI-MS/MS and the result used to confirm the glycan sequence. Each peak in the chromatogram corresponds to a polymer, e.g., glycan, consisting of a certain number of repeat units and fragments, e.g., sugar residues, thereof. The chromatogram thus allows measurement of the polymer, e.g., glycan, length distribution. The elution time is an indication for polymer length, while fluorescence intensity correlates with molar abundance for the respective polymer, e.g., glycan. Other methods for assessing glycans associated with antigen-binding fragments include those described by Bondt et al., 2014, Mol. & Cell. Proteomics 13.11:3029-3039, Huang et al., 2006, Anal. Biochem. 349:197-207, and/or Song et al., 2014, Anal. Chem. 86:5661-5666.


Homogeneity or heterogeneity of the glycan patterns associated with antibodies (including antigen-binding fragments), as it relates to both glycan length or size and numbers glycans present across glycosylation sites, can be assessed using methods known in the art, e.g., methods that measure glycan length or size and hydrodynamic radius. HPLC, such as Size exclusion, normal phase, reversed phase, and anion exchange HPLC, as well as capillary electrophoresis, allows the measurement of the hydrodynamic radius. Higher numbers of glycosylation sites in a protein lead to higher variation in hydrodynamic radius compared to a carrier with less glycosylation sites. However, when single glycan chains are analyzed, they may be more homogenous due to the more controlled length. Glycan length can be measured by hydrazinolysis, SDS PAGE, and capillary gel electrophoresis. In addition, homogeneity can also mean that certain glycosylation site usage patterns change to a broader/narrower range. These factors can be measured by Glycopeptide LC-MS/MS.


Benefits of N-Glycosylation


N-glycosylation confers numerous benefits on the HuGlyFabVEGFi used in the methods described herein. Such benefits are unattainable by production of antigen-binding fragments in E. coli, because E. coli does not naturally possess components needed for N-glycosylation. Further, some benefits are unattainable through antibody production in, e.g., CHO cells, because CHO cells lack components needed for addition of certain glycans (e.g., 2,6 sialic acid and bisecting GlcNAc) and because CHO cells can add glycans, e.g., Neu5Gc not typical to humans. See, e.g., Song et al., 2014, Anal. Chem. 86:5661-5666. Accordingly, by virtue of the discovery set forth herein that anti-VEGF antigen-binding fragments, e.g., ranibizumab, comprise non-canonical N-glycosylation sites (including both reverse and non-consensus glycosylation sites), a method of expressing such anti-VEGF antigen-binding fragments in a manner that results in their glycosylation (and thus improved benefits associated with the antigen-binding fragments) has been realized. In particular, expression of anti-VEGF antigen-binding fragments in human retinal cells results in the production of HuGlyFabVEGFi (e.g., ranibizumab) comprising beneficial glycans that otherwise would not be associated with the antigen-binding fragments or their parent antibody.


While non-canonical glycosylation sites usually result in low level glycosylation (e.g., 1-5%) of the antibody population, the functional benefits may be significant in immunoprivileged organs, such as the eye (See, e.g., van de Bovenkamp et al., 2016, J. Immunol. 196:1435-1441). For example, Fab glycosylation may affect the stability, half-life, and binding characteristics of an antibody. To determine the effects of Fab glycosylation on the affinity of the antibody for its target, any technique known to one of skill in the art may be used, for example, enzyme linked immunosorbent assay (ELISA), or surface plasmon resonance (SPR). To determine the effects of Fab glycosylation on the half-life of the antibody, any technique known to one of skill in the art may be used, for example, by measurement of the levels of radioactivity in the blood or organs (e.g., the eye) in a subject to whom a radiolabeled antibody has been administered. To determine the effects of Fab glycosylation on the stability, for example, levels of aggregation or protein unfolding, of the antibody, any technique known to one of skill in the art may be used, for example, differential scanning calorimetry (DSC), high performance liquid chromatography (HPLC), e.g., size exclusion high performance liquid chromatography (SEC-HPLC), capillary electrophoresis, mass spectrometry, or turbidity measurement. Provided herein, the HuGlyFabVEGFi transgene results in production of an antigen-binding fragment which is 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% or more glycosylated at non-canonical sites. In certain embodiments, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% or more antigen-binding fragments from a population of antigen-binding fragments are glycosylated at non-canonical sites. In certain embodiments, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% or more non-canonical sites are glycosylated. In certain embodiments, the glycosylation of the antigen-binding fragment at these non-canonical sites is 25%, 50%, 100%, 200%, 300%, 400%, 500%, or more greater than the amount of glycosylation of these non-canonical sites in an antigen-binding fragment produced in HEK293 cells.


The presence of sialic acid on HuGlyFabVEGFi used in the methods described herein can impact clearance rate of the HuGlyFabVEGFi, e.g., the rate of clearance from the vitreous humour. Accordingly, sialic acid patterns of a HuGlyFabVEGFi can be used to generate a therapeutic having an optimized clearance rate. Method of assessing antigen-binding fragment clearance rate are known in the art. See, e.g., Huang et al., 2006, Anal. Biochem. 349:197-207.


In another specific embodiment, a benefit conferred by N-glycosylation is reduced aggregation. Occupied N-glycosylation sites can mask aggregation prone amino acid residues, resulting in decreased aggregation. Such N-glycosylation sites can be native to an antigen-binding fragment used herein, or engineered into an antigen-binding fragment used herein, resulting in HuGlyFabVEGFi that is less prone to aggregation when expressed, e.g., expressed in retinal cells. Methods of assessing aggregation of antibodies are known in the art. See, e.g., Courtois et al., 2016, mAbs 8:99-112 which is incorporated by reference herein in its entirety.


In another specific embodiment, a benefit conferred by N-glycosylation is reduced immunogenicity. Such N-glycosylation sites can be native to an antigen-binding fragment used herein, or engineered into an antigen-binding fragment used herein, resulting in HuGlyFabVEGFi that is less prone to immunogenicity when expressed, e.g., expressed in retinal cells.


In another specific embodiment, a benefit conferred by N-glycosylation is protein stability. N-glycosylation of proteins is well-known to confer stability on them, and methods of assessing protein stability resulting from N-glycosylation are known in the art. See, e.g., Sola and Griebenow, 2009, J Pharm Sci., 98(4): 1223-1245.


In another specific embodiment, a benefit conferred by N-glycosylation is altered binding affinity. It is known in the art that the presence of N-glycosylation sites in the variable domains of an antibody can increase the affinity of the antibody for its antigen. See, e.g., Bovenkamp et al., 2016, J. Immunol. 196:1435-1441. Assays for measuring antibody binding affinity are known in the art. See, e.g., Wright et al., 1991, EMBO J. 10:2717-2723; and Leibiger et al., 1999, Biochem. J. 338:529-538.


(b) Tyrosine Sulfation

Tyrosine sulfation occurs at tyrosine (Y) residues with glutamate (E) or aspartate (D) within +5 to −5 position of Y, and where position −1 of Y is a neutral or acidic charged amino acid, but not a basic amino acid, e.g., arginine (R), lysine (K), or histidine (H) that abolishes sulfation. Surprisingly, anti-VEGF antigen-binding fragments for use in accordance with the methods described herein, e.g., ranibizumab, comprise tyrosine sulfation sites (see FIG. 1). Accordingly, the methods described herein comprise use of anti-VEGF antigen-binding fragments, e.g., HuPTMFabVEGFi, that comprise at least one tyrosine sulfation site, such the anti-VEGF antigen-binding fragments, when expressed in retinal cells, can be tyrosine sulfated.


Importantly, tyrosine-sulfated antigen-binding fragments, e.g., ranibizumab, cannot be produced in E. coli, which naturally does not possess the enzymes required for tyrosine-sulfation. Further, CHO cells are deficient for tyrosine sulfation—they are not secretory cells and have a limited capacity for post-translational tyrosine-sulfation. See, e.g., Mikkelsen & Ezban, 1991, Biochemistry 30: 1533-1537. Advantageously, the methods provided herein call for expression of anti-VEGF antigen-binding fragments, e.g., HuPTMFabVEGFi, for example, ranibizumab, in retinal cells, which are secretory and do have capacity for tyrosine sulfation. See Kanan et al., 2009, Exp. Eye Res. 89: 559-567 and Kanan & Al-Ubaidi, 2015, Exp. Eye Res. 133: 126-131 reporting the production of tyrosine-sulfated glycoproteins secreted by retinal cells.


Tyrosine sulfation is advantageous for several reasons. For example, tyrosine-sulfation of the antigen-binding fragment of therapeutic antibodies against targets has been shown to dramatically increase avidity for antigen and activity. See, e.g., Loos et al., 2015, PNAS 112: 12675-12680, and Choe et al., 2003, Cell 114: 161-170. Assays for detection tyrosine sulfation are known in the art. See, e.g., Yang et al., 2015, Molecules 20:2138-2164.


(c) O-Glycosylation

O-glycosylation comprises the addition of N-acetyl-galactosamine to serine or threonine residues by the enzyme. It has been demonstrated that amino acid residues present in the hinge region of antibodies can be 0-glycosylated. In certain embodiments, the anti-VEGF antigen-binding fragments, e.g., ranibizumab, used in accordance with the methods described herein comprise all or a portion of their hinge region, and thus are capable of being 0-glycosylated when expressed in human retinal cells. The possibility of O-glycosylation confers another advantage to the HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, provided herein, as compared to, e.g., antigen-binding fragments produced in E. coli, again because the E. coli naturally does not contain machinery equivalent to that used in human O-glycosylation. (Instead, O-glycosylation in E. coli has been demonstrated only when the bacteria is modified to contain specific O-glycosylation machinery. See, e.g., Faridmoayer et al., 2007, J. Bacteriol. 189:8088-8098) O-glycosylated HuPTMFabVEGFi, e.g., HuGlyFabVEGFi, by virtue of possessing glycans, shares advantageous characteristics with N-glycosylated HuGlyFabVEGFi (as discussed above).


6.3.2 Constructs and Formulations


In some aspects, the disclosure provides for a nucleic acid for use, wherein the nucleic acid encodes a HuPTMFabVEGFi, e.g., HuGlyFabVEGFi operatively linked to a promoter selected from the group consisting of: cytomegalovirus (CMV) promoter, Rous sarcoma virus (RSV) promoter, MMT promoter, EF-1 alpha promoter, UB6 promoter, chicken beta-actin promoter, CAG promoter, RPE65 promoter and opsin promoter.


In a specific embodiment, the recombinant vectors described herein comprise the following components: (1) AAV2 inverted terminal repeats that flank the expression cassette; (2) Control elements, which include a) the CB7 promoter, comprising the CMV enhancer/chicken β-actin promoter, b) a chicken β-actin intron and c) a rabbit β-globin poly A signal; and (3) nucleic acid sequences coding for the heavy and light chains of anti-VEGF antigen-binding fragment, separated by a self-cleaving furin (F)/F2A linker, ensuring expression of equal amounts of the heavy and the light chain polypeptides.


The HuPTMFabVEGFi, e.g., HuGlyFabVEGFi encoded by the transgene can include, but is not limited to an antigen-binding fragment of an antibody that binds to VEGF, such as bevacizumab; an anti-VEGF Fab moiety such as ranibizumab; or such bevacizumab or ranibizumab Fab moieties engineered to contain additional glycosylation sites on the Fab domain (e.g., see Courtois et al., 2016, mAbs 8: 99-112 which is incorporated by reference herein in its entirety for it description of derivatives of bevacizumab that are hyperglycosylated on the Fab domain of the full length antibody).


In certain embodiments, the recombinant vectors provided herein encode an anti-VEGF antigen-binding fragment transgene. In specific embodiments, the anti-VEGF antigen-binding fragment transgene is controlled by appropriate expression control elements for expression in retinal cells: In certain embodiments, the anti-VEGF antigen-binding fragment transgene comprises bevacizumab Fab portion of the light and heavy chain cDNA sequences (SEQ ID NOs. 10 and 11, respectively). In certain embodiments, the anti-VEGF antigen-binding fragment transgene comprises ranibizumab light and heavy chain cDNA sequences (SEQ ID NOs. 12 and 13, respectively). In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes a bevacizumab Fab, comprising a light chain and a heavy chain of SEQ ID NOs: 3 and 4, respectively. In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain comprising an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence set forth in SEQ ID NO: 3. In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a heavy chain comprising an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence set forth in SEQ ID NO: 4. In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain comprising an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence set forth in SEQ ID NO: 3 and a heavy chain comprising an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence set forth in SEQ ID NO: 4. In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes a hyperglycosylated ranibizumab, comprising a light chain and a heavy chain of SEQ ID NOs: 1 and 2, respectively. In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain comprising an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence set forth in SEQ ID NO: 1. In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a heavy chain comprising an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence set forth in SEQ ID NO: 2. In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain comprising an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence set forth in SEQ ID NO: 1 and a heavy chain comprising an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence set forth in SEQ ID NO: 2.


In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes a hyperglycosylated bevacizumab Fab, comprising a light chain and a heavy chain of SEQ ID NOs: 3 and 4, with one or more of the following mutations: L118N (heavy chain), E195N (light chain), or Q160N or Q1605 (light chain). In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes a hyperglycosylated ranibizumab, comprising a light chain and a heavy chain of SEQ ID NOs: 1 and 2, with one or more of the following mutations: L118N (heavy chain), E195N (light chain), or Q160N or Q1605 (light chain). The sequences of the antigen-binding fragment transgene cDNAs may be found, for example, in Table 2. In certain embodiments, the sequence of the antigen-binding fragment transgene cDNAs is obtained by replacing the signal sequence of SEQ ID NOs: 10 and 11 or SEQ ID NOs: 12 and 13 with one or more signal sequences listed in Table 1.


In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment and comprises the nucleotide sequences of the six bevacizumab CDRs. In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment and comprises the nucleotide sequences of the six ranibizumab CDRs. In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a heavy chain variable region comprising heavy chain CDRs 1-3 of ranibizumab (SEQ ID NOs: 20, 18, and 21). In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain variable region comprising light chain CDRs 1-3 of ranibizumab (SEQ ID NOs: 14-16). In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a heavy chain variable region comprising heavy chain CDRs 1-3 of bevacizumab (SEQ ID NOs: 17-19). In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain variable region comprising light chain CDRs 1-3 of bevacizumab (SEQ ID NOs: 14-16). In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a heavy chain variable region comprising heavy chain CDRs 1-3 of ranibizumab (SEQ ID NOs: 20, 18, and 21) and a light chain variable region comprising light chain CDRs 1-3 of ranibizumab (SEQ ID NOs: 14-16). In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a heavy chain variable region comprising heavy chain CDRs 1-3 of bevacizumab (SEQ ID NOs: 17-19) and a light chain variable region comprising light chain CDRs 1-3 of bevacizumab (SEQ ID NOs: 14-16).


In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain variable region comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16, wherein the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain variable region comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16, wherein the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14) each carries one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain variable region comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16, wherein the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. In a specific embodiment, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain variable region comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16, wherein the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14) each carries one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. In a preferred embodiment, the chemical modification(s) or lack of chemical modification(s) (as the case may be) described herein is determined by mass spectrometry.


In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a heavy chain variable region comprising heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a heavy chain variable region comprising heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a heavy chain variable region comprising heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated. In a specific embodiment, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a heavy chain variable region comprising heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated. In a preferred embodiment, the chemical modification(s) or lack of chemical modification(s) (as the case may be) described herein is determined by mass spectrometry.


In certain embodiments, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain variable region comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16 and a heavy chain variable region comprising heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain variable region comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16 and a heavy chain variable region comprising heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein: (1) the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu); and (2) the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14) each carries one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the anti-VEGF antigen-binding fragment transgene encodes an antigen-binding fragment comprising a light chain variable region comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16 and a heavy chain variable region comprising heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated, and wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated. In a specific embodiment, the antigen-binding fragment comprises a heavy chain CDR1 of SEQ ID NO. 20, wherein: (1) the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated; and (2) the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14) each carries one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. In a preferred embodiment, the chemical modification(s) or lack of chemical modification(s) (as the case may be) described herein is determined by mass spectrometry.


In certain aspects, also provided herein are anti-VEGF antigen-binding fragments comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, and transgenes encoding such antigen-VEGF antigen-binding fragments, wherein the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14) each carries one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14) each carries one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. The anti-VEGF antigen-binding fragments and transgenes provided herein can be used in any method according to the invention described herein. In a preferred embodiment, the chemical modification(s) or lack of chemical modification(s) (as the case may be) described herein is determined by mass spectrometry.


In certain aspects, also provided herein are anti-VEGF antigen-binding fragments comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, and transgenes encoding such antigen-VEGF antigen-binding fragments, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated. In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated. The anti-VEGF antigen-binding fragments and transgenes provided herein can be used in any method according to the invention described herein. In a preferred embodiment, the chemical modification(s) or lack of chemical modification(s) (as the case may be) described herein is determined by mass spectrometry.


In certain aspects, also provided herein are anti-VEGF antigen-binding fragments comprising light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, and transgenes encoding such antigen-VEGF antigen-binding fragments, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein: (1) the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu); and (2) the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14) each carries one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) does not carry one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu). In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated, and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. In a specific embodiment, the antigen-binding fragment comprises light chain CDRs 1-3 of SEQ ID NOs: 14-16 and heavy chain CDRs 1-3 of SEQ ID NOs: 20, 18, and 21, wherein: (1) the ninth amino acid residue of the heavy chain CDR1 (i.e., the M in GYDFTHYGMN (SEQ ID NO. 20)) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), the third amino acid residue of the heavy chain CDR2 (i.e., the N in WINTYTGEPTYAADFKR (SEQ ID NO. 18) carries one or more of the following chemical modifications: acetylation, deamidation, and pyroglutamation (pyro Glu), and the last amino acid residue of the heavy chain CDR1 (i.e., the N in GYDFTHYGMN (SEQ ID NO. 20)) is not acetylated; and (2) the eighth and eleventh amino acid residues of the light chain CDR1 (i.e., the two Ns in SASQDISNYLN (SEQ ID NO. 14) each carries one or more of the following chemical modifications: oxidation, acetylation, deamidation, and pyroglutamation (pyro Glu), and the second amino acid residue of the light chain CDR3 (i.e., the second Q in QQYSTVPWTF (SEQ ID NO. 16)) is not acetylated. The anti-VEGF antigen-binding fragments and transgenes provided herein can be used in any method according to the invention described herein. In a preferred embodiment, the chemical modification(s) or lack of chemical modification(s) (as the case may be) described herein is determined by mass spectrometry.









TABLE 2







Exemplary anti-VEGF transgene and antibody sequences








VEGF antigen-



binding fragment



(SEQ ID NO.)
Sequence





bevacizumab cDNA
gctagcgcca ccatgggctg gtcctgcatc atcctgttcc tggtggccac


(Light chain)
cgccaccggc gtgcactccg acatccagat gacccagtcc ccctcctccc


(10)
tgtccgcctc cgtgggcgac cgggtgacca tcacctgctc cgcctcccag



gacatctcca actacctgaa ctggtaccag cagaagcccg gcaaggcccc



caaggtgctg atctacttca cctcctccct gcactccggc gtgccctccc



ggttctccgg ctccggctcc ggcaccgact tcaccctgac catctcctcc



ctgcagcccg aggacttcgc cacctactac tgccagcagt actccaccgt



gccctggacc ttcggccagg gcaccaaggt ggagatcaag cggaccgtgg



ccgccccctc cgtgttcatc ttccccccct ccgacgagca gctgaagtcc



ggcaccgcct ccgtggtgtg cctgctgaac aacttctacc cccgggaggc



caaggtgcag tggaaggtgg acaacgccct gcagtccggc aactcccagg



agtccgtgac cgagcaggac tccaaggact ccacctactc cctgtcctcc



accctgaccc tgtccaaggc cgactacgag aagcacaagg tgtacgcctg



cgaggtgacc caccagggcc tgtcctcccc cgtgaccaag tccttcaacc



ggggcgagtg ctgagcggcc gcctcgag





bevacizumab cDNA
gctagcgcca ccatgggctg gtcctgcatc atcctgttcc tggtggccac


(Heavy chain)
cgccaccggc gtgcactccg aggtgcagct ggtggagtcc ggcggcggcc


(11)
tggtgcagcc cggcggctcc ctgcggctgt cctgcgccgc ctccggctac



accttcacca actacggcat gaactgggtg cggcaggccc ccggcaaggg



cctggagtgg gtgggctgga tcaacaccta caccggcgag cccacctacg



ccgccgactt caagcggcgg ttcaccttct ccctggacac ctccaagtcc



accgcctacc tgcagatgaa ctccctgcgg gccgaggaca ccgccgtgta



ctactgcgcc aagtaccccc actactacgg ctcctcccac tggtacttcg



acgtgtgggg ccagggcacc ctggtgaccg tgtcctccgc ctccaccaag



ggcccctccg tgttccccct ggccccctcc tccaagtcca cctccggcgg



caccgccgcc ctgggctgcc tggtgaagga ctacttcccc gagcccgtga



ccgtgtcctg gaactccggc gccctgacct ccggcgtgca caccttcccc



gccgtgctgc agtcctccgg cctgtactcc ctgtcctccg tggtgaccgt



gccctcctcc tccctgggca cccagaccta catctgcaac gtgaaccaca



agccctccaa caccaaggtg gacaagaagg tggagcccaa gtcctgcgac



aagacccaca cctgcccccc ctgccccgcc cccgagctgc tgggcggccc



ctccgtgttc ctgttccccc ccaagcccaa ggacaccctg atgatctccc



ggacccccga ggtgacctgc gtggtggtgg acgtgtccca cgaggacccc



gaggtgaagt tcaactggta cgtggacggc gtggaggtgc acaacgccaa



gaccaagccc cgggaggagc agtacaactc cacctaccgg gtggtgtccg



tgctgaccgt gctgcaccag gactggctga acggcaagga gtacaagtgc



aaggtgtcca acaaggccct gcccgccccc atcgagaaga ccatctccaa



ggccaagggc cagccccggg agccccaggt gtacaccctg cccccctccc



gggaggagat gaccaagaac caggtgtccc tgacctgcct ggtgaagggc



ttctacccct ccgacatcgc cgtggagtgg gagtccaacg gccagcccga



gaacaactac aagaccaccc cccccgtgct ggactccgac ggctccttct



tcctgtactc caagctgacc gtggacaagt cccggtggca gcagggcaac



gtgttctcct gctccgtgat gcacgaggcc ctgcacaacc actacaccca



gaagtccctg tccctgtccc ccggcaagtg agcggccgcc





bevacizumab Fab
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLH


Amino Acid
SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTV


Sequence (Light
AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE


chain)
QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


(3)






bevacizumab Fab
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYT


Amino Acid
GEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYF


Sequence (Heavy
DVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN


chain)
SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK


(4)
VEPKSCDKTHL





ranibizumab cDNA
gagctccatg gagtttttca aaaagacggc acttgccgca ctggttatgg


(Light chain
gttttagtgg tgcagcattg gccgatatcc agctgaccca gagcccgagc


comprising a
agcctgagcg caagcgttgg tgatcgtgtt accattacct gtagcgcaag


signal sequence)
ccaggatatt agcaattatc tgaattggta tcagcagaaa ccgggtaaag


(12)
caccgaaagt tctgatttat tttaccagca gcctgcatag cggtgttccg



agccgtttta gcggtagcgg tagtggcacc gattttaccc tgaccattag



cagcctgcag ccggaagatt ttgcaaccta ttattgtcag cagtatagca



ccgttccgtg gacctttggt cagggcacca aagttgaaat taaacgtacc



gttgcagcac cgagcgtttt tatttttccg cctagtgatg aacagctgaa



aagcggcacc gcaagcgttg tttgtctgct gaataatttt tatccgcgtg



aagcaaaagt gcagtggaaa gttgataatg cactgcagag cggtaatagc



caagaaagcg ttaccgaaca ggatagcaaa gatagcacct atagcctgag



cagcaccctg accctgagca aagcagatta tgaaaaacac aaagtgtatg



cctgcgaagt tacccatcag ggtctgagca gtccggttac caaaagtttt



aatcgtggcg aatgctaata gaagcttggt acc





ranibizumab cDNA
gagctcatat gaaatacctg ctgccgaccg ctgctgctgg tctgctgctc


(Heavy chain
ctcgctgccc agccggcgat ggccgaagtt cagctggttg aaagcggtgg


comprising a
tggtctggtt cagcctggtg gtagcctgcg tctgagctgt gcagcaagcg


signal sequence)
gttatgattt tacccattat ggtatgaatt gggttcgtca ggcaccgggt


(13)
aaaggtctgg aatgggttgg ttggattaat acctataccg gtgaaccgac



ctatgcagca gattttaaac gtcgttttac ctttagcctg gataccagca



aaagcaccgc atatctgcag atgaatagcc tgcgtgcaga agataccgca



gtttattatt gtgccaaata tccgtattac tatggcacca gccactggta



tttcgatgtt tggggtcagg gcaccctggt taccgttagc agcgcaagca



ccaaaggtcc gagcgttttt ccgctggcac cgagcagcaa aagtaccagc



ggtggcacag cagcactggg ttgtctggtt aaagattatt ttccggaacc



ggttaccgtg agctggaata gcggtgcact gaccagcggt gttcatacct



ttccggcagt tctgcagagc agcggtctgt atagcctgag cagcgttgtt



accgttccga gcagcagcct gggcacccag acctatattt gtaatgttaa



tcataaaccg agcaatacca aagtggataa aaaagttgag ccgaaaagct



gcgataaaac ccatctgtaa tagggtacc





ranibizumab Fab
DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLH


Amino Acid
SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTV


Sequence (Light
AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE


chain)
QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC


(1)






ranibizumab Fab
EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYT


Amino Acid
GEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYF


Sequence (Heavy
DVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN


chain)
SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK


(2)
VEPKSCDKTHL





bevacizumab Light
SASQDISNYLN


Chain CDRs
FTSSLHS


(14, 15, and 16)
QQYSTVPWT





bevacizumab Heavy
GYTFTNYGMN


Chain CDRs
WINTYTGEPTYAADFKR


(17, 18, and 19)
YPHYYGSSHWYFDV





ranibizumab Light
SASQDISNYLN


Chain CDRs
FTSSLHS


(14, 15, and 16)
QQYSTVPWT





ranibizumab Heavy
GYDFTHYGMN


Chain CDRs
WINTYTGEPTYAADFKR


(20, 18, and 21)
YPYYYGTSHWYFDV









In certain embodiments, the recombinant vectors provided herein comprise the following elements in the following order: a) a constitutive or a hypoxia-inducible promoter sequence, and b) a sequence encoding the transgene (e.g., an anti-VEGF antigen-binding fragment moiety). In certain embodiments, the sequence encoding the transgene comprises multiple ORFs separated by IRES elements. In certain embodiments, the ORFs encode the heavy and light chain domains of the anti-VEGF antigen-binding fragment. In certain embodiments, the sequence encoding the transgene comprises multiple subunits in one ORF separated by F/F2A sequences. In certain embodiments, the sequence comprising the transgene encodes the heavy and light chain domains of the anti-VEGF antigen-binding fragment separated by an F/F2A sequence. In certain embodiments, the viral vectors provided herein comprise the following elements in the following order: a) a constitutive or a hypoxia-inducible promoter sequence, and b) a sequence encoding the transgene (e.g., an anti-VEGF antigen-binding fragment moiety), wherein the transgene comprises the signal peptide of VEGF (SEQ ID NO: 5), and wherein the transgene encodes a light chain and a heavy chain sequence separated by an IRES element. In certain embodiments, the recombinant vectors provided herein comprise the following elements in the following order: a) a constitutive or a hypoxia-inducible promoter sequence, and b) a sequence encoding the transgene (e.g., an anti-VEGF antigen-binding fragment moiety), wherein the transgene comprises the signal peptide of VEGF (SEQ ID NO: 5), and wherein the transgene encodes a light chain and a heavy chain sequence separated by a cleavable F/F2A sequence.


In certain embodiments, the recombinant vectors provided herein comprise the following elements in the following order: a) a first ITR sequence, b) a first linker sequence, c) a constitutive or a hypoxia-inducible promoter sequence, d) a second linker sequence, e) an intron sequence, f) a third linker sequence, g) a first UTR sequence, h) a sequence encoding the transgene (e.g., an anti-VEGF antigen-binding fragment moiety), i) a second UTR sequence, j) a fourth linker sequence, k) a poly A sequence, 1) a fifth linker sequence, and m) a second ITR sequence.


In certain embodiments, the recombinant vectors provided herein comprise the following elements in the following order: a) a first ITR sequence, b) a first linker sequence, c) a constitutive or a hypoxia-inducible promoter sequence, d) a second linker sequence, e) an intron sequence, f) a third linker sequence, g) a first UTR sequence, h) a sequence encoding the transgene (e.g., an anti-VEGF antigen-binding fragment moiety), i) a second UTR sequence, j) a fourth linker sequence, k) a poly A sequence, 1) a fifth linker sequence, and m) a second ITR sequence, wherein the transgene comprises the signal peptide of VEGF (SEQ ID NO: 5), and wherein the transgene encodes a light chain and a heavy chain sequence separated by a cleavable F/F2A sequence.


In a specific embodiment, the recombinant vector provided herein is Construct II, wherein the Construct II comprise the following components: (1) AAV2 inverted terminal repeats that flank the expression cassette; (2) control elements, which include a) the CB7 promoter, comprising the CMV enhancer/chicken β-actin promoter, b) a chicken β-actin intron and c) a rabbit β-globin poly A signal; and (3) nucleic acid sequences coding for the heavy and light chains of anti-VEGF antigen-binding fragment, separated by a self-cleaving furin (F)/F2A linker, ensuring expression of equal amounts of the heavy and the light chain polypeptides. In a specific embodiment, the construct described herein is illustrated in FIG. 5.


6.3.3 Gene Therapy


(a) Target Patient Populations

In certain embodiments, the methods provided herein are for the administration to patients diagnosed with an ocular disease (for example, wet AMD, dry AMD, retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR) (in particular, wet AMD)), in particular an ocular disease caused by increased neovascularization.


In certain embodiments, the methods provided herein are for the administration to patients diagnosed with severe AMD. In certain embodiments, the methods provided herein are for the administration to patients diagnosed with attenuated AMD.


In certain embodiments, the methods provided herein are for the administration to patients diagnosed with severe wet AMD. In certain embodiments, the methods provided herein are for the administration to patients diagnosed with attenuated wet AMD.


In certain embodiments, the methods provided herein are for the administration to patients diagnosed with severe diabetic retinopathy. In certain embodiments, the methods provided herein are for the administration to patients diagnosed with attenuated diabetic retinopathy.


In certain embodiments, the methods provided herein are for the administration to patients diagnosed with AMD who have been identified as responsive to treatment with an anti-VEGF antibody.


In certain embodiments, the methods provided herein are for the administration to patients diagnosed with AMD who have been identified as responsive to treatment with an anti-VEGF antigen-binding fragment.


In certain embodiments, the methods provided herein are for the administration to patients diagnosed with AMD who have been identified as responsive to treatment with an anti-VEGF antigen-binding fragment injected intravitreally prior to treatment with gene therapy.


In certain embodiments, the methods provided herein are for the administration to patients diagnosed with AMD who have been identified as responsive to treatment with LUCENTIS® (ranibizumab), EYLEA® (aflibercept), and/or AVASTIN® (bevacizumab).


In certain embodiments, a patient diagnosed with AMD is identified as responsive to treatment with an anti-VEGF antigen-binding fragment (e.g., ranibizumab) if the patient has improvement in fluid after intravitreal injection of the anti-VEGF antigen-binding fragment to the patient prior to treatment with gene therapy. In certain embodiments, a patient diagnosed with AMD is identified as responsive to treatment with an anti-VEGF antigen-binding fragment (e.g., ranibizumab) if the patient has improvement in fluid and has a central retinal thickness (CRT) <400 μm after intravitreal injection of the anti-VEGF antigen-binding fragment to the patient prior to treatment with gene therapy. In some embodiments, the anti-VEGF antigen-binding fragment is intravitreally injected to the patient at 0.5 mg per month for two months prior to treatment with gene therapy. In other embodiments, the anti-VEGF antigen-binding fragment is intravitreally injected to the patient at 0.5 mg per month for three months prior to treatment with gene therapy. In a preferred embodiment, a patient has improvement in fluid if he or she has an improvement in inner retinal (parafovea 3 mm) fluid of >50 μm or 30% relative to the level prior to the intravitreal injection of the anti-VEGF antigen-binding fragment, or has an improvement in center subfield thickness of >50 μm or 30% as determined by the CRC relative to the level prior to the intravitreal injection of the anti-VEGF antigen-binding fragment.


In certain embodiments, the methods provided herein are for the administration to patients diagnosed with AMD who have disease other than fluid contributing to an increase in CRT (i.e., pigment epithelial detachment (PED) or subretinal hyperreflective material (SHRM)) and who have <75 μm of fluid (intraretinal or subretinal), as determined by the CRC.


In certain embodiments of the methods described herein, the patient has a BCVA in the eye to be treated that is ≤20/20 and ≥20/400 before treatment. In a specific embodiment, the patient has a BCVA in the eye to be treated that is ≤20/63 and ≥20/400 before treatment.


In certain embodiments of the methods described herein, the patient has an Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA letter score between ≤78 and ≥44 in the eye to be treated before treatment.


In certain embodiments of the methods described herein, the patient is not concurrently having an anticoagulation therapy.


(b) Dosage

In certain embodiments, doses that maintain a concentration of the therapeutic product at a Cmin of at least 0.330 μg/mL in the Vitreous humour, or 0.110 μg/mL in the Aqueous humour (the anterior chamber of the eye) for three months are desired; thereafter, Vitreous Cmin concentrations of the therapeutic product ranging from 1.70 to 6.60 μg/mL, and/or Aqueous Cmin concentrations ranging from 0.567 to 2.20 μg/mL should be maintained. However, because the therapeutic product is continuously produced (under the control of a constitutive promoter or induced by hypoxic conditions when using an hypoxia-inducible promoter), maintenance of lower concentrations can be effective. Vitreous humour concentrations can be measured directly in patient samples of fluid collected from the vitreous humour or the anterior chamber, or estimated and/or monitored by measuring the patient's serum concentrations of the therapeutic product—the ratio of systemic to vitreal exposure to the therapeutic product is about 1:90,000. (E.g., see, vitreous humor and serum concentrations of ranibizumab reported in Xu L, et al., 2013, Invest. Opthal. Vis. Sci. 54: 1616-1624, at p. 1621 and Table 5 at p. 1623, which is incorporated by reference herein in its entirety).


In certain embodiments, dosages are measured by genome copies per ml or the number of genome copies administered to the eye of the patient (e.g., administered suprachoroidally, subretinally, intravitreally, juxtasclerally, subconjunctivally, and/or intraretinally (e.g., by suprachoroidal injection, subretinal injection via the transvitreal approach (a surgical procedure), subretinal administration via the suprachoroidal space, or a posterior juxtascleral depot procedure)). In certain embodiments, 2.4×1011 genome copies per ml to 1×1013 genome copies per ml are administered. In a specific embodiment, 2.4×1011 genome copies per ml to 5×1011 genome copies per ml are administered. In another specific embodiment, 5×1011 genome copies per ml to 1×1012 genome copies per ml are administered. In another specific embodiment, 1×1012 genome copies per ml to 5×1012 genome copies per ml are administered. In another specific embodiment, 5×1012 genome copies per ml to 1×1013 genome copies per ml are administered. In another specific embodiment, about 2.4×1011 genome copies per ml are administered. In another specific embodiment, about 5×1011 genome copies per ml are administered. In another specific embodiment, about 1×1012 genome copies per ml are administered. In another specific embodiment, about 5×1012 genome copies per ml are administered. In another specific embodiment, about 1×1013 genome copies per ml are administered. In certain embodiments, 1×109 to 1×1012 genome copies are administered. In specific embodiments, 3×109 to 2.5×1011 genome copies are administered. In specific embodiments, 1×109 to 2.5×1011 genome copies are administered. In specific embodiments, 1×109 to 1×1011 genome copies are administered. In specific embodiments, 1×109 to 5×109 genome copies are administered. In specific embodiments, 6×109 to 3×1010 genome copies are administered. In specific embodiments, 4×1010 to 1×1011 genome copies are administered. In specific embodiments, 2×1011 to 1×1012 genome copies are administered. In a specific embodiment, about 3×109 genome copies are administered (which corresponds to about 1.2×1010 genome copies per ml in a volume of 250 μl). In another specific embodiment, about 1×1010 genome copies are administered (which corresponds to about 4×1010 genome copies per ml in a volume of 250 μl). In another specific embodiment, about 6×1010 genome copies are administered (which corresponds to about 2.4×1011 genome copies per ml in a volume of 250 μl). In another specific embodiment, about 1.6×1011 genome copies are administered (which corresponds to about 6.2×1011 genome copies per ml in a volume of 250 μl). In another specific embodiment, about 1.55×1011 genome copies are administered (which corresponds to about 6.2×1011 genome copies per ml in a volume of 250 μl). In another specific embodiment, about 2.5×1011 genome copies (which corresponds to about 1.0×1012 genome copies per ml in a volume of 250 μl) are administered.


In certain embodiments, about 6.0×1010 genome copies per eye are administered. In certain embodiments, about 1.6×1011 genome copies per eye are administered. In certain embodiments, about 2.5×1011 genome copies per eye are administered. In certain embodiments, about 5.0×1011 genome copies per eye are administered. In certain embodiments, about 3×1012 genome copies per eye are administered. In certain embodiments, about 1.0×1012 genome copies per ml per eye are administered. In certain embodiments, about 2.5×1012 genome copies per ml per eye are administered. In certain embodiments, about 3.0×1013 genome copies per eye are administered. In certain embodiments, up to 3.0×1013 genome copies per eye are administered.


In certain embodiments, about 6.0×1010 genome copies per eye are administered by subretinal injection. In certain embodiments, about 1.6×1011 genome copies per eye are administered by subretinal injection. In certain embodiments, about 2.5×1011 genome copies per eye are administered by subretinal injection. In certain embodiments, about 3.0×1013 genome copies per eye are administered by subretinal injection. In certain embodiments, up to 3.0×1013 genome copies per eye are administered by subretinal injection.


In certain embodiments, about 2.5×1011 genome copies per eye are administered by suprachoroidal injection. In certain embodiments, about 5.0×1011 genome copies per eye are administered by suprachoroidal injection. In certain embodiments, about 3×1012 genome copies per eye are administered by suprachoroidal injection. In certain embodiments, about 2.5×1011 genome copies per eye are administered by a single suprachoroidal injection. In certain embodiments, about 5.0×1011 genome copies per eye are administered by double suprachoroidal injections. In certain embodiments, about 3.0×1013 genome copies per eye are administered by suprachoroidal injection. In certain embodiments, up to 3.0×1013 genome copies per eye are administered suprachoroidal injection. In certain embodiments, about 2.5×1012 genome copies per ml per eye are administered by a single suprachoroidal injection in a volume of 100 μl. In certain embodiments, about 2.5×1012 genome copies per ml per eye are administered by double suprachoroidal injections, wherein each injection is in a volume of 100 μl.


As used herein and unless otherwise specified, the term “about” means within plus or minus 10% of a given value or range. In certain embodiments, the term “about” encompasses the exact number recited.


(c) Sampling and Monitoring of Efficacy

Effects of the methods provided herein on visual deficits may be measured by BCVA (Best-Corrected Visual Acuity), intraocular pressure, slit lamp biomicroscopy, and/or indirect ophthalmoscopy.


In specific embodiments, effects of the methods provided herein on visual deficits may be measured by whether the human patient's eye that is treated by a method described herein achieves BCVA of greater than 43 letters post-treatment (e.g., 46-50 weeks or 98-102 weeks post-treatment). A BCVA of 43 letters corresponds to 20/160 approximate Snellen equivalent. In a specific embodiment, the human patient's eye that is treated by a method described herein achieves BCVA of greater than 43 letters post-treatment (e.g., 46-50 weeks or 98-102 weeks post-treatment).


In specific embodiments, effects of the methods provided herein on visual deficits may be measured by whether the human patient's eye that is treated by a method described herein achieves BCVA of greater than 84 letters post-treatment (e.g., 46-50 weeks or 98-102 weeks post-treatment). A BCVA of 84 letters corresponds to 20/20 approximate Snellen equivalent. In a specific embodiment, the human patient's eye that is treated by a method described herein achieves BCVA of greater than 84 letters post-treatment (e.g., 46-50 weeks or 98-102 weeks post-treatment).


Effects of the methods provided herein on physical changes to eye/retina may be measured by SD-OCT (SD-Optical Coherence Tomography).


Efficacy may be monitored as measured by electroretinography (ERG).


Effects of the methods provided herein may be monitored by measuring signs of vision loss, infection, inflammation and other safety events, including retinal detachment.


Retinal thickness may be monitored to determine efficacy of the methods provided herein. Without being bound by any particular theory, thickness of the retina may be used as a clinical readout, wherein the greater reduction in retinal thickness or the longer period of time before thickening of the retina, the more efficacious the treatment. Retinal function may be determined, for example, by ERG. ERG is a non-invasive electrophysiologic test of retinal function, approved by the FDA for use in humans, which examines the light sensitive cells of the eye (the rods and cones), and their connecting ganglion cells, in particular, their response to a flash stimulation. Retinal thickness may be determined, for example, by SD-OCT. SD-OCT is a three-dimensional imaging technology which uses low-coherence interferometry to determine the echo time delay and magnitude of backscattered light reflected off an object of interest. OCT can be used to scan the layers of a tissue sample (e.g., the retina) with 3 to 15 μm axial resolution, and SD-OCT improves axial resolution and scan speed over previous forms of the technology (Schuman, 2008, Trans. Am. Opthamol. Soc. 106:426-458).


Effects of the methods provided herein may also be measured by a change from baseline in National Eye Institute Visual Functioning Questionnaire, the Rasch-scored version (NEI-VFQ-28-R) (composite score; activity limitation domain score; and socio-emotional functioning domain score). Effects of the methods provided herein may also be measured by a change from baseline in National Eye Institute Visual Functioning Questionnaire 25-item version (NEI-VFQ-25) (composite score and mental health subscale score). Effects of the methods provided herein may also be measured by a change from baseline in Macular Disease Treatment Satisfaction Questionnaire (MacTSQ) (composite score; safety, efficacy, and discomfort domain score; and information provision and convenience domain score).


In specific embodiments, the efficacy of a method described herein is reflected by an improvement in vision at about 4 weeks, 12 weeks, 6 months, 12 months, 24 months, 36 months, or at other desired timepoints. In a specific embodiment, the improvement in vision is characterized by an increase in BCVA, for example, an increase by 1 letter, 2 letters, 3 letters, 4 letters, 5 letters, 6 letters, 7 letters, 8 letters, 9 letters, 10 letters, 11 letters, or 12 letters, or more. In a specific embodiment, the improvement in vision is characterized by a 5%, 10%, 15%, 20%, 30%, 40%, 50% or more increase in visual acuity from baseline.


In specific embodiments, the efficacy of a method described herein is reflected by an reduction in central retinal thickness (CRT) at about 4 weeks, 12 weeks, 6 months, 12 months, 24 months, 36 months, or at other desired timepoint, for example, a 5%, 10%, 15%, 20%, 30%, 40%, 50% or more decrease in central retinal thickness from baseline.


In specific embodiments, there is no inflammation in the eye after treatment or little inflammation in the eye after treatment (for example, an increase in the level of inflammation by 10%, 5%, 2%, 1% or less from baseline).


If the human patient is a child, visual function can be assessed using an optokinetic nystagmus (OKN)-based approach or a modified OKN-based approach.


6.4 Combination Therapies


The methods provided herein may be combined with one or more additional therapies. In one aspect, the methods provided herein are administered with laser photocoagulation. In one aspect, the methods provided herein are administered with photodynamic therapy with verteporfin.


In one aspect, the methods provided herein are administered with intravitreal (IVT) injections with the therapeutic product. In a specific embodiment wherein the therapeutic product is an anti-VEGF antibody or antigen-binding fragment, the methods provided herein are administered with IVT injections with anti-VEGF agents, including but not limited to HuPTMFabVEGFi, e.g., HuGlyFabVEGFi produced in human cell lines (Dumont et al., 2015, supra), or other anti-VEGF agents such as pegaptanib, ranibizumab, aflibercept, or bevacizumab.


The additional therapies may be administered before, concurrently or subsequent to the gene therapy treatment.


The efficacy of the gene therapy treatment may be indicated by the elimination of or reduction in the number of rescue treatments using standard of care. For example, when the therapeutic product is anti-VEGF antibody or antigen-binding fragment, the efficacy of the gene therapy treatment may be indicated by the elimination or reduction in the number of rescue treatments of intravitreal injections with anti-VEGF agents, including but not limited to HuPTMFabVEGFi, e.g., HuGlyFabVEGFi produced in human cell lines, or other anti-VEGF agents such as pegaptanib, ranibizumab, aflibercept, or bevacizumab.


7. SEQUENCES










SEQ ID NO: 1



RANIBIZUMAB FAB AMINO ACID SEQUENCE (LIGHT CHAIN)



DIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLH





SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTV





AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE





QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC





SEQ ID NO: 2



RANIBIZUMAB FAB AMINO ACID SEQUENCE (HEAVY CHAIN)



EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYT





GEPTYAADFKRRFTESLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYF





DVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN





SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK





VEPKSCDKTHL





SEQ ID NO: 3



BEVACIZUMAB FAB AMINO ACID SEQUENCE (LIGHT CHAIN)



DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLH





SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTV





AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE





QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC





SEQ ID NO: 4



BEVACIZUMAB FAB AMINO ACID SEQUENCE (HEAVY CHAIN)



EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYT





GEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYF





DVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN





SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK





VEPKSCDKTHL





SEQ ID NO: 5



VEGF-A SIGNAL PEPTIDE



MNFLLSWVHW SLALLLYLHH AKWSQA





SEQ ID NO: 6



FIBULIN-1 SIGNAL PEPTIDE



MERAAPSRRV PLPLLLLGGL ALLAAGVDA





SEQ ID NO: 7



VITRONECTIN SIGNAL PEPTIDE



MAPLRPLLIL ALLAWVALA





SEQ ID NO: 8



COMPLEMENT FACTOR H SIGNAL PEPTIDE



MRLLAKIICLMLWAICVA





SEQ ID NO: 9



OPTICIN SIGNAL PEPTIDE



MRLLAFLSLL ALVLQETGT





SEQ ID NO: 10



BEVACIZUMAB CDNA (LIGHT CHAIN)



GCTAGCGCCA CCATGGGCTG GTCCTGCATC ATCCTGTTCC TGGTGGCCAC CGCCACCGGC GTGCACTCCG





ACATCCAGAT GACCCAGTCC CCCTCCTCCC TGTCCGCCTC CGTGGGCGAC CGGGTGACCA TCACCTGCTC





CGCCTCCCAG GACATCTCCA ACTACCTGAA CTGGTACCAG CAGAAGCCCG GCAAGGCCCC CAAGGTGCTG





ATCTACTTCA CCTCCTCCCT GCACTCCGGC GTGCCCTCCC GGTTCTCCGG CTCCGGCTCC GGCACCGACT





TCACCCTGAC CATCTCCTCC CTGCAGCCCG AGGACTTCGC CACCTACTAC TGCCAGCAGT ACTCCACCGT





GCCCTGGACC TTCGGCCAGG GCACCAAGGT GGAGATCAAG CGGACCGTGG CCGCCCCCTC CGTGTTCATC





TTCCCCCCCT CCGACGAGCA GCTGAAGTCC GGCACCGCCT CCGTGGTGTG CCTGCTGAAC AACTTCTACC





CCCGGGAGGC CAAGGTGCAG TGGAAGGTGG ACAACGCCCT GCAGTCCGGC AACTCCCAGG AGTCCGTGAC





CGAGCAGGAC TCCAAGGACT CCACCTACTC CCTGTCCTCC ACCCTGACCC TGTCCAAGGC CGACTACGAG





AAGCACAAGG TGTACGCCTG CGAGGTGACC CACCAGGGCC TGTCCTCCCC CGTGACCAAG TCCTTCAACC





GGGGCGAGTG CTGAGCGGCC GCCTCGAG





SEQ ID NO: 11



Bevacizumab cDNA (Heavy chain)



gctagcgcca ccatgggctg gtcctgcatc atcctgttcc tggtggccac cgccaccggc gtgcactccg





aggtgcagct ggtggagtcc ggcggcggcc tggtgcagcc cggcggctcc ctgcggctgt cctgcgccgc





ctccggctac accttcacca actacggcat gaactgggtg cggcaggccc ccggcaaggg cctggagtgg





gtgggctgga tcaacaccta caccggcgag cccacctacg ccgccgactt caagcggcgg ttcaccttct





ccctggacac ctccaagtcc accgcctacc tgcagatgaa ctccctgcgg gccgaggaca ccgccgtgta





ctactgcgcc aagtaccccc actactacgg ctcctcccac tggtacttcg acgtgtgggg ccagggcacc





ctggtgaccg tgtcctccgc ctccaccaag ggcccctccg tgttccccct ggccccctcc tccaagtcca





cctccggcgg caccgccgcc ctgggctgcc tggtgaagga ctacttcccc gagcccgtga ccgtgtcctg





gaactccggc gccctgacct ccggcgtgca caccttcccc gccgtgctgc agtcctccgg cctgtactcc





ctgtcctccg tggtgaccgt gccctcctcc tccctgggca cccagaccta catctgcaac gtgaaccaca





agccctccaa caccaaggtg gacaagaagg tggagcccaa gtcctgcgac aagacccaca cctgcccccc





ctgccccgcc cccgagctgc tgggcggccc ctccgtgttc ctgttccccc ccaagcccaa ggacaccctg





atgatctccc ggacccccga ggtgacctgc gtggtggtgg acgtgtccca cgaggacccc gaggtgaagt





tcaactggta cgtggacggc gtggaggtgc acaacgccaa gaccaagccc cgggaggagc agtacaactc





cacctaccgg gtggtgtccg tgctgaccgt gctgcaccag gactggctga acggcaagga gtacaagtgc





aaggtgtcca acaaggccct gcccgccccc atcgagaaga ccatctccaa ggccaagggc cagccccggg





agccccaggt gtacaccctg cccccctccc gggaggagat gaccaagaac caggtgtccc tgacctgcct





ggtgaagggc ttctacccct ccgacatcgc cgtggagtgg gagtccaacg gccagcccga gaacaactac





aagaccaccc cccccgtgct ggactccgac ggctccttct tcctgtactc caagctgacc gtggacaagt





cccggtggca gcagggcaac gtgttctcct gctccgtgat gcacgaggcc ctgcacaacc actacaccca





gaagtccctg tccctgtccc ccggcaagtg agcggccgcc





SEQ ID NO: 12



ranibizumab cDNA (Light chain comprising a signal sequence)



gagctccatg gagtttttca aaaagacggc acttgccgca ctggttatgg gttttagtgg tgcagcattg





gccgatatcc agctgaccca gagcccgagc agcctgagcg caagcgttgg tgatcgtgtt accattacct





gtagcgcaag ccaggatatt agcaattatc tgaattggta tcagcagaaa ccgggtaaag caccgaaagt





tctgatttat tttaccagca gcctgcatag cggtgttccg agccgtttta gcggtagcgg tagtggcacc





gattttaccc tgaccattag cagcctgcag ccggaagatt ttgcaaccta ttattgtcag cagtatagca





ccgttccgtg gacctttggt cagggcacca aagttgaaat taaacgtacc gttgcagcac cgagcgtttt





tatttttccg cctagtgatg aacagctgaa aagcggcacc gcaagcgttg tttgtctgct gaataatttt





tatccgcgtg aagcaaaagt gcagtggaaa gttgataatg cactgcagag cggtaatagc caagaaagcg





ttaccgaaca ggatagcaaa gatagcacct atagcctgag





cagcaccctg accctgagca aagcagatta tgaaaaacac aaagtgtatg cctgcgaagt tacccatcag





ggtctgagca gtccggttac caaaagtttt aatcgtggcg aatgctaata gaagcttggt





SEQ ID NO: 13



ranibizumab cDNA (Heavy chain comprising a signal sequence)



gagctcatat gaaatacctg ctgccgaccg ctgctgctgg tctgctgctc ctcgctgccc agccggcgat





ggccgaagtt cagctggttg aaagcggtgg tggtctggtt cagcctggtg gtagcctgcg tctgagctgt





gcagcaagcg gttatgattt tacccattat ggtatgaatt gggttcgtca ggcaccgggt aaaggtctgg





aatgggttgg ttggattaat acctataccg gtgaaccgac ctatgcagca gattttaaac gtcgttttac





ctttagcctg gataccagca





aaagcaccgc atatctgcag atgaatagcc tgcgtgcaga agataccgca gtttattatt gtgccaaata





tccgtattac tatggcacca gccactggta tttcgatgtt tggggtcagg gcaccctggt taccgttagc





agcgcaagca ccaaaggtcc gagcgttttt ccgctggcac cgagcagcaa aagtaccagc ggtggcacag





cagcactggg ttgtctggtt aaagattatt ttccggaacc ggttaccgtg agctggaata gcggtgcact





gaccagcggt gttcatacct





ttccggcagt tctgcagagc agcggtctgt atagcctgag cagcgttgtt accgttccga gcagcagcct





gggcacccag acctatattt gtaatgttaa tcataaaccg agcaatacca aagtggataa aaaagttgag





ccgaaaagct gcgataaaac ccatctgtaa tagggtacc





SEQ ID NO: 14



Bevacizumab and Ranibizumab Light Chain CDR1



SASQDISNYLN





SEQ ID NO: 15



Bevacizumab and Ranibizumab Light Chain CDR2



FTSSLHS





SEQ ID NO: 16



Bevacizumab and Ranibizumab Light Chain CDR3



QQYSTVPWT





SEQ ID NO: 17



bevacizumab Heavy Chain CDR1



GYTFTNYGMN





SEQ ID NO: 18



Bevacizumab and Ranibizumab Heavy Chain CDR2



WINTYTGEPTYAADFKR





SEQ ID NO: 19



Bevacizumab Heavy Chain CDR3



YPHYYGSSHWYFDV





SEQ ID NO: 20



ranibizumab Heavy Chain CDR1



GYDFTHYGMN





SEQ ID NO: 21



ranibizumab Heavy Chain CDR1



YPYYYGTSHWYFDV





SEQ ID NO: 22



Albumin signal peptide



MKWVTFISLLFLFSSAYS





SEQ ID NO: 23



Chymotrypsinogen signal peptide



MAFLWLLSCWALLGTTFG





SEQ ID NO: 24



Interleukin-2 signal peptide



MYRMQLLSCIALILALVTNS





SEQ ID NO: 25



Trypsinogen-2 signal peptide



MNLLLILTFVAAAVA





SEQ ID NO: 26



F2A site



LLNFDLLKLAGDVESNPGP





SEQ ID NO: 27



T2A site



(GSG)EGRGSLLTCGDVEENPGP





SEQ ID NO: 28



P2A site



(GSG)ATNFSLLKQAGDVEENPGP





SEQ ID NO: 29



E2A site



(GSG)QCTNYALLKLAGDVESNPGP





SEQ ID NO: 30



F2A site



(GSG)VKQTLNFDLLKLAGDVESNPGP





SEQ ID NO: 31



Furin linker



RKRR





SEQ ID NO: 32



Furin linker



RRRR





SEQ ID NO: 33



Furin linker



RRKR





SEQ ID NO: 34



Furin linker



RKKR





SEQ ID NO: 35



Furin linker



R-X-K/R-R





SEQ ID NO: 36



Furin linker



RXKR





SEQ ID NO: 37



Furin linker



RXRR





SEQ ID NO: 38



Ranibizumab Fab amino acid sequence (Light chain)



MDIQLTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTIS





SLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA





LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC





SEQ ID NO: 39



Ranibizumab Fab amino acid sequence (Heavy chain)



MEVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSK





STAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK





DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH





LRKRR





SEQ ID NO: 40



Ranibizumab Fab amino acid sequence (Heavy chain)



MEVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSK





STAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK





DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH





L





SEQ ID NO: 41



AAV1



MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDK





AYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEQSPQEPD





SSSGIGKTGQQPAKKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGNASGNWHCD





STWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFR





PKRLNFKLFNIQVKEVTTNDGVTTIANNLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGS





QAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEEVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQNQSGSAQNKDLL





FSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSNFTWTGASKYNLNGRESIINPGTAMASHKDDEDKFFPMSG





VMIFGKESAGASNTALDNVMITDEEEIKATNPVATERFGTVAVNFQSSSTDPATGDVHAMGALPGMVWQDRDVYLQG





PIWAKIPHTDGHFHPSPLMGGFGLKNPPPQILIKNTPVPANPPAEFSATKFASFITQYSTGQVSVEIEWELQKENSK





RWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGTRYLTRPL





SEQ ID NO: 42



AAV2



MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGYKYLGPFNGLDKGEPVNEADAAALEHDK





AYDRQLDSGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRVLEPLGLVEEPVKTAPGKKRPVEHSPVEPD





SSSGTGKAGQQPARKRLNFGQTGDADSVPDPQPLGQPPAAPSGLGTNTMATGSGAPMADNNEGADGVGNSSGNWHCD





STWMGDRVITTSTRTWALPTYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRP





KRLNFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQ





AVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTNTPSGTTTQSRLQF





SQAGASDIRDQSRNWLPGPCYRQQRVSKTSADNNNSEYSWTGATKYHLNGRDSLVNPGPAMASHKDDEEKFFPQSGV





LIFGKQGSEKTNVDIEKVMITDEEEIRTTNPVATEQYGSVSTNLQRGNRQAATADVNTQGVLPGMVWQDRDVYLQGP





IWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPSTTFSAAKFASFITQYSTGQVSVEIEWELQKENSKR





WNPEIQYTSNYNKSVNVDFTVDTNGVYSEPRPIGTRYLTRNL





SEQ ID NO: 43



AAV3-3



MAADGYLPDWLEDNLSEGIREWWALKPGVPQPKANQQHQDNRRGLVLPGYKYLGPGNGLDKGEPVNEADAAALEHDK





AYDQQLKAGDNPYLKYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRILEPLGLVEEAAKTAPGKKGAVDQSPQEPD





SSSGVGKSGKQPARKRLNFGQTGDSESVPDPQPLGEPPAAPTSLGSNTMASGGGAPMADNNEGADGVGNSSGNWHCD





SQWLGDRVITTSTRTWALPTYNNHLYKQISSQSGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRP





KKLSFKLFNIQVRGVTQNDGTTTIANNLTSTVQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQ





AVGRSSFYCLEYFPSQMLRTGNNFQFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQGTTSGTTNQSRLL





FSQAGPQSMSLQARNWLPGPCYRQQRLSKTANDNNNSNFPWTAASKYHLNGRDSLVNPGPAMASHKDDEEKFFPMHG





NLIFGKEGTTASNAELDNVMITDEEEIRTTNPVATEQYGTVANNLQSSNTAPTTGTVNHQGALPGMVWQDRDVYLQG





PIWAKIPHTDGHFHPSPLMGGFGLKHPPPQIMIKNTPVPANPPTTFSPAKFASFITQYSTGQVSVEIEWELQKENSK





RWNPEIQYTSNYNKSVNVDFTVDTNGVYSEPRPIGTRYLTRNL





SEQ ID NO: 44



AAV4-4



MTDGYLPDWLEDNLSEGVREWWALQPGAPKPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADAAALEHDKA





YDQQLKAGDNPYLKYNHADAEFQQRLQGDTSEGGNLGRAVFQAKKRVLEPLGLVEQAGETAPGKKRPLIESPQQPDS





STGIGKKGKQPAKKKLVFEDETGAGDGPPEGSTSGAMSDDSEMRAAAGGAAVEGGQGADGVGNASGDWHCDSTWSEG





HVTTTSTRTWVLPTYNNHLYKRLGESLQSNTYNGFSTPWGYFDENRFHCHFSPRDWQRLINNNWGMRPKAMRVKIFN





IQVKEVTTSNGETTVANNLTSTVQIFADSSYELPYVMDAGQEGSLPPFPNDVFMVPQYGYCGLVTGNTSQQQTDRNA





FYCLEYFPSQMLRTGNNFEITYSFEKVPFHSMYAHSQSLDRLMNPLIDQYLWGLQSTTTGTTLNAGTATTNFTKLRP





TNFSNFKKNWLPGPSIKQQGFSKTANQNYKIPATGSDSLIKYETHSTLDGRWSALTPGPPMATAGPADSKFSNSQLI





FAGPKQNGNTATVPGTLIFTSEEELAATNATDTDMWGNLPGGDQSNSNLPTVDRLTALGAVPGMVWQNRDIYYQGPI





WAKIPHTDGHFHPSPLIGGFGLKHPPPQIFIKNTPVPANPATTFSSTPVNSFITQYSTGQVSVQIDWEIQKERSKRW





NPEVQFTSNYGQQNSLLWAPDAAGKYTEPRAIGTRYLTHHL





SEQ ID NO: 45



AAV5



MSFVDHPPDWLEEVGEGLREFLGLEAGPPKPKPNQQHQDQARGLVLPGYNYLGPGNGLDRGEPVNRADEVAREHDIS





YNEQLEAGDNPYLKYNHADAEFQEKLADDTSFGGNLGKAVFQAKKRVLEPFGLVEEGAKTAPTGKRIDDHFPKRKKA





RTEEDSKPSTSSDAEAGPSGSQQLQIPAQPASSLGADTMSAGGGGPLGDNNQGADGVGNASGDWHCDSTWMGDRVVT





KSTRTWVLPSYNNHQYREIKSGSVDGSNANAYFGYSTPWGYFDFNRFHSHWSPRDWQRLINNYWGFRPRSLRVKIFN





IQVKEVTVQDSTTTIANNLTSTVQVFTDDDYQLPYVVGNGTEGCLPAFPPQVFTLPQYGYATLNRDNTENPTERSSF





FCLEYFPSKMLRTGNNFEFTYNFEEVPFHSSFAPSQNLFKLANPLVDQYLYRFVSTNNTGGVQFNKNLAGRYANTYK





NWFPGPMGRTQGWNLGSGVNRASVSAFATTNRMELEGASYQVPPQPNGMTNNLQGSNTYALENTMIFNSQPANPGTT





ATYLEGNMLITSESETQPVNRVAYNVGGQMATNNQSSTTAPATGTYNLQEIVPGSVWMERDVYLQGPIWAKIPETGA





HFHPSPAMGGFGLKHPPPMMLIKNTPVPGNITSFSDVPVSSFITQYSTGQVTVEMEWELKKENSKRWNPEIQYTNNY





NDPQFVDFAPDSTGEYRTTRPIGTRYLTRPL





SEQ ID NO: 46



AAV6



MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDK





AYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPFGLVEEGAKTAPGKKRPVEQSPQEPD





SSSGIGKTGQQPAKKRLNFGQTGDSESVPDPQPLGEPPATPAAVGPTTMASGGGAPMADNNEGADGVGNASGNWHCD





STWLGDRVITTSTRTWALPTYNNHLYKQISSASTGASNDNHYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFR





PKRLNFKLFNIQVKEVTTNDGVTTIANNLTSTVQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGS





QAVGRSSFYCLEYFPSQMLRTGNNFTFSYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLNRTQNQSGSAQNKDLL





FSRGSPAGMSVQPKNWLPGPCYRQQRVSKTKTDNNNSNFTWTGASKYNLNGRESIINPGTAMASHKDDKDKFFPMSG





VMIFGKESAGASNTALDNVMITDEEEIKATNPVATERFGTVAVNLQSSSTDPATGDVHVMGALPGMVWQDRDVYLQG





PIWAKIPHTDGHFHPSPLMGGFGLKHPPPQILIKNTPVPANPPAEFSATKFASFITQYSTGQVSVEIEWELQKENSK





RWNPEVQYTSNYAKSANVDFTVDNNGLYTEPRPIGTRYLTRPL





SEQ ID NO: 47



AAV7



MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDNGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDK





AYDQQLKAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPAKKRPVEPSPQRSP





DSSTGIGKKGQQPARKRLNFGQTGDSESVPDPQPLGEPPAAPSSVGSGTVAAGGGAPMADNNEGADGVGNASGNWHC





DSTWLGDRVITTSTRTWALPTYNNHLYKQISSETAGSTNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGF





RPKKLRFKLFNIQVKEVTTNDGVTTIANNLTSTIQVFSDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNG





SQSVGRSSFYCLEYFPSQMLRTGNNFEFSYSFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLARTQSNPGGTAGNRE





LQFYQGGPSTMAEQAKNWLPGPCFRQQRVSKTLDQNNNSNFAWTGATKYHLNGRNSLVNPGVAMATHKDDEDRFFPS





SGVLIFGKTGATNKTTLENVLMTNEEEIRPTNPVATEEYGIVSSNLQAANTAAQTQVVNNQGALPGMVWQNRDVYLQ





GPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPANPPEVFTPAKFASFITQYSTGQVSVEIEWELQKENS





KRWNPEIQYTSNFEKQTGVDFAVDSQGVYSEPRPIGTRYLTRNL





SEQ ID NO: 48



AAV8



MAADGYLPDWLEDNLSEGIREWWALKPGAPKPKANQQKQDDGRGLVLPGYKYLGPFNGLDKGEPVNAADAAALEHDK





AYDQQLQAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVEEGAKTAPGKKRPVEPSPQRSP





DSSTGIGKKGQQPARKRLNFGQTGDSESVPDPQPLGEPPAAPSGVGPNTMAAGGGAPMADNNEGADGVGSSSGNWHC





DSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGATNDNTYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWG





FRPKRLSFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNN





GSQAVGRSSFYCLEYFPSQMLRTGNNFQFTYTFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQTTGGTANTQT





LGFSQGGPNTMANQAKNWLPGPCYRQQRVSTTTGQNNNSNFAWTAGTKYHLNGRNSLANPGIAMATHKDDEERFFPS





NGILIFGKQNAARDNADYSDVMLTSEEEIKTTNPVATEEYGIVADNLQQQNTAPQIGTVNSQGALPGMVWQNRDVYL





QGPIWAKIPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQSKLNSFITQYSTGQVSVEIEWELQKEN





SKRWNPEIQYTSNYYKSTSVDFAVNTEGVYSEPRPIGTRYLTRNL





SEQ ID NO: 49



hu31



MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGYKYLGPGNGLDKGEPVNAADAAALEHDK





AYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPD





SSAGIGKSGSQPAKKKLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCD





SQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGF





RPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDG





GQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLK





FSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSG





SLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDVYLQG





PIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSK





RWNPEIQYTSNYYKSNNVEFAVSTEGVYSEPRPIGTRYLTRNL





SEQ ID NO: 50



hu32



MAADGYLPDWLEDTLSEGIRQWWKLKPGPPPPKPAERHKDDSRGLVLPGYKYLGPGNGLDKGEPVNAADAAALEHDK





AYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPD





SSAGIGKSGSQPAKKKLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCD





SQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGF





RPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDG





SQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLK





FSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSG





SLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDVYLQG





PIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSK





RWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL





SEQ ID NO: 51



AAV9



MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADAAALEHDK





AYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSPQEPD





SSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSSGNWHCD





SQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGF





RPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIPQYGYLTLNDG





SQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKTINGSGQNQQTLK





FSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMASHKEGEDRFFPLSG





SLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQGILPGMVWQDRDVYLQG





PIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYSTGQVSVEIEWELQKENSK





RWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL





SEQ ID NO: 52



SPERMATOGENESIS ASSOCIATED 7 (SPATA7);



AAH90875.1









1
MDGSRRVRAT SVLPRYGPPC LFKGHLSTKS NAAVDCSVPV SVSTSIKYAD QQRREKLKKE






61
LAQCEKEFKL TKTAMRANYK NNSKSLFNTL QKPSGEPQIE DDMLKEEMNG FSSFARSLVP





121
SSERLHLSLH KSSKVITNGP EKNSSSSPSS VDYAASGPRK LSSGALYGRR PRSTFPNSHR





181
FQLVISKAPS GDLLDKHSEL FSNKQLPFTP RTLKTEAKSF LSQYRYYTPA KRKKDFTDQR





241
IEAETQTELS FKSELGTAET KNMTDSEMNI KQASNCVTYD AKEKIAPLPL EGHDSTWDEI





301
KDDALQHSSP RAMCQYSLKP PSTRKIYSDE EELLYLSFIE DVTDEILKLG LFSNRFLERL





361
FERHIKQNKH LEEEKMRHLL HVLKVDLGCT SEENSVKQND VDMLNVFDFE KAGNSEPNEL





421
KNESEVTIQQ ERQQYQKALD MLLSAPKDEN EIFPSPTEFF MPIYKSKHSE GVIIQQVNDE





481
TNLETSTLDE NHPSISDSLT DRETSVNVIE GDSDPEKVEI SNGLCGLNTS PSQSVQFSSV





541
KGDNNHDMEL STLKIMEMSI EDCPLDV











SEQ ID NO: 53



LEBERCILIN (LCA5)



NP_001116241.1









1
MGERAGSPGT DQERKAGKHH YSYLSDFETP QSSGRSSLVS SSPASVRRKN PKRQTSDGQV






61
HHQAPRKPSP KGLPNRKGVR VGFRSQSLNR EPLRKDTDLV TKRILSARLL KINELQNEVS





121
ELQVKLAELL KENKSLKRLQ YRQEKALNKF EDAENEISQL IFRHNNEITA LKERLRKSQE





181
KERATEKRVK DTESELFRTK FSLQKLKEIS EARHLPERDD LAKKLVSAEL KLDDTERRIK





241
ELSKNLELST NSFQRQLLAE RKRAYEAHDE NKVLQKEVQR LYHKLKEKER ELDIKNIYSN





301
RLPKSSPNKE KELALRKNAA CQSDFADLCT KGVQTMEDFK PEEYPLTPET IMCYENKWEE





361
PGHLTLDLQS QKQDRHGEAG ILNPIMEREE KFVTDEELHV VKQEVEKLED EWEREELDKK





421
QKEKASLLER EEKPEWETGR YQLGMYPIQN MDKLQGEEEE RLKREMLLAK LNEIDRELQD





481
SRNLKYPVLP LLPDFESKLH SPERSPKTYR FSESSERLFN GHHLQDISFS TPKGEGQNSG





541
NVRSPASPNE FAFGSYVPSF AKTSERSNPF SQKSSFLDFQ RNSMEKLSKD GVDLITRKEK





601
KANLMEQLFG ASGSSTISSK SSDPNSVASS KGDIDPLNFL PGNKGSRDQE HDEDEGFFLS





661
EGRSFNPNRH RLKHADDKPA VKAADSVEDE IEEVALR











SEQ ID NO: 54



RPGR INTERACTING PROTEIN 1 (RPGRIP1)



CAD01135.1









1
MSHLVDPTSG DLPVRDIDAI PLVLPASKGK NMKTQPPLSR MNREELEDSF FRLREDHMLV






61
KELSWKQQDE IKRLRTTLLR LTAAGRDLRV AEEAAPLSET ARRGQKAGWR QRLSMHQRPQ





121
MHRLQGHFHC VGPASPRRAQ PRVQVGHRQL HTAGAPVPEK PKRGPRDRLS YTAPPSFKEH





181
ATNENRGEVA SKPSELVSGS NSIISFSSVI SMAKPIGLCM PNSAHIMASN TMQVEEPPKS





241
PEKMWPKDEN FEQRSSLECA QKAAELRASI KEKVELIRLK KLLHERNASL VMTKAQLTEV





301
QEAYETLLQK NQGILSAAHE ALLKQVNELR AELKEESKKA VSLKSQLEDV SILQMTLKEF





361
QERVEDLEKE RKLLNDNYDK LLESMLDSSD SSSQPHWSNE LIAEQLQQQV SQLQDQLDAE





421
LEDKRKVLLE LSREKAQNED LKLEVTNILQ KHKQEVELLQ NAATISQPPD RQSEPATHPA





481
VLQENTQIEP SEPKNQEEKK LSQVLNELQV SHAETTLELE KTRDMLILQR KINVCYQEEL





541
EAMMTKADND NRDHKEKLER LTRLLDLKNN RIKQLEGILR SHDLPTSEQL KDVAYGTRPL





601
SLCLETLPAH GDEDKVDISL LHQGENLFEL HIHQAFLTSA ALAQAGDTQP TTFCTYSFYD





661
FETHCTPLSV GPQPLYDFTS QYVMETDSLF LHYLQEASAR LDIHQAMASE HSTLAAGWIC





721
FDRVLETVEK VHGLATLIGA GGEEFGVLEY WMRLRFPIKP SLQACNKRKK AQVYLSTDVL





781
GGRKAQEEEF RSESWEPQNE LWIEITKCCG LRSRWLGTQP SPYAVYRFFT FSDHDTAIIP





841
ASNNPYFRDQ ARFPVLVTSD LDHYLRREAL SIHVFDDEDL EPGSYLGRAR VPLLPLAKNE





901
SIKGDFNLTD PAEKPNGSIQ VQLDWKFPYI PPESFLKPEA QTKGKDTKDS SKISSEEEKA





961
SFPSQDQMAS PEVPIEAGQY RSKRKPPHGG ERKEKEHQVV SYSRRKHGKR IGVQGKNRME





1021
YLSLNILNGN TPQQVNYTEW KFSETNSFIG DGFKNQHEEE EMTLSHSALK QKEPLHPVND





1081
KESSEQGSEV SEAQTTDSDD VIVPPMSQKY PKADSEKMCI EIVSLAFYPE AEVMSDENIK





1141
QVYVEYKFYD LPLSETETPV SLRKPRAGEE IHFHFSKVID LDPQEQQGRR RFLFDMLNGQ





1201
DPDQGHLKFT VVSDPLDEEK KECEEVGYAY LQLWQILESG RDILEQELDI VSPEDLATPI





1261
GRLKVSLQAA AVLHAIYKEM TEDLFS











SEQ ID NO: 55



CONE-ROD HOMEOBOX (CRX)



EAW57515.1









1
MMAYMNPGPH YSVNALALSG PSVDLMHQAV PYPSAPRKQR RERTTFTRSQ LEELEALFAK






61
TQYPDVYARE EVALKINLPE SRVQVWFKNR RAKCRQQRQQ QKQQQQPPGG QAKARPAKRK





121
AGTSPRPSTD VCPDPLGISD SYSPPLPGPS GSPTTAVATV SIWSPASESP LPEAQRAGLV





181
ASGPSLTSAP YAMTYAPASA FCSSPSAYGS PSSYFSGLDP YLSPMVPQLG GPALSPLSGP





241
SVGPSLAQSP TSLSGQSYGA YSPVDSLEFK DPTGTWKFTY NPMDPLDYKD QSAWKFQIL











SEQ ID NO: 56



CRUMBS CELL POLARITY COMPLEX COMPONENT 1 (CRB1), HOMOLOG 1 ISOFORM 1



PRECURSOR


NP_957705.1









1
MALKNINYLL IFYLSFSLLI YIKNSFCNKN NTRCLSNSCQ NNSTCKDFSK DNDCSCSDTA






61
NNLDKDCDNM KDPCFSNPCQ GSATCVNTPG ERSFLCKCPP GYSGTICETT IGSCGKNSCQ





121
HGGICHQDPI YPVCICPAGY AGRFCEIDHD ECASSPCQNG AVCQDGIDGY SCFCVPGYQG





181
RHCDLEVDEC ASDPCKNEAT CLNEIGRYTC ICPHNYSGVN CELEIDECWS QPCLNGATCQ





241
DALGAYFCDC APGFLGDHCE LNTDECASQP CLHGGLCVDG ENRYSCNCTG SGFTGTHCET





301
LMPLCWSKPC HNNATCEDSV DNYTCHCWPG YTGAQCEIDL NECNSNPCQS NGECVELSSE





361
KQYGRITGLP SSFSYHEASG YVCICQPGFT GIHCEEDVNE CSSNPCQNGG TCENLPGNYT





421
CHCPFDNLSR TFYGGRDCSD ILLGCTHQQC LNNGTCIPHF QDGQHGFSCL CPSGYTGSLC





481
EIATTLSFEG DGFLWVKSGS VTTKGSVCNI ALRFQTVQPM ALLLFRSNRD VFVKLELLSG





541
YIHLSIQVNN QSKVLLFISH NTSDGEWHFV EVIFAEAVTL TLIDDSCKEK CIAKAPTPLE





601
SDQSICAFQN SFLGGLPVGM TSNGVALLNF YNMPSTPSFV GCLQDIKIDW NHITLENISS





661
GSSLNVKAGC VRKDWCESQP CQSRGRCINL WLSYQCDCHR PYEGPNCLRE YVAGRFGQDD





721
STGYVIFTLD ESYGDTISLS MFVRTLQPSG LLLALENSTY QYIRVWLERG RLAMLTPNSP





781
KLVVKFVLND GNVHLISLKI KPYKIELYQS SQNLGFISAS TWKIEKGDVI YIGGLPDKQE





841
TELNGGFFKG CIQDVRLNNQ NLEFFPNPTN NASLNPVLVN VTQGCAGDNS CKSNPCHNGG





901
VCHSRWDDFS CSCPALTSGK ACEEVQWCGF SPCPHGAQCQ PVLQGFECIA NAVFNGQSGQ





961
ILFRSNGNIT RELTNITFGF RTRDANVIIL HAEKEPEFLN ISIQDSRLFF QLQSGNSFYM





1021
LSLTSLQSVN DGTWHEVTLS MTDPLSQTSR WQMEVDNETP FVTSTIATGS LNFLKDNTDI





1081
YVGDRAIDNI KGLQGCLSTI EIGGIYLSYF ENVHGFINKP QEEQFLKIST NSVVTGCLQL





1141
NVCNSNPCLH GGNCEDIYSS YHCSCPLGWS GKHCELNIDE CFSNPCIHGN CSDRVAAYHC





1201
TCEPGYTGVN CEVDIDNCQS HQCANGATCI SHTNGYSCLC FGNFTGKFCR QSRLPSTVCG





1261
NEKTNLTCYN GGNCTEFQTE LKCMCRPGFT GEWCEKDIDE CASDPCVNGG LCQDLLNKFQ





1321
CLCDVAFAGE RCEVDLADDL ISDIFTTIGS VTVALLLILL LAIVASVVTS NKRATQGTYS





1381
PSRQEKEGSR VEMWNLMPPP AMERLI











SEQ ID NO: 57



CRUMBS CELL POLARITY COMPLEX COMPONENT 1 (CRB1), HOMOLOG 1 ISOFORM 2



PRECURSOR


NP_001180569.1









1
MALKNINYLL IFYLSFSLLI YIKNSFCNKN NTRCLSNSCQ NNSTCKDFSK DNDCSCSDTA






61
NNLDKDCDNM KDPCFSNPCQ GSATCVNTPG ERSFLCKCPP GYSGTICETT IGSCGKNSCQ





121
HGGICHQDPI YPVCICPAGY AGRFCEIDHD ECASSPCQNG AVCQDGIDGY SCFCVPGYQG





181
RHCDLEVDEC ASDPCKNEAT CLNEIGRYTC ICPHNYSGYT GAQCEIDLNE CNSNPCQSNG





241
ECVELSSEKQ YGRITGLPSS FSYHEASGYV CICQPGFTGI HCEEDVNECS SNPCQNGGTC





301
ENLPGNYTCH CPFDNLSRTF YGGRDCSDIL LGCTHQQCLN NGTCIPHFQD GQHGFSCLCP





361
SGYTGSLCEI ATTLSFEGDG FLWVKSGSVT TKGSVCNIAL RFQTVQPMAL LLFRSNRDVF





421
VKLELLSGYI HLSIQVNNQS KVLLFISHNT SDGEWHFVEV IFAEAVTLTL IDDSCKEKCI





481
AKAPTPLESD QSICAFQNSF LGGLPVGMTS NGVALLNFYN MPSTPSFVGC LQDIKIDWNH





541
ITLENISSGS SLNVKAGCVR KDWCESQPCQ SRGRCINLWL SYQCDCHRPY EGPNCLREYV





601
AGRFGQDDST GYVIFTLDES YGDTISLSMF VRTLQPSGLL LALENSTYQY IRVWLERGRL





661
AMLTPNSPKL VVKFVLNDGN VHLISLKIKP YKIELYQSSQ NLGFISASTW KIEKGDVIYI





721
GGLPDKQETE LNGGFFKGCI QDVRLNNQNL EFFPNPTNNA SLNPVLVNVT QGCAGDNSCK





781
SNPCHNGGVC HSRWDDFSCS CPALTSGKAC EEVQWCGFSP CPHGAQCQPV LQGFECIANA





841
VFNGQSGQIL FRSNGNITRE LTNITFGFRT RDANVIILHA EKEPEFLNIS IQDSRLFFQL





901
QSGNSFYMLS LTSLQSVNDG TWHEVTLSMT DPLSQTSRWQ MEVDNETPFV TSTIATGSLN





961
FLKDNTDIYV GDRAIDNIKG LQGCLSTIEI GGIYLSYFEN VHGFINKPQE EQFLKISTNS





1021
VVTGCLQLNV CNSNPCLHGG NCEDIYSSYH CSCPLGWSGK HCELNIDECF SNPCIHGNCS





1081
DRVAAYHCTC EPGYTGVNCE VDIDNCQSHQ CANGATCISH TNGYSCLCFG NFTGKFCRQS





1141
RLPSTVCGNE KTNLTCYNGG NCTEFQTELK CMCRPGFTGE WCEKDIDECA SDPCVNGGLC





1201
QDLLNKFQCL CDVAFAGERC EVDLADDLIS DIFTTIGSVT VALLLILLLA IVASVVTSNK





1261
RATQGTYSPS RQEKEGSRVE MWNLMPPPAM ERLI











SEQ ID NO: 58



NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 1 (NMNAT1)



Q9HAN9.1









1
MENSEKTEVV LLACGSFNPI TNMHLRLFEL AKDYMNGTGR YTVVKGIISP VGDAYKKKGL






61
IPAYHRVIMA ELATKNSKWV EVDTWESLQK EWKETLKVLR HHQEKLEASD CDHQQNSPTL





121
ERPGRKRKWT ETQDSSQKKS LEPKTKAVPK VKLLCGADLL ESFAVPNLWK SEDITQIVAN





181
YGLICVTRAG NDAQKFIYES DVLWKHRSNI HVVNEWIAND ISSTKIRRAL RRGQSIRYLV





241
PDLVQEYIEK HNLYSSESED RNAGVILAPL QRNTAEAKT











SEQ ID NO: 59



NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 1 (NMNAT1); ISOFORM CRA_A



EAW71635.1









1
MENSEKTEVV LLACGSFNPI TNMHLRLFEL AKDYMNGTGR YTVVKGIISP VGDAYKKKGL






61
IPAYHRVIMA ELATKNSKWV EVDTWESLQK EWKETLKVLR HHQEKLEASD CDHQQNSPTL





121
ERPGRKRKWT ETQDSSQKKS LEPKTKAVPK VKLLCGADLL ESFAVPNLWK SEDITQIVAN





181
YGLICVTRAG NDAQKFIYES DVLWKHRSNI HVVNEWIAND ISSTKIRRAL RRGQSIRYLV





241
PDLVQEYIEK HNLYSSESED RNAGVILAPL QRNTAEAKT











SEQ ID NO: 60



NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 1 (NMNAT1), ISOFORM 2



NP_001284708.1









1
MENSEKTEVV LLACGSFNPI TNMHLRLFEL AKDYMNGTGR YTVVKGIISP VGDAYKKKGL






61
IPAYHRVIMA ELATKNSKWV EVDTWESLQK EWKETLKVLR HHQEKLEASD CDHQQNSPTL





121
ERPGRKRKWT ETQDSSQKKS LEPKTKDGVS LYHPGWSAVA











SEQ ID NO: 61



NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 1 (NMNAT1), ISOFORM 1



NP_073624.2









1
MENSEKTEVV LLACGSFNPI TNMHLRLFEL AKDYMNGTGR YTVVKGIISP VGDAYKKKGL






61
IPAYHRVIMA ELATKNSKWV EVDTWESLQK EWKETLKVLR HHQEKLEASD CDHQQNSPTL





121
ERPGRKRKWT ETQDSSQKKS LEPKTKAVPK VKLLCGADLL ESFAVPNLWK SEDITQIVAN





181
YGLICVTRAG NDAQKFIYES DVLWKHRSNI HVVNEWIAND ISSTKIRRAL RRGQSIRYLV





241
PDLVQEYIEK HNLYSSESED RNAGVILAPL QRNTAEAKT











SEQ ID NO: 62



CENTROSOMAL PROTEIN 290 (CEP290);



NP_079390.3









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKNE FLSRELIEKE RDLERSRTVI AKFQNKLKEL VEENKQLEEG MKEILQAIKE





661
MQKDPDVKGG ETSLIIPSLE RLVNAIESKN AEGIFDASLH LKAQVDQLTG RNEELRQELR





721
ESRKEAINYS QQLAKANLKI DHLEKETSLL RQSEGSNVVF KGIDLPDGIA PSSASIINSQ





781
NEYLIHLLQE LENKEKKLKN LEDSLEDYNR KFAVIRHQQS LLYKEYLSEK ETWKTESKTI





841
KEEKRKLEDQ VQQDAIKVKE YNNLLNALQM DSDEMKKILA ENSRKITVLQ VNEKSLIRQY





901
TTLVELERQL RKENEKQKNE LLSMEAEVCE KIGCLQRFKE MAIFKIAALQ KVVDNSVSLS





961
ELELANKQYN ELTAKYRDIL QKDNMLVQRT SNLEHLECEN ISLKEQVESI NKELEITKEK





1021
LHTIEQAWEQ ETKLGNESSM DKAKKSITNS DIVSISKKIT MLEMKELNER QRAEHCQKMY





1081
EHLRTSLKQM EERNFELETK FAELTKINLD AQKVEQMLRD ELADSVSKAV SDADRQRILE





1141
LEKNEMELKV EVSKLREISD IARRQVEILN AQQQSRDKEV ESLRMQLLDY QAQSDEKSLI





1201
AKLHQHNVSL QLSEATALGK LESITSKLQK MEAYNLRLEQ KLDEKEQALY YARLEGRNRA





1261
KHLRQTIQSL RRQFSGALPL AQQEKFSKTM IQLQNDKLKI MQEMKNSQQE HRNMENKTLE





1321
MELKLKGLEE LISTLKDTKG AQKVINWHMK IEELRLQELK LNRELVKDKE EIKYLNNIIS





1381
EYERTISSLE EEIVQQNKFH EERQMAWDQR EVDLERQLDI FDRQQNEILN AAQKFEEATG





1441
SIPDPSLPLP NQLEIALRKI KENIRIILET RATCKSLEEK LKEKESALRL AEQNILSRDK





1501
VINELRLRLP ATAEREKLIA ELGRKEMEPK SHHTLKIAHQ TIANMQARLN QKEEVLKKYQ





1561
RLLEKAREEQ REIVKKHEED LHILHHRLEL QADSSLNKFK QTAWDLMKQS PTPVPTNKHF





1621
IRLAEMEQTV AEQDDSLSSL LVKLKKVSQD LERQREITEL KVKEFENIKL QLQENHEDEV





1681
KKVKAEVEDL KYLLDQSQKE SQCLKSELQA QKEANSRAPT TTMRNLVERL KSQLALKEKQ





1741
QKALSRALLE LRAEMTAAAE ERIISATSQK EAHLNVQQIV DRHTRELKTQ VEDLNENLLK





1801
LKEALKTSKN RENSLTDNLN DLNNELQKKQ KAYNKILREK EEIDQENDEL KRQIKRLTSG





1861
LQGKPLTDNK QSLIEELQRK VKKLENQLEG KVEEVDLKPM KEKNAKEELI RWEEGKKWQA





1921
KIEGIRNKLK EKEGEVFTLT KQLNTLKDLF AKADKEKLTL QRKLKTTGMT VDQVLGIRAL





1981
ESEKELEELK KRNLDLENDI LYMRAHQALP RDSVVEDLHL QNRYLQEKLH ALEKQFSKDT





2041
YSKPSISGIE SDDHCQREQE LQKENLKLSS ENIELKFQLE QANKDLPRLK NQVRDLKEMC





2101
EFLKKEKAEV QRKLGHVRGS GRSGKTIPEL EKTIGLMKKV VEKVQRENEQ LKKASGILTS





2161
EKMANIEQEN EKLKAELEKL KAHLGHQLSM HYESKTKGTE KIIAENERLR KELKKETDAA





2221
EKLRIAKNNL EILNEKMTVQ LEETGKRLQF AESRGPQLEG ADSKSWKSIV VTRMYETKLK





2281
ELETDIAKKN QSITDLKQLV KEATEREQKV NKYNEDLEQQ IKILKHVPEG AETEQGLKRE





2341
LQVLRLANHQ LDKEKAELIH QIEANKDQSG AESTIPDADQ LKEKIKDLET QLKMSDLEKQ





2401
HLKEEIKKLK KELENFDPSF FEEIEDLKYN YKEEVKKNIL LEEKVKKLSE QLGVELTSPV





2461
AASEEFEDEE ESPVNFPIY











SEQ ID NO: 63



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X1



XP_011537059.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKIR SSDKAELLHR RSSFNTPQSD QNETEENMTI GSLSRMLSEI HHSVESGMHP





661
FVPLTRLSSS MQVKENSTPE TITIREIFKA PCLQSSRNLE SLVSTFSRES HEEINDICLF





721
SDDCMKKVSR SHQALEKTSF VQKSNSSFHG LSTASDIMQK LSLRQKSAIF CQQIHENRAD





781
MDKSQVATLE EEQVHSQVKY ADINLKEDII KSEVPLQTEI LKNKLKVNLP DPVSITAQSK





841
LSQINSLENL IEQLRRELVF LRSQNEIIAQ EFLIKEAECR NADIELEHHR SQAEQNEFLS





901
RELIEKERDL ERSRTVIAKF QNKLKELVEE NKQLEEGMKE ILQAIKEMQK DPDVKGGETS





961
LIIPSLERLV NAIESKNAEG IFDASLHLKA QVDQLTGRNE ELRQELRESR KEAINYSQQL





1021
AKANLKIDHL EKETSLLRQS EGSNVVFKGI DLPDGIAPSS ASIINSQNEY LIHLLQELEN





1081
KEKKLKNLED SLEDYNRKFA VIRHQQSLLY KEYLSEKETW KTESKTIKEE KRKLEDQVQQ





1141
DAIKVKEYNN LLNALQMDSD EMKKILAENS RKITVLQVNE KSLIRQYTTL VELERQLRKE





1201
NEKQKNELLS MEAEVCEKIG CLQRFKEMAI FKIAALQKVV DNSVSLSELE LANKQYNELT





1261
AKYRDILQKD NMLVQRTSNL EHLECENISL KEQVESINKE LEITKEKLHT IEQAWEQETK





1321
LGNESSMDKA KKSITNSDIV SISKKITMLE MKELNERQRA EHCQKMYEHL RTSLKQMEER





1381
NFELETKFAE LTKINLDAQK VEQMLRDELA DSVSKAVSDA DRQRILELEK NEMELKVEVS





1441
KLREISDIAR RQVEILNAQQ QSRDKEVESL RMQLLDYQAQ SDEKSLIAKL HQHNVSLQLS





1501
EATALGKLES ITSKLQKMEA YNLRLEQKLD EKEQALYYAR LEGRNRAKHL RQTIQSLRRQ





1561
FSGALPLAQQ EKFSKTMIQL QNDKLKIMQE MKNSQQEHRN MENKTLEMEL KLKGLEELIS





1621
TLKDTKGAQK VINWHMKIEE LRLQELKLNR ELVKDKEEIK YLNNIISEYE RTISSLEEEI





1681
VQQNKFHEER QMAWDQREVD LERQLDIFDR QQNEILNAAQ KFEEATGSIP DPSLPLPNQL





1741
EIALRKIKEN IRIILETRAT CKSLEEKLKE KESALRLAEQ NILSRDKVIN ELRLRLPATA





1801
EREKLIAELG RKEMEPKSHH TLKIAHQTIA NMQARLNQKE EVLKKYQRLL EKAREEQREI





1861
VKKHEEDLHI LHHRLELQAD SSLNKFKQTA WDLMKQSPTP VPTNKHFIRL AEMEQTVAEQ





1921
DDSLSSLLVK LKKVSQDLER QREITELKVK EFENIKLQLQ ENHEDEVKKV KAEVEDLKYL





1981
LDQSQKESQC LKSELQAQKE ANSRAPTTTM RNLVERLKSQ LALKEKQQKA LSRALLELRA





2041
EMTAAAEERI ISATSQKEAH LNVQQIVDRH TRELKTQVED LNENLLKLKE ALKTSKNREN





2101
SLTDNLNDLN NELQKKQKAY NKILREKEEI DQENDELKRQ IKRLTSGLQG KPLTDNKQSL





2161
IEELQRKVKK LENQLEGKVE EVDLKPMKEK NAKEELIRWE EGKKWQAKIE GIRNKLKEKE





2221
GEVFTLTKQL NTLKDLFAKA DKEKLTLQRK LKTTGMTVDQ VLGIRALESE KELEELKKRN





2281
LDLENDILYM RAHQALPRDS VVEDLHLQNR YLQEKLHALE KQFSKDTYSK PSQNQISGIE





2341
SDDHCQREQE LQKENLKLSS ENIELKFQLE QANKDLPRLK NQVRDLKEMC EFLKKEKAEV





2401
QRKLGHVRGS GRSGKTIPEL EKTIGLMKKV VEKVQRENEQ LKKASGILTS EKMANIEQEN





2461
EKLKAELEKL KAHLGHQLSM HYESKTKGTE KIIAENERLR KELKKETDAA EKLRIAKNNL





2521
EILNEKMTVQ LEETGKRLQF AESRGPQLEG ADSKSWKSIV VTRMYETKLK ELETDIAKKN





2581
QSITDLKQLV KEATEREQKV NKYNEDLEQQ IKILKHVPEG AETEQGLKRE LQVLRLANHQ





2641
LDKEKAELIH QIEANKDQSG AESTIPDADQ LKEKIKDLET QLKMSDLEKQ HLKEEIKKLK





2701
KELENFDPSF FEEIEDLKYN YKEEVKKNIL LEEKVKKLSE QLGVELTSPV AASEEFEDEE





2761
ESPVNFPIY











SEQ ID NO: 64



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X2



XP_011537060.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKIR SSDKAELLHR RSSFNTPQSD QNETEENMTI GSLSRMLSEI HHSVESGMHP





661
FVPLTRLSSS MQVKENSTPE TITIREIFKA PCLQSSRNLE SLVSTFSRES HEEINDICLF





721
SDDCMKKVSR SHQALEKTSF VQKSNSSFHG LSTASDIMQK LSLRQKSAIF CQQIHENRAD





781
MDKSQVATLE EEQVHSQVKY ADINLKEDII KSEVPLQTEI LKNKLKVNLP DPVSITAQSK





841
LSQINSLENL IEQLRRELVF LRSQNEIIAQ EFLIKEAECR NADIELEHHR SQAEQNEFLS





901
RELIEKERDL ERSRTVIAKF QNKLKELVEE NKQLEEGMKE ILQAIKEMQK DPDVKGGETS





961
LIIPSLERLV NAIESKNAEG IFDASLHLKA QVDQLTGRNE ELRQELRESR KEAINYSQQL





1021
AKANLKIDHL EKETSLLRQS EGSNVVFKGI DLPDGIAPSS ASIINSQNEY LIHLLQELEN





1081
KEKKLKNLED SLEDYNRKFA VIRHQQSLLY KEYLSEKETW KTESKTIKEE KRKLEDQVQQ





1141
DAIKVKEYNN LLNALQMDSD EMKKILAENS RKITVLQVNE KSLIRQYTTL VELERQLRKE





1201
NEKQKNELLS MEAEVCEKIG CLQRFKEMAI FKIAALQKVV DNSVSLSELE LANKQYNELT





1261
AKYRDILQKD NMLVQRTSNL EHLECENISL KEQVESINKE LEITKEKLHT IEQAWEQETK





1321
LGNESSMDKA KKSITNSDIV SISKKITMLE MKELNERQRA EHCQKMYEHL RTSLKQMEER





1381
NFELETKFAE LTKINLDAQK VEQMLRDELA DSVSKAVSDA DRQRILELEK NEMELKVEVS





1441
KLREISDIAR RQVEILNAQQ QSRDKEVESL RMQLLDYQAQ SDEKSLIAKL HQHNVSLQLS





1501
EATALGKLES ITSKLQKMEA YNLRLEQKLD EKEQALYYAR LEGRNRAKHL RQTIQSLRRQ





1561
FSGALPLAQQ EKFSKTMIQL QNDKLKIMQE MKNSQQEHRN MENKTLEMEL KLKGLEELIS





1621
TLKDTKGAQK VINWHMKIEE LRLQELKLNR ELVKDKEEIK YLNNIISEYE RTISSLEEEI





1681
VQQNKFHEER QMAWDQREVD LERQLDIFDR QQNEILNAAQ KFEEATGSIP DPSLPLPNQL





1741
EIALRKIKEN IRIILETRAT CKSLEEKLKE KESALRLAEQ NILSRDKVIN ELRLRLPATA





1801
EREKLIAELG RKEMEPKSHH TLKIAHQTIA NMQARLNQKE EVLKKYQRLL EKAREEQREI





1861
VKKHEEDLHI LHHRLELQAD SSLNKFKQTA WDLMKQSPTP VPTNKHFIRL AEMEQTVAEQ





1921
DDSLSSLLVK LKKVSQDLER QREITELKVK EFENIKLQLQ ENHEDEVKKV KAEVEDLKYL





1981
LDQSQKESQC LKSELQAQKE ANSRAPTTTM RNLVERLKSQ LALKEKQQKA LSRALLELRA





2041
EMTAAAEERI ISATSQKEAH LNVQQIVDRH TRELKTQVED LNENLLKLKE ALKTSKNREN





2101
SLTDNLNDLN NELQKKQKAY NKILREKEEI DQENDELKRQ IKRLTSGLQG KPLTDNKQSL





2161
IEELQRKVKK LENQLEGKVE EVDLKPMKEK NAKEELIRWE EGKKWQAKIE GIRNKLKEKE





2221
GEVFTLTKQL NTLKDLFAKA DKEKLTLQRK LKTTGMTVDQ VLGIRALESE KELEELKKRN





2281
LDLENDILYM RAHQALPRDS VVEDLHLQNR YLQEKLHALE KQFSKDTYSK PSNQISGIES





2341
DDHCQREQEL QKENLKLSSE NIELKFQLEQ ANKDLPRLKN QVRDLKEMCE FLKKEKAEVQ





2401
RKLGHVRGSG RSGKTIPELE KTIGLMKKVV EKVQRENEQL KKASGILTSE KMANIEQENE





2461
KLKAELEKLK AHLGHQLSMH YESKTKGTEK IIAENERLRK ELKKETDAAE KLRIAKNNLE





2521
ILNEKMTVQL EETGKRLQFA ESRGPQLEGA DSKSWKSIVV TRMYETKLKE LETDIAKKNQ





2581
SITDLKQLVK EATEREQKVN KYNEDLEQQI KILKHVPEGA ETEQGLKREL QVLRLANHQL





2641
DKEKAELIHQ IEANKDQSGA ESTIPDADQL KEKIKDLETQ LKMSDLEKQH LKEEIKKLKK





2701
ELENFDPSFF EEIEDLKYNY KEEVKKNILL EEKVKKLSEQ LGVELTSPVA ASEEFEDEEE





2761
SPVNFPIY











SEQ ID NO: 65



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X3



XP_011537061.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKIR SSDKAELLHR RSSFNTPQSD QNETEENMTI GSLSRMLSEI HHSVESGMHP





661
FVPLTRLSSS MQVKENSTPE TITIREIFKA PCLQSSRNLE SLVSTFSRES HEEINDICLF





721
SDDCMKKVSR SHQALEKTSF VQKSNSSFHG LSTASDIMQK LSLRQKSAIF CQQIHENRAD





781
MDKSQVATLE EEQVHSQVKY ADINLKEDII KSEVPLQTEI LKNKLKVNLP DPVSITAQSK





841
LSQINSLENL IEQLRRELVF LRSQNEIIAQ EFLIKEAECR NADIELEHHR SQAEQNEFLS





901
RELIEKERDL ERSRTVIAKF QNKLKELVEE NKQLEEGMKE ILQAIKEMQK DPDVKGGETS





961
LIIPSLERLV NAIESKNAEG IFDASLHLKA QVDQLTGRNE ELRQELRESR KEAINYSQQL





1021
AKANLKIDHL EKETSLLRQS EGSNVVFKGI DLPDGIAPSS ASIINSQNEY LIHLLQELEN





1081
KEKKLKNLED SLEDYNRKFA VIRHQQSLLY KEYLSEKETW KTESKTIKEE KRKLEDQVQQ





1141
DAIKVKEYNN LLNALQMDSD EMKKILAENS RKITVLQVNE KSLIRQYTTL VELERQLRKE





1201
NEKQKNELLS MEAEVCEKIG CLQRFKEMAI FKIAALQKVV DNSVSLSELE LANKQYNELT





1261
AKYRDILQKD NMLVQRTSNL EHLECENISL KEQVESINKE LEITKEKLHT IEQAWEQETK





1321
LGNESSMDKA KKSITNSDIV SISKKITMLE MKELNERQRA EHCQKMYEHL RTSLKQMEER





1381
NFELETKFAE LTKINLDAQK VEQMLRDELA DSVSKAVSDA DRQRILELEK NEMELKVEVS





1441
KLREISDIAR RQVEILNAQQ QSRDKEVESL RMQLLDYQAQ SDEKSLIAKL HQHNVSLQLS





1501
EATALGKLES ITSKLQKMEA YNLRLEQKLD EKEQALYYAR LEGRNRAKHL RQTIQSLRRQ





1561
FSGALPLAQQ EKFSKTMIQL QNDKLKIMQE MKNSQQEHRN MENKTLEMEL KLKGLEELIS





1621
TLKDTKGAQK VINWHMKIEE LRLQELKLNR ELVKDKEEIK YLNNIISEYE RTISSLEEEI





1681
VQQNKFHEER QMAWDQREVD LERQLDIFDR QQNEILNAAQ KFEEATGSIP DPSLPLPNQL





1741
EIALRKIKEN IRIILETRAT CKSLEEKLKE KESALRLAEQ NILSRDKVIN ELRLRLPATA





1801
EREKLIAELG RKEMEPKSHH TLKIAHQTIA NMQARLNQKE EVLKKYQRLL EKAREEQREI





1861
VKKHEEDLHI LHHRLELQAD SSLNKFKQTA WDLMKQSPTP VPTNKHFIRL AEMEQTVAEQ





1921
DDSLSSLLVK LKKVSQDLER QREITELKVK EFENIKLQLQ ENHEDEVKKV KAEVEDLKYL





1981
LDQSQKESQC LKSELQAQKE ANSRAPTTTM RNLVERLKSQ LALKEKQQKA LSRALLELRA





2041
EMTAAAEERI ISATSQKEAH LNVQQIVDRH TRELKTQVED LNENLLKLKE ALKTSKNREN





2101
SLTDNLNDLN NELQKKQKAY NKILREKEEI DQENDELKRQ IKRLTSGLQG KPLTDNKQSL





2161
IEELQRKVKK LENQLEGKVE EVDLKPMKEK NAKEELIRWE EGKKWQAKIE GIRNKLKEKE





2221
GEVFTLTKQL NTLKDLFAKA DKEKLTLQRK LKTTGMTVDQ VLGIRALESE KELEELKKRN





2281
LDLENDILYM RAHQALPRDS VVEDLHLQNR YLQEKLHALE KQFSKDTYSK PSISGIESDD





2341
HCQREQELQK ENLKLSSENI ELKFQLEQAN KDLPRLKNQV RDLKEMCEFL KKEKAEVQRK





2401
LGHVRGSGRS GKTIPELEKT IGLMKKVVEK VQRENEQLKK ASGILTSEKM ANIEQENEKL





2461
KAELEKLKAH LGHQLSMHYE SKTKGTEKII AENERLRKEL KKETDAAEKL RIAKNNLEIL





2521
NEKMTVQLEE TGKRLQFAES RGPQLEGADS KSWKSIVVTR MYETKLKELE TDIAKKNQSI





2581
TDLKQLVKEA TEREQKVNKY NEDLEQQIKI LKHVPEGAET EQGLKRELQV LRLANHQLDK





2641
EKAELIHQIE ANKDQSGAES TIPDADQLKE KIKDLETQLK MSDLEKQHLK EEIKKLKKEL





2701
ENFDPSFFEE IEDLKYNYKE EVKKNILLEE KVKKLSEQLG VELTSPVAAS EEFEDEEESP





2761
VNFPIY











SEQ ID NO: 66



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X4



XP_011537062.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKIR SSDKAELLHR RSSFNTPQSD QNETEENMTI GSLSRMLSEI HHSVESGMHP





661
FVPLTRLSSS MQVKENSTPE TITIREIFKA PCLQSSRNLE SLVSTFSRES HEEINDICLF





721
SDDCMKKVSR SHQALEKTSF VQKSNSSFHG LSTASDIMQK LSLRQKSAIF CQQIHENRAD





781
MDKSQVATLE EEQVHSQVKY ADINLKEDII KSEVPLQTEI LKNKLKVNLP DPVSITAQSK





841
LSQINSLENL IEQLRRELVF LRSQNEIIAQ EFLIKEAECR NADIELEHHR SQAEQNEFLS





901
RELIEKERDL ERSRTVIAKF QNKLKELVEE NKQLEEGMKE ILQAIKEMQK DPDVKGGETS





961
LIIPSLERLV NAIESKNAEG IFDASLHLKA QVDQLTGRNE ELRQELRESR KEAINYSQQL





1021
AKANLKIDHL EKETSLLRQS EGSNVVFKGI DLPDGIAPSS ASIINSQNEY LIHLLQELEN





1081
KEKKLKNLED SLEDYNRKFA VIRHQQSLLY KEYLSEKETW KTESKTIKEE KRKLEDQVQQ





1141
DAIKVKEYNN LLNALQMDSD EMKKILAENS RKITVLQVNE KSLIRQYTTL VELERQLRKE





1201
NEKQKNELLS MEAEVCEKIG CLQRFKEMAI FKIAALQKVV DNSVSLSELE LANKQYNELT





1261
AKYRDILQKD NMLVQRTSNL EHLECENISL KEQVESINKE LEITKEKLHT IEQAWEQETK





1321
LGNESSMDKA KKSITNSDIV SISKKITMLE MKELNERQRA EHCQKMYEHL RTSLKQMEER





1381
NFELETKFAE LTKINLDAQK VEQMLRDELA DSVSKAVSDA DRQRILELEK NEMELKVEVS





1441
KLREISDIAR RQVEILNAQQ QSRDKEVESL RMQLLDYQAQ SDEKSLIAKL HQHNVSLQLS





1501
EATALGKLES ITSKLQKMEA YNLRLEQKLD EKEQALYYAR LEGRNRAKHL RQTIQSLRRQ





1561
FSGALPLAQQ EKFSKTMIQL QNDKLKIMQE MKNSQQEHRN MENKTLEMEL KLKGLEELIS





1621
TLKDTKGAQK VINWHMKIEE LRLQELKLNR ELVKDKEEIK YLNNIISEYE RTISSLEEEI





1681
VQQNKFHEER QMAWDQREVD LERQLDIFDR QQNEILNAAQ KFEEATGSIP DPSLPLPNQL





1741
EIALRKIKEN IRIILETRAT CKSLEEKLKE KESALRLAEQ NILSRDKVIN ELRLRLPATA





1801
EREKLIAELG RKEMEPKSHH TLKIAHQTIA NMQARLNQKE EVLKKYQRLL EKAREEQREI





1861
VKKHEEDLHI LHHRLELQAD SSLNKFKQTA WDLMKQSPTP VPTNKHFIRL AEMEQTVAEQ





1921
DDSLSSLLVK LKKVSQDLER QREITELKVK EFENIKLQLQ ENHEDEVKKV KAEVEDLKYL





1981
LDQSQKESQC LKSELQAQKE ANSRAPTTTM RNLVERLKSQ LALKEKQQKA LSRALLELRA





2041
EMTAAAEERI ISATSQKEAH LNVQQIVDRH TRELKTQVED LNENLLKLKE ALKTSKNREN





2101
SLTDNLNDLN NELQKKQKAY NKILREKEEI DQENDELKRQ IKRLTSGLQG KPLTDNKQSL





2161
IEELQRKVKK LENQLEGKVE EVDLKPMKEK NAKEELIRWE EGKKWQAKIE GIRNKLKEKE





2221
GEVFTLTKQL NTLKDLFAKA DKEKLTLQRK LKTTGMTVDQ VLGIRALESE KELEELKKRN





2281
LDLENDILYM RAHQALPRDS VVEDLHLQNR YLQEKLHALE KQFSKDTYSK PSQNQISGIE





2341
SDDHCQREQE LQKENLKLSS ENIELKFQLE QANKDLPRLK NQVRDLKEMC EFLKKEKAEV





2401
QRKLGHVRGS GRSGKTIPEL EKTIGLMKKV VEKVQRENEQ LKKASGILTS EKMANIEQEN





2461
EKLKETDAAE KLRIAKNNLE ILNEKMTVQL EETGKRLQFA ESRGPQLEGA DSKSWKSIVV





2521
TRMYETKLKE LETDIAKKNQ SITDLKQLVK EATEREQKVN KYNEDLEQQI KILKHVPEGA





2581
ETEQGLKREL QVLRLANHQL DKEKAELIHQ IEANKDQSGA ESTIPDADQL KEKIKDLETQ





2641
LKMSDLEKQH LKEEIKKLKK ELENFDPSFF EEIEDLKYNY KEEVKKNILL EEKVKKLSEQ





2701
LGVELTSPVA ASEEFEDEEE SPVNFPIY











SEQ ID NO: 67



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X5



XP_016875469.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKIR SSDKAELLHR RSSFNTPQSD QNETEENMTI GSLSRMLSEI HHSVESGMHP





661
FVPLTRLSSS MQVKENSTPE TITIREIFKA PCLQSSRNLE SLVSTFSRES HEEINDICLF





721
SDDCMKKVSR SHQALEKTSF VQKSNSSFHG LSTASDIMQK LSLRQKSAIF CQQIHENRAD





781
MDKSQVATLE EEQVHSQVKY ADINLKEDII KSEVPLQTEI LKNKLKVNLP DPVSITAQSK





841
LSQINSLENL IEQLRRELVF LRSQNEIIAQ EFLIKEAECR NADIELEHHR SQAEQNEFLS





901
RELIEKERDL ERSRTVIAKF QNKLKELVEE NKQLEEGMKE ILQAIKEMQK DPDVKGGETS





961
LIIPSLERLV NAIESKNAEG IFDASLHLKA QVDQLTGRNE ELRQELRESR KEAINYSQQL





1021
AKANLKIDHL EKETSLLRQS EGSNVVFKGI DLPDGIAPSS ASIINSQNEY LIHLLQELEN





1081
KEKKLKNLED SLEDYNRKFA VIRHQQSLLY KEYLSEKETW KTESKTIKEE KRKLEDQVQQ





1141
DAIKVKEYNN LLNALQMDSD EMKKILAENS RKITVLQVNE KSLIRQYTTL VELERQLRKE





1201
NEKQKNELLS MEAEVCEKIG CLQRFKEMAI FKIAALQKVV DNSVSLSELE LANKQYNELT





1261
AKYRDILQKD NMLVQRTSNL EHLECENISL KEQVESINKE LEITKEKLHT IEQAWEQETK





1321
LGNESSMDKA KKSITNSDIV SISKKITMLE MKELNERQRA EHCQKMYEHL RTSLKQMEER





1381
NFELETKFAE LTKINLDAQK VEQMLRDELA DSVSKAVSDA DRQRILELEK NEMELKVEVS





1441
KLREISDIAR RQVEILNAQQ QSRDKEVESL RMQLLDYQAQ SDEKSLIAKL HQHNVSLQLS





1501
EATALGKLES ITSKLQKMEA YNLRLEQKLD EKEQALYYAR LEGRNRAKHL RQTIQSLRRQ





1561
FSGALPLAQQ EKFSKTMIQL QNDKLKIMQE MKNSQQEHRN MENKTLEMEL KLKGLEELIS





1621
TLKDTKGAQK VINWHMKIEE LRLQELKLNR ELVKDKEEIK YLNNIISEYE RTISSLEEEI





1681
VQQNKFHEER QMAWDQREVD LERQLDIFDR QQNEILNAAQ KFEEATGSIP DPSLPLPNQL





1741
EIALRKIKEN IRIILETRAT CKSLEEKLKE KESALRLAEQ NILSRDKVIN ELRLRLPATA





1801
EREKLIAELG RKEMEPKSHH TLKIAHQTIA NMQARLNQKE EVLKKYQRLL EKAREEQREI





1861
VKKHEEDLHI LHHRLELQAD SSLNKFKQTA WDLMKQSPTP VPTNKHFIRL AEMEQTVAEQ





1921
DDSLSSLLVK LKKVSQDLER QREITELKVK EFENIKLQLQ ENHEDEVKKV KAEVEDLKYL





1981
LDQSQKESQC LKSELQAQKE ANSRAPTTTM RNLVERLKSQ LALKEKQQKA LSRALLELRA





2041
EMTAAAEERI ISATSQKEAH LNVQQIVDRH TRELKTQVED LNENLLKLKE ALKTSKNREN





2101
SLTDNLNDLN NELQKKQKAY NKILREKEEI DQENDELKRQ IKRLTSGLQG KPLTDNKQSL





2161
IEELQRKVKK LENQLEGKVE EVDLKPMKEK NAKEELIRWE EGKKWQAKIE GIRNKLKEKE





2221
GEVFTLTKQL NTLKDLFAKA DKEKLTLQRK LKTTGMTVDQ VLGIRALESE KELEELKKRN





2281
LDLENDILYM RAHQALPRDS VVEDLHLQNR YLQEKLHALE KQFSKDTYSK PSISGIESDD





2341
HCQREQELQK ENLKLSSENI ELKFQLEQAN KDLPRLKNQV RDLKEMCEFL KKEKAEVQRK





2401
LGHVRGSGRS GKTIPELEKT IGLMKKVVEK VQRENEQLKK ASGILTSEKM ANIEQENEKL





2461
KETDAAEKLR IAKNNLEILN EKMTVQLEET GKRLQFAESR GPQLEGADSK SWKSIVVTRM





2521
YETKLKELET DIAKKNQSIT DLKQLVKEAT EREQKVNKYN EDLEQQIKIL KHVPEGAETE





2581
QGLKRELQVL RLANHQLDKE KAELIHQIEA NKDQSGAEST IPDADQLKEK IKDLETQLKM





2641
SDLEKQHLKE EIKKLKKELE NFDPSFFEEI EDLKYNYKEE VKKNILLEEK VKKLSEQLGV





2701
ELTSPVAASE EFEDEEESPV NFPIY











SEQ ID NO: 68



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X6



XP_011537063.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKIR SSDKAELLHR RSSFNTPQSD QNETEENMTI GSLSRMLSEI HHSVESGMHP





661
FVPLTRLSSS MQVKENSTPE TITIREIFKA PCLQSSRNLE SLVSTFSRES HEEINDICLF





721
SDDCMKKVSR SHQALEKTSF VQKSNSSFHG LSTASDIMQK LSLRQKSAIF CQQIHENRAD





781
MDKSQVATLE EEQVHSQVKY ADINLKEDII KSEVPLQTEI LKNKLKVNLP DPVSITAQSK





841
LSQINSLENL IEQLRRELVF LRSQNEIIAQ EFLIKEAECR NADIELEHHR SQAEQNEFLS





901
RELIEKERDL ERSRTVIAKF QNKLKELVEE NKQLEEGMKE ILQAIKEMQK DPDVKGGETS





961
LIIPSLERLV NAIESKNAEG IFDASLHLKA QVDQLTGRNE ELRQELRESR KEAINYSQQL





1021
AKANLKIDHL EKETSLLRQS EGSNVVFKGI DLPDGIAPSS ASIINSQNEY LIHLLQELEN





1081
KEKKLKNLED SLEDYNRKFA VIRHQQSLLY KEYLSEKETW KTESKTIKEE KRKLEDQVQQ





1141
DAIKVKEYNN LLNALQMDSD EMKKILAENS RKITVLQVNE KSLIRQYTTL VELERQLRKE





1201
NEKQKNELLS MEAEVCEKIG CLQRFKEMAI FKIAALQKVV DNSVSLSELE LANKQYNELT





1261
AKYRDILQKD NMLVQRTSNL EHLECENISL KEQVESINKE LEITKEKLHT IEQAWEQETK





1321
LGNESSMDKA KKSITNSDIV SISKKITMLE MKELNERQRA EHCQKMYEHL RTSLKQMEER





1381
NFELETKFAE LTKINLDAQK VEQMLRDELA DSVSKAVSDA DRQRILELEK NEMELKVEVS





1441
KLREISDIAR RQVEILNAQQ QSRDKEVESL RMQLLDYQAQ SDEKSLIAKL HQHNVSLQLS





1501
EATALGKLES ITSKLQKMEA YNLRLEQKLD EKEQALYYAR LEGRNRAKHL RQTIQSLRRQ





1561
FSGALPLAQQ EKFSKTMIQL QNDKLKIMQE MKNSQQEHRN MENKTLEMEL KLKGLEELIS





1621
TLKDTKGAQK VINWHMKIEE LRLQELKLNR ELVKDKEEIK YLNNIISEYE RTISSLEEEI





1681
VQQNKFHEER QMAWDQREVD LERQLDIFDR QQNEILNAAQ KFEEATGSIP DPSLPLPNQL





1741
EIALRKIKEN IRIILETRAT CKSLEEKLKE KESALRLAEQ NILSRDKVIN ELRLRLPATA





1801
EREKLIAELG RKEMEPKSHH TLKIAHQTIA NMQARLNQKE EVLKKYQRLL EKAREEQREI





1861
VKKHEEDLHI LHHRLELQAD SSLNKFKQTA WDLMKQSPTP VPTNKHFIRL AEMEQTVAEQ





1921
DDSLSSLLVK LKKVSQDLER QREITELKVK EFENIKLQLQ ENHEDEVKKV KAEVEDLKYL





1981
LDQSQKESQC LKSELQAQKE ANSRAPTTTM RNLVERLKSQ LALKEKQQKA LSRALLELRA





2041
EMTAAAEERI ISATSQKEAH LNVQQIVDRH TRELKTQVED LNENLLKLKE ALKTSKNREN





2101
SLTDNLNDLN NELQKKQKAY NKILREKEEI DQENDELKRQ IKRLTSGLQG KPLTDNKQSL





2161
IEELQRKVKK LENQLEGKVE EVDLKPMKEK NAKEELIRWE EGKKWQAKIE GIRNKLKEKE





2221
GEVFTLTKQL NTLKDLFAKA DKEKLTLQRK LKTTGMTVDQ VLGIRALESE KELEELKKRN





2281
LDLENDILYM RAHQALPRDS VVEDLHLQNR YLQEKLHALE KQFSKDTYSK PSQNQISGIE





2341
SDDHCQREQE LQKENLKLSS ENIELKFQLE QANKDLPRLK NQVRDLKEMC EFLKKEKAEV





2401
QRKLGHVRGA ELEKLKAHLG HQLSMHYESK TKGTEKIIAE NERLRKELKK ETDAAEKLRI





2461
AKNNLEILNE KMTVQLEETG KRLQFAESRG PQLEGADSKS WKSIVVTRMY ETKLKELETD





2521
IAKKNQSITD LKQLVKEATE REQKVNKYNE DLEQQIKILK HVPEGAETEQ GLKRELQVLR





2581
LANHQLDKEK AELIHQIEAN KDQSGAESTI PDADQLKEKI KDLETQLKMS DLEKQHLKEE





2641
IKKLKKELEN FDPSFFEEIE DLKYNYKEEV KKNILLEEKV KKLSEQLGVE LTSPVAASEE





2701
FEDEEESPVN FPIY











SEQ ID NO: 69



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X7



XP_016875470.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKIR SSDKAELLHR RSSFNTPQSD QNETEENMTI GSLSRMLSEI HHSVESGMHP





661
FVPLTRLSSS MQVKENSTPE TITIREIFKA PCLQSSRNLE SLVSTFSRES HEEINDICLF





721
SDDCMKKVSR SHQALEKTSF VQKSNSSFHG LSTASDIMQK LSLRQKSAIF CQQIHENRAD





781
MDKSQVATLE EEQVHSQVKY ADINLKEDII KSEVPLQTEI LKNKLKVNLP DPVSITAQSK





841
LSQINSLENL IEQLRRELVF LRSQNEIIAQ EFLIKEAECR NADIELEHHR SQAEQNEFLS





901
RELIEKERDL ERSRTVIAKF QNKLKELVEE NKQLEEGMKE ILQAIKEMQK DPDVKGGETS





961
LIIPSLERLV NAIESKNAEG IFDASLHLKA QVDQLTGRNE ELRQELRESR KEAINYSQQL





1021
AKANLKIDHL EKETSLLRQS EGSNVVFKGI DLPDGIAPSS ASIINSQNEY LIHLLQELEN





1081
KEKKLKNLED SLEDYNRKFA VIRHQQSLLY KEYLSEKETW KTESKTIKEE KRKLEDQVQQ





1141
DAIKVKEYNN LLNALQMDSD EMKKILAENS RKITVLQVNE KSLIRQYTTL VELERQLRKE





1201
NEKQKNELLS MEAEVCEKIG CLQRFKEMAI FKIAALQKVV DNSVSLSELE LANKQYNELT





1261
AKYRDILQKD NMLVQRTSNL EHLECENISL KEQVESINKE LEITKEKLHT IEQAWEQETK





1321
LGNESSMDKA KKSITNSDIV SISKKITMLE MKELNERQRA EHCQKMYEHL RTSLKQMEER





1381
NFELETKFAE LTKINLDAQK VEQMLRDELA DSVSKAVSDA DRQRILELEK NEMELKVEVS





1441
KLREISDIAR RQVEILNAQQ QSRDKEVESL RMQLLDYQAQ SDEKSLIAKL HQHNVSLQLS





1501
EATALGKLES ITSKLQKMEA YNLRLEQKLD EKEQALYYAR LEGRNRAKHL RQTIQSLRRQ





1561
FSGALPLAQQ EKFSKTMIQL QNDKLKIMQE MKNSQQEHRN MENKTLEMEL KLKGLEELIS





1621
TLKDTKGAQK VINWHMKIEE LRLQELKLNR ELVKDKEEIK YLNNIISEYE RTISSLEEEI





1681
VQQNKFHEER QMAWDQREVD LERQLDIFDR QQNEILNAAQ KFEEATGSIP DPSLPLPNQL





1741
EIALRKIKEN IRIILETRAT CKSLEEKLKE KESALRLAEQ NILSRDKVIN ELRLRLPATA





1801
EREKLIAELG RKEMEPKSHH TLKIAHQTIA NMQARLNQKE EVLKKYQRLL EKAREEQREI





1861
VKKHEEDLHI LHHRLELQAD SSLNKFKQTA WDLMKQSPTP VPTNKHFIRL AEMEQTVAEQ





1921
DDSLSSLLVK LKKVSQDLER QREITELKVK EFENIKLQLQ ENHEDEVKKV KAEVEDLKYL





1981
LDQSQKESQC LKSELQAQKE ANSRAPTTTM RNLVERLKSQ LALKEKQQKA LSRALLELRA





2041
EMTAAAEERI ISATSQKEAH LNVQQIVDRH TRELKTQVED LNENLLKLKE ALKTSKNREN





2101
SLTDNLNDLN NELQKKQKAY NKILREKEEI DQENDELKRQ IKRLTSGLQG KPLTDNKQSL





2161
IEELQRKVKK LENQLEGKVE EVDLKPMKEK NAKEELIRWE EGKKWQAKIE GIRNKLKEKE





2221
GEVFTLTKQL NTLKDLFAKA DKEKLTLQRK LKTTGMTVDQ VLGIRALESE KELEELKKRN





2281
LDLENDILYM RAHQALPRDS VVEDLHLQNR YLQEKLHALE KQFSKDTYSK PSISGIESDD





2341
HCQREQELQK ENLKLSSENI ELKFQLEQAN KDLPRLKNQV RDLKEMCEFL KKEKAEVQRK





2401
LGHVRGAELE KLKAHLGHQL SMHYESKTKG TEKIIAENER LRKELKKETD AAEKLRIAKN





2461
NLEILNEKMT VQLEETGKRL QFAESRGPQL EGADSKSWKS IVVIRMYETK LKELETDIAK





2521
KNQSITDLKQ LVKEATEREQ KVNKYNEDLE QQIKILKHVP EGAETEQGLK RELQVLRLAN





2581
HQLDKEKAEL IHQIEANKDQ SGAESTIPDA DQLKEKIKDL ETQLKMSDLE KQHLKEEIKK





2641
LKKELENFDP SFFEEIEDLK YNYKEEVKKN ILLEEKVKKL SEQLGVELTS PVAASEEFED





2701
EEESPVNFPI Y











SEQ ID NO: 70



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X8



XP_016875471.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKIR SSDKAELLHR RSSFNTPQSD QNETEENMTI GSLSRMLSEI HHSVESGMHP





661
FVPLTRLSSS MQVKENSTPE TITIREIFKA PCLQSSRNLE SLVSTFSRES HEEINDICLF





721
SDDCMKKVSR SHQALEKTSF VQKSNSSFHG LSTASDIMQK LSLRQKSAIF CQQIHENRAD





781
MDKSQVATLE EEQVHSQVKY ADINLKEDII KSEVPLQTEI LKNKLKVNLP DPVSITAQSK





841
LSQINSLENL IEQLRRELVF LRSQNEIIAQ EFLIKEAECR NADIELEHHR SQAEQNEFLS





901
RELIEKERDL ERSRTVIAKF QNKLKELVEE NKQLEEGMKE ILQAIKEMQK DPDVKGGETS





961
LIIPSLERLV NAIESKNAEG IFDASLHLKA QVDQLTGRNE ELRQELRESR KEAINYSQQL





1021
AKANLKIDHL EKETSLLRQS EGSNVVFKGI DLPDGIAPSS ASIINSQNEY LIHLLQELEN





1081
KEKKLKNLED SLEDYNRKFA VIRHQQSLLY KEYLSEKETW KTESKTIKEE KRKLEDQVQQ





1141
DAIKVKEYNN LLNALQMDSD EMKKILAENS RKITVLQVNE KSLIRQYTTL VELERQLRKE





1201
NEKQKNELLS MEAEVCEKIG CLQRFKEMAI FKIAALQKVV DNSVSLSELE LANKQYNELT





1261
AKYRDILQKD NMLVQRTSNL EHLECENISL KEQVESINKE LEITKEKLHT IEQAWEQETK





1321
LGNESSMDKA KKSITNSDIV SISKKITMLE MKELNERQRA EHCQKMYEHL RTSLKQMEER





1381
NFELETKFAE LTKINLDAQK VEQMLRDELA DSVSKAVSDA DRQRILELEK NEMELKVEVS





1441
KLREISDIAR RQVEILNAQQ QSRDKEVESL RMQLLDYQAQ SDEKSLIAKL HQHNVSLQLS





1501
EATALGKLES ITSKLQKMEA YNLRLEQKLD EKEQALYYAR LEGRNRAKHL RQTIQSLRRQ





1561
FSGALPLAQQ EKFSKTMIQL QNDKLKIMQE MKNSQQEHRN MENKTLEMEL KLKGLEELIS





1621
TLKDTKGAQK VINWHMKIEE LRLQELKLNR ELVKDKEEIK YLNNIISEYE RTISSLEEEI





1681
VQQNKFHEER QMAWDQREVD LERQLDIFDR QQNEILNAAQ KFEEATGSIP DPSLPLPNQL





1741
EIALRKIKEN IRIILETRAT CKSLEEKLKE KESALRLAEQ NILSRDKVIN ELRLRLPATA





1801
EREKLIAELG RKEMEPKSHH TLKIAHQTIA NMQARLNQKE EVLKKYQRLL EKAREEQREI





1861
VKKHEEDLHI LHHRLELQAD SSLNKFKQTA WDLMKQSPTP VPTNKHFIRL AEMEQTVAEQ





1921
DDSLSSLLVK LKKVSQDLER QREITELKVK EFENIKLQLQ ENHEDEVKKV KAEVEDLKYL





1981
LDQSQKESQC LKSELQAQKE ANSRAPTTTM RNLVERLKSQ LALKEKQQKA LSRALLELRA





2041
EMTAAAEERI ISATSQKEAH LNVQQIVDRH TRELKTQVED LNENLLKLKE ALKTSKNREN





2101
SLTDNLNDLN NELQKKQKAY NKILREKEEI DQENDELKRQ IKRLTSGLQG KPLTDNKQSL





2161
IEELQRKVKK LENQLEGKVE EVDLKPMKEK NAKEELIRWE EGKKWQAKIE GIRNKLKEKE





2221
GEVFTLTKQL NTLKDLFAKA DKEKLTLQRK LKTTGMTVDQ VLGIRALESE KELEELKKRN





2281
LDLENDILYM RAHQALPRDS VVEDLHLQNR YLQEKLHALE KQFSKDTYSK PSQNQISGIE





2341
SDDHCQREQE LQKENLKLSS ENIELKFQLE QANKDLPRLK NQVRDLKEMC EFLKKEKAEV





2401
QRKLGHVRGS GRSGKTIPEL EKTIGLMKKV VEKVQRENEQ LKKASGILTS EKMANIEQEN





2461
EKLKAELEKL KAHLGHQLSM HYESKTKGTE KIIAENERLR KELKKETDAA EKLRIAKNNL





2521
EILNEKMTVQ LEETGKRLQF AESRGPQLEG ADSKSWKSIV VTRMYETKLK ELETDIAKKN





2581
QSITDLKQLV KEATEREQKV NKYNEDLEQQ IS











SEQ ID NO: 71



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X9



XP_011537064.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKNE IIAQEFLIKE AECRNADIEL EHHRSQAEQN EFLSRELIEK ERDLERSRTV





661
IAKFQNKLKE LVEENKQLEE GMKEILQAIK EMQKDPDVKG GETSLIIPSL ERLVNAIESK





721
NAEGIFDASL HLKAQVDQLT GRNEELRQEL RESRKEAINY SQQLAKANLK IDHLEKETSL





781
LRQSEGSNVV FKGIDLPDGI APSSASIINS QNEYLIHLLQ ELENKEKKLK NLEDSLEDYN





841
RKFAVIRHQQ SLLYKEYLSE KETWKTESKT IKEEKRKLED QVQQDAIKVK EYNNLLNALQ





901
MDSDEMKKIL AENSRKITVL QVNEKSLIRQ YTTLVELERQ LRKENEKQKN ELLSMEAEVC





961
EKIGCLQRFK EMAIFKIAAL QKVVDNSVSL SELELANKQY NELTAKYRDI LQKDNMLVQR





1021
TSNLEHLECE NISLKEQVES INKELEITKE KLHTIEQAWE QETKLGNESS MDKAKKSITN





1081
SDIVSISKKI TMLEMKELNE RQRAEHCQKM YEHLRTSLKQ MEERNFELET KFAELTKINL





1141
DAQKVEQMLR DELADSVSKA VSDADRQRIL ELEKNEMELK VEVSKLREIS DIARRQVEIL





1201
NAQQQSRDKE VESLRMQLLD YQAQSDEKSL IAKLHQHNVS LQLSEATALG KLESITSKLQ





1261
KMEAYNLRLE QKLDEKEQAL YYARLEGRNR AKHLRQTIQS LRRQFSGALP LAQQEKFSKT





1321
MIQLQNDKLK IMQEMKNSQQ EHRNMENKTL EMELKLKGLE ELISTLKDTK GAQKVINWHM





1381
KIEELRLQEL KLNRELVKDK EEIKYLNNII SEYERTISSL EEEIVQQNKF HEERQMAWDQ





1441
REVDLERQLD IFDRQQNEIL NAAQKFEEAT GSIPDPSLPL PNQLEIALRK IKENIRIILE





1501
TRATCKSLEE KLKEKESALR LAEQNILSRD KVINELRLRL PATAEREKLI AELGRKEMEP





1561
KSHHTLKIAH QTIANMQARL NQKEEVLKKY QRLLEKAREE QREIVKKHEE DLHILHHRLE





1621
LQADSSLNKF KQTAWDLMKQ SPTPVPTNKH FIRLAEMEQT VAEQDDSLSS LLVKLKKVSQ





1681
DLERQREITE LKVKEFENIK LQLQENHEDE VKKVKAEVED LKYLLDQSQK ESQCLKSELQ





1741
AQKEANSRAP TTTMRNLVER LKSQLALKEK QQKALSRALL ELRAEMTAAA EERIISATSQ





1801
KEAHLNVQQI VDRHTRELKT QVEDLNENLL KLKEALKTSK NRENSLTDNL NDLNNELQKK





1861
QKAYNKILRE KEEIDQENDE LKRQIKRLTS GLQGKPLTDN KQSLIEELQR KVKKLENQLE





1921
GKVEEVDLKP MKEKNAKEEL IRWEEGKKWQ AKIEGIRNKL KEKEGEVFTL TKQLNTLKDL





1981
FAKADKEKLT LQRKLKTTGM TVDQVLGIRA LESEKELEEL KKRNLDLEND ILYMRAHQAL





2041
PRDSVVEDLH LQNRYLQEKL HALEKQFSKD TYSKPSQNQI SGIESDDHCQ REQELQKENL





2101
KLSSENIELK FQLEQANKDL PRLKNQVRDL KEMCEFLKKE KAEVQRKLGH VRGSGRSGKT





2161
IPELEKTIGL MKKVVEKVQR ENEQLKKASG ILTSEKMANI EQENEKLKAE LEKLKAHLGH





2221
QLSMHYESKT KGTEKIIAEN ERLRKELKKE TDAAEKLRIA KNNLEILNEK MTVQLEETGK





2281
RLQFAESRGP QLEGADSKSW KSIVVTRMYE TKLKELETDI AKKNQSITDL KQLVKEATER





2341
EQKVNKYNED LEQQIKILKH VPEGAETEQG LKRELQVLRL ANHQLDKEKA ELIHQIEANK





2401
DQSGAESTIP DADQLKEKIK DLETQLKMSD LEKQHLKEEI KKLKKELENF DPSFFEEIED





2461
LKYNYKEEVK KNILLEEKVK KLSEQLGVEL TSPVAASEEF EDEEESPVNF PIY














SEQ ID NO: 72



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X10



XP_011537065.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKNE FLSRELIEKE RDLERSRTVI AKFQNKLKEL VEENKQLEEG MKEILQAIKE





661
MQKDPDVKGG ETSLIIPSLE RLVNAIESKN AEGIFDASLH LKAQVDQLTG RNEELRQELR





721
ESRKEAINYS QQLAKANLKI DHLEKETSLL RQSEGSNVVF KGIDLPDGIA PSSASIINSQ





781
NEYLIHLLQE LENKEKKLKN LEDSLEDYNR KFAVIRHQQS LLYKEYLSEK ETWKTESKTI





841
KEEKRKLEDQ VQQDAIKVKE YNNLLNALQM DSDEMKKILA ENSRKITVLQ VNEKSLIRQY





901
TTLVELERQL RKENEKQKNE LLSMEAEVCE KIGCLQRFKE MAIFKIAALQ KVVDNSVSLS





961
ELELANKQYN ELTAKYRDIL QKDNMLVQRT SNLEHLECEN ISLKEQVESI NKELEITKEK





1021
LHTIEQAWEQ ETKLGNESSM DKAKKSITNS DIVSISKKIT MLEMKELNER QRAEHCQKMY





1081
EHLRTSLKQM EERNFELETK FAELTKINLD AQKVEQMLRD ELADSVSKAV SDADRQRILE





1141
LEKNEMELKV EVSKLREISD IARRQVEILN AQQQSRDKEV ESLRMQLLDY QAQSDEKSLI





1201
AKLHQHNVSL QLSEATALGK LESITSKLQK MEAYNLRLEQ KLDEKEQALY YARLEGRNRA





1261
KHLRQTIQSL RRQFSGALPL AQQEKFSKTM IQLQNDKLKI MQEMKNSQQE HRNMENKTLE





1321
MELKLKGLEE LISTLKDTKG AQKVINWHMK IEELRLQELK LNRELVKDKE EIKYLNNIIS





1381
EYERTISSLE EEIVQQNKFH EERQMAWDQR EVDLERQLDI FDRQQNEILN AAQKFEEATG





1441
SIPDPSLPLP NQLEIALRKI KENIRIILET RATCKSLEEK LKEKESALRL AEQNILSRDK





1501
VINELRLRLP ATAEREKLIA ELGRKEMEPK SHHTLKIAHQ TIANMQARLN QKEEVLKKYQ





1561
RLLEKAREEQ REIVKKHEED LHILHHRLEL QADSSLNKFK QTAWDLMKQS PTPVPTNKHF





1621
IRLAEMEQTV AEQDDSLSSL LVKLKKVSQD LERQREITEL KVKEFENIKL QLQENHEDEV





1681
KKVKAEVEDL KYLLDQSQKE SQCLKSELQA QKEANSRAPT TTMRNLVERL KSQLALKEKQ





1741
QKALSRALLE LRAEMTAAAE ERIISATSQK EAHLNVQQIV DRHTRELKTQ VEDLNENLLK





1801
LKEALKTSKN RENSLTDNLN DLNNELQKKQ KAYNKILREK EEIDQENDEL KRQIKRLTSG





1861
LQGKPLTDNK QSLIEELQRK VKKLENQLEG KVEEVDLKPM KEKNAKEELI RWEEGKKWQA





1921
KIEGIRNKLK EKEGEVFTLT KQLNTLKDLF AKADKEKLTL QRKLKTTGMT VDQVLGIRAL





1981
ESEKELEELK KRNLDLENDI LYMRAHQALP RDSVVEDLHL QNRYLQEKLH ALEKQFSKDT





2041
YSKPSQNQIS GIESDDHCQR EQELQKENLK LSSENIELKF QLEQANKDLP RLKNQVRDLK





2101
EMCEFLKKEK AEVQRKLGHV RGSGRSGKTI PELEKTIGLM KKVVEKVQRE NEQLKKASGI





2161
LTSEKMANIE QENEKLKAEL EKLKAHLGHQ LSMHYESKTK GTEKIIAENE RLRKELKKET





2221
DAAEKLRIAK NNLEILNEKM TVQLEETGKR LQFAESRGPQ LEGADSKSWK SIVVTRMYET





2281
KLKELETDIA KKNQSITDLK QLVKEATERE QKVNKYNEDL EQQIKILKHV PEGAETEQGL





2341
KRELQVLRLA NHQLDKEKAE LIHQIEANKD QSGAESTIPD ADQLKEKIKD LETQLKMSDL





2401
EKQHLKEEIK KLKKELENFD PSFFEEIEDL KYNYKEEVKK NILLEEKVKK LSEQLGVELT





2461
SPVAASEEFE DEEESPVNFP IY











SEQ ID NO: 73



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X11



XP_016875472.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENEQLC QDIIDYQKQI





181
DSQKETLLSR RGEDSDYRSQ LSKKNYELIQ YLDEIQTLTE ANEKIEVQNQ EMRKNLEESV





241
QEMEKMTDEY NRMKAIVHQT DNVIDQLKKE NDHYQLQVQE LTDLLKSKNE EDDPIMVAVN





301
AKVEEWKLIL SSKDDEIIEY QQMLHNLREK LKNAQLDADK SNVMALQQGI QERDSQIKML





361
TEQVEQYTKE MEKNTCIIED LKNELQRNKG ASTLSQQTHM KIQSTLDILK EKTKEAERTA





421
ELAEADAREK DKELVEALKR LKDYESGVYG LEDAVVEIKN CKNQIKIRDR EIEILTKEIN





481
KLELKISDFL DENEALRERV GLEPKTMIDL TEFRNSKHLK QQQYRAENQI LLKEIESLEE





541
ERLDLKKKIR QMAQERGKRS ATSGLTTEDL NLTENISQGD RISERKLDLL SLKNMSEAQS





601
KNEFLSRELI EKERDLERSR TVIAKFQNKL KELVEENKQL EEGMKEILQA IKEMQKDPDV





661
KGGETSLIIP SLERLVNAIE SKNAEGIFDA SLHLKAQVDQ LTGRNEELRQ ELRESRKEAI





721
NYSQQLAKAN LKIDHLEKET SLLRQSEGSN VVFKGIDLPD GIAPSSASII NSQNEYLIHL





781
LQELENKEKK LKNLEDSLED YNRKFAVIRH QQSLLYKEYL SEKETWKTES KTIKEEKRKL





841
EDQVQQDAIK VKEYNNLLNA LQMDSDEMKK ILAENSRKIT VLQVNEKSLI RQYTTLVELE





901
RQLRKENEKQ KNELLSMEAE VCEKIGCLQR FKEMAIFKIA ALQKVVDNSV SLSELELANK





961
QYNELTAKYR DILQKDNMLV QRTSNLEHLE CENISLKEQV ESINKELEIT KEKLHTIEQA





1021
WEQETKLGNE SSMDKAKKSI TNSDIVSISK KITMLEMKEL NERQRAEHCQ KMYEHLRTSL





1081
KQMEERNFEL ETKFAELTKI NLDAQKVEQM LRDELADSVS KAVSDADRQR ILELEKNEME





1141
LKVEVSKLRE ISDIARRQVE ILNAQQQSRD KEVESLRMQL LDYQAQSDEK SLIAKLHQHN





1201
VSLQLSEATA LGKLESITSK LQKMEAYNLR LEQKLDEKEQ ALYYARLEGR NRAKHLRQTI





1261
QSLRRQFSGA LPLAQQEKFS KTMIQLQNDK LKIMQEMKNS QQEHRNMENK TLEMELKLKG





1321
LEELISTLKD TKGAQKVINW HMKIEELRLQ ELKLNRELVK DKEEIKYLNN IISEYERTIS





1381
SLEEEIVQQN KFHEERQMAW DQREVDLERQ LDIFDRQQNE ILNAAQKFEE ATGSIPDPSL





1441
PLPNQLEIAL RKIKENIRII LETRATCKSL EEKLKEKESA LRLAEQNILS RDKVINELRL





1501
RLPATAEREK LIAELGRKEM EPKSHHTLKI AHQTIANMQA RLNQKEEVLK KYQRLLEKAR





1561
EEQREIVKKH EEDLHILHHR LELQADSSLN KFKQTAWDLM KQSPTPVPTN KHFIRLAEME





1621
QTVAEQDDSL SSLLVKLKKV SQDLERQREI TELKVKEFEN IKLQLQENHE DEVKKVKAEV





1681
EDLKYLLDQS QKESQCLKSE LQAQKEANSR APTTTMRNLV ERLKSQLALK EKQQKALSRA





1741
LLELRAEMTA AAEERIISAT SQKEAHLNVQ QIVDRHTREL KTQVEDLNEN LLKLKEALKT





1801
SKNRENSLTD NLNDLNNELQ KKQKAYNKIL REKEEIDQEN DELKRQIKRL TSGLQGKPLT





1861
DNKQSLIEEL QRKVKKLENQ LEGKVEEVDL KPMKEKNAKE ELIRWEEGKK WQAKIEGIRN





1921
KLKEKEGEVF TLTKQLNTLK DLFAKADKEK LTLQRKLKTT GMTVDQVLGI RALESEKELE





1981
ELKKRNLDLE NDILYMRAHQ ALPRDSVVED LHLQNRYLQE KLHALEKQFS KDTYSKPSQN





2041
QISGIESDDH CQREQELQKE NLKLSSENIE LKFQLEQANK DLPRLKNQVR DLKEMCEFLK





2101
KEKAEVQRKL GHVRGSGRSG KTIPELEKTI GLMKKVVEKV QRENEQLKKA SGILTSEKMA





2161
NIEQENEKLK AELEKLKAHL GHQLSMHYES KTKGTEKIIA ENERLRKELK KETDAAEKLR





2221
IAKNNLEILN EKMTVQLEET GKRLQFAESR GPQLEGADSK SWKSIVVTRM YETKLKELET





2281
DIAKKNQSIT DLKQLVKEAT EREQKVNKYN EDLEQQIKIL KHVPEGAETE QGLKRELQVL





2341
RLANHQLDKE KAELIHQIEA NKDQSGAEST IPDADQLKEK IKDLETQLKM SDLEKQHLKE





2401
EIKKLKKELE NFDPSFFEEI EDLKYNYKEE VKKNILLEEK VKKLSEQLGV ELTSPVAASE





2461
EFEDEEESPV NFPIY











SEQ ID NO: 74



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X12



XP_011537066.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKIR SSDKAELLHR RSSFNTPQSD QNETEENMTI GSLSRMLSEI HHSVESGMHP





661
FVPLTRLSSS MQVKENSTPE TITIREIFKA PCLQSSRNLE SLVSTFSRES HEEINDICLF





721
SDDCMKKVSR SHQALEKTSF VQKSNSSFHG LSTASDIMQK LSLRQKSAIF CQQIHENRAD





781
MDKSQVATLE EEQVHSQVKY ADINLKEDII KSEVPLQTEI LKNKLKVNLP DPVSITAQSK





841
LSQINSLENL IEQLRRELVF LRSQNEIIAQ EFLIKEAECR NADIELEHHR SQAEQNEFLS





901
RELIEKERDL ERSRTVIAKF QNKLKELVEE NKQLEEGMKE ILQAIKEMQK DPDVKGGETS





961
LIIPSLERLV NAIESKNAEG IFDASLHLKA QVDQLTGRNE ELRQELRESR KEAINYSQQL





1021
AKANLKIDHL EKETSLLRQS EGSNVVFKGI DLPDGIAPSS ASIINSQNEY LIHLLQELEN





1081
KEKKLKNLED SLEDYNRKFA VIRHQQSLLY KEYLSEKETW KTESKTIKEE KRKLEDQVQQ





1141
DAIKVKEYNN LLNALQMDSD EMKKILAENS RKITVLQVNE KSLIRQYTTL VELERQLRKE





1201
NEKQKNELLS MEAEVCEKIG CLQRFKEMAI FKIAALQKVV DNSVSLSELE LANKQYNELT





1261
AKYRDILQKD NMLVQRTSNL EHLECENISL KEQVESINKE LEITKEKLHT IEQAWEQETK





1321
LGNESSMDKA KKSITNSDIV SISKKITMLE MKELNERQRA EHCQKMYEHL RTSLKQMEER





1381
NFELETKFAE LTKINLDAQK VEQMLRDELA DSVSKAVSDA DRQRILELEK NEMELKVEVS





1441
KLREISDIAR RQVEILNAQQ QSRDKEVESL RMQLLDYQAQ SDEKSLIAKL HQHNVSLQLS





1501
EATALGKLES ITSKLQKMEA YNLRLEQKLD EKEQALYYAR LEGRNRAKHL RQTIQSLRRQ





1561
FSGALPLAQQ EKFSKTMIQL QNDKLKIMQE MKNSQQEHRN MENKTLEMEL KLKGLEELIS





1621
TLKDTKGAQK VINWHMKIEE LRLQELKLNR ELVKDKEEIK YLNNIISEYE RTISSLEEEI





1681
VQQNKFHEER QMAWDQREVD LERQLDIFDR QQNEILNAAQ KFEEATGSIP DPSLPLPNQL





1741
EIALRKIKEN IRIILETRAT CKSLEEKLKE KESALRLAEQ NILSRDKVIN ELRLRLPATA





1801
EREKLIAELG RKEMEPKSHH TLKIAHQTIA NMQARLNQKE EVLKKYQRLL EKAREEQREI





1861
VKKHEEDLHI LHHRLELQAD SSLNKFKQTA WDLMKQSPTP VPTNKHFIRL AEMEQTVAEQ





1921
DDSLSSLLVK LKKVSQDLER QREITELKVK EFENIKLQLQ ENHEDEVKKV KAEVEDLKYL





1981
LDQSQKESQC LKSELQAQKE ANSRAPTTTM RNLVERLKSQ LALKEKQQKA LSRALLELRA





2041
EMTAAAEERI ISATSQKEAH LNVQQIVDRH TRELKTQVED LNENLLKLKE ALKTSKNREN





2101
SLTDNLNDLN NELQKKQKAY NKILREKEEI DQENDELKRQ IKRLTSGLQG KPLTDNKQSL





2161
IEELQRKVKK LENQLEGKVE EVDLKPMKEK NAKEELIRWE EGKKWQAKIE GIRNKLKEKE





2221
GEVFTLTKQL NTLKDLFAKA DKEKLTLQRK LKTTGMTVDQ VLGIRALESE KELEELKKRN





2281
LDLENDILYM RAHQALPRDS VVEDLHLQNR YLQEKLHALE KQFSKDTYSK PSQNQDTSHS





2341
RIGFTLKSHF NLNTSVKTQS PNKVTF











SEQ ID NO: 75



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X13



XP_011537067.1









1
MPPNINWKEI MKVDPDDLPR QEELADNLLI SLSKVEVNEL KSEKQENVIH LFRITQSLMK






61
MKAQEVELAL EEVEKAGEEQ AKFENQLKTK VMKLENELEM AQQSAGGRDT RFLRNEICQL





121
EKQLEQKDRE LEDMEKELEK EKKVNEQLAL RNEEAENENS KLRRENKRLK KKNEQLCQDI





181
IDYQKQIDSQ KETLLSRRGE DSDYRSQLSK KNYELIQYLD EIQTLTEANE KIEVQNQEMR





241
KNLEESVQEM EKMTDEYNRM KAIVHQTDNV IDQLKKENDH YQLQVQELTD LLKSKNEEDD





301
PIMVAVNAKV EEWKLILSSK DDEIIEYQQM LHNLREKLKN AQLDADKSNV MALQQGIQER





361
DSQIKMLTEQ VEQYTKEMEK NTCIIEDLKN ELQRNKGAST LSQQTHMKIQ STLDILKEKT





421
KEAERTAELA EADAREKDKE LVEALKRLKD YESGVYGLED AVVEIKNCKN QIKIRDREIE





481
ILTKEINKLE LKISDFLDEN EALRERVGLE PKTMIDLTEF RNSKHLKQQQ YRAENQILLK





541
EIESLEEERL DLKKKIRQMA QERGKRSATS GLTTEDLNLT ENISQGDRIS ERKLDLLSLK





601
NMSEAQSKIR SSDKAELLHR RSSFNTPQSD QNETEENMTI GSLSRMLSEI HHSVESGMHP





661
FVPLTRLSSS MQVKENSTPE TITIREIFKA PCLQSSRNLE SLVSTFSRES HEEINDICLF





721
SDDCMKKVSR SHQALEKTSF VQKSNSSFHG LSTASDIMQK LSLRQKSAIF CQQIHENRAD





781
MDKSQVATLE EEQVHSQVKY ADINLKEDII KSEVPLQTEI LKNKLKVNLP DPVSITAQSK





841
LSQINSLENL IEQLRRELVF LRSQNEIIAQ EFLIKEAECR NADIELEHHR SQAEQNEFLS





901
RELIEKERDL ERSRTVIAKF QNKLKELVEE NKQLEEGMKE ILQAIKEMQK DPDVKGGETS





961
LIIPSLERLV NAIESKNAEG IFDASLHLKA QVDQLTGRNE ELRQELRESR KEAINYSQQL





1021
AKANLKIDHL EKETSLLRQS EGSNVVFKGI DLPDGIAPSS ASIINSQNEY LIHLLQELEN





1081
KEKKLKNLED SLEDYNRKFA VIRHQQSLLY KEYLSEKETW KTESKTIKEE KRKLEDQVQQ





1141
DAIKVKEYNN LLNALQMDSD EMKKILAENS RKITVLQVNE KSLIRQYTTL VELERQLRKE





1201
NEKQKNELLS MEAEVCEKIG CLQRFKEMAI FKIAALQKVV DNSVSLSELE LANKQYNELT





1261
AKYRDILQKD NMLVQRTSNL EHLECENISL KEQVESINKE LEITKEKLHT IEQAWEQETK





1321
LGNESSMDKA KKSITNSDIV SISKKITMLE MKELNERQRA EHCQKMYEHL RTSLKQMEER





1381
NFELETKFAE LTKINLDAQK VEQMLRDELA DSVSKAVSDA DRQRILELEK NEMELKVEVS





1441
KLREISDIAR RQVEILNAQQ QSRDKEVESL RMQLLDYQAQ SDEKSLIAKL HQHNVSLQLS





1501
EATALGKLES ITSKLQKMEA YNLRLEQKLD EKEQALYYAR LEGRNRAKHL RQTIQSLRRQ





1561
FSGALPLAQQ EKFSKTMIQL QNDKLKIMQE MKNSQQEHRN MENKTLEMEL KLKGLEELIS





1621
TLKDTKGAQK VINWHMKIEE LRLQELKLNR ELVKDKEEIK YLNNIISEYE RTISSLEEEI





1681
VQQNKFHEER QMAWDQREVD LERQLDIFDR QQNEILNAAQ KFEEATGSIP DPSLPLPNQL





1741
EIALRKIKEN IRIILETRAT CKSLEEKLKE KESALRLAEQ NILSRDKVIN ELRLRLPATA





1801
EREKLIAELG RKEMEPKSHH TLKIAHQTIA NMQARLNQKE EVLKKYQRLL EKAREEQREI





1861
VKKHEEDLHI LHHRLELQAD SSLNKFKQTA WDLMKQSPTP VPTNKHFIRL AEMEQTVAEQ





1921
DDSLSSLLVK LKKVSQDLER QREITELKVK EFENIKLQLQ ENHEDEVKKV KAEVEDLKYL





1981
LDQSQKESQC LKSELQAQKE ANSRAPTTTM RNLVERLKSQ LALKEKQQKA LSRALLELRA





2041
EMTAAAEERI ISATSQKEAH LNVQQIVDRH TRELKTQVED LNENLLKLKE ALKTSKNREN





2101
SLTDNLNDLN NELQKKQKAY NKILREKEEI DQENDELKRQ IKRLTSGLQG KPLTDNKQSL





2161
IEELQRKVKK LENQLEGKVE EVDLKPMKEK NAKEELIRWE EGKKWQAKIE GIRNKLKEKE





2221
GEVFTLTKQL NTLKDLFAKA DKEKLTLQRK LKTTGMTVDQ VLGIRALESE KELEELKKRN





2281
LDLENDILYM RAHQALPRDS VVEDLHLQNR YLQEKLHALE KQFSKDTYSK PSNQDTSHSR





2341
IGFTLKSHFN LNTSVKTQSP NKVTF











SEQ ID NO: 76



CENTROSOMAL PROTEIN 290 (CEP290), ISOFORM X14



XP_011537068.1









1
MIDLTEFRNS KHLKQQQYRA ENQILLKEIE SLEEERLDLK KKIRQMAQER GKRSATSGLT






61
TEDLNLTENI SQGDRISERK LDLLSLKNMS EAQSKIRSSD KAELLHRRSS FNTPQSDQNE





121
TEENMTIGSL SRMLSEIHHS VESGMHPFVP LTRLSSSMQV KENSTPETIT IREIFKAPCL





181
QSSRNLESLV STFSRESHEE INDICLFSDD CMKKVSRSHQ ALEKTSFVQK SNSSFHGLST





241
ASDIMQKLSL RQKSAIFCQQ IHENRADMDK SQVATLEEEQ VHSQVKYADI NLKEDIIKSE





301
VPLQTEILKN KLKVNLPDPV SITAQSKLSQ INSLENLIEQ LRRELVFLRS QNEIIAQEFL





361
IKEAECRNAD IELEHHRSQA EQNEFLSREL IEKERDLERS RTVIAKFQNK LKELVEENKQ





421
LEEGMKEILQ AIKEMQKDPD VKGGETSLII PSLERLVNAI ESKNAEGIFD ASLHLKAQVD





481
QLTGRNEELR QELRESRKEA INYSQQLAKA NLKIDHLEKE TSLLRQSEGS NVVFKGIDLP





541
DGIAPSSASI INSQNEYLIH LLQELENKEK KLKNLEDSLE DYNRKFAVIR HQQSLLYKEY





601
LSEKETWKTE SKTIKEEKRK LEDQVQQDAI KVKEYNNLLN ALQMDSDEMK KILAENSRKI





661
TVLQVNEKSL IRQYTTLVEL ERQLRKENEK QKNELLSMEA EVCEKIGCLQ RFKEMAIFKI





721
AALQKVVDNS VSLSELELAN KQYNELTAKY RDILQKDNML VQRTSNLEHL ECENISLKEQ





781
VESINKELEI TKEKLHTIEQ AWEQETKLGN ESSMDKAKKS ITNSDIVSIS KKITMLEMKE





841
LNERQRAEHC QKMYEHLRTS LKQMEERNFE LETKFAELTK INLDAQKVEQ MLRDELADSV





901
SKAVSDADRQ RILELEKNEM ELKVEVSKLR EISDIARRQV EILNAQQQSR DKEVESLRMQ





961
LLDYQAQSDE KSLIAKLHQH NVSLQLSEAT ALGKLESITS KLQKMEAYNL RLEQKLDEKE





1021
QALYYARLEG RNRAKHLRQT IQSLRRQFSG ALPLAQQEKF SKTMIQLQND KLKIMQEMKN





1081
SQQEHRNMEN KTLEMELKLK GLEELISTLK DTKGAQKVIN WHMKIEELRL QELKLNRELV





1141
KDKEEIKYLN NIISEYERTI SSLEEEIVQQ NKFHEERQMA WDQREVDLER QLDIFDRQQN





1201
EILNAAQKFE EATGSIPDPS LPLPNQLEIA LRKIKENIRI ILETRATCKS LEEKLKEKES





1261
ALRLAEQNIL SRDKVINELR LRLPATAERE KLIAELGRKE MEPKSHHTLK IAHQTIANMQ





1321
ARLNQKEEVL KKYQRLLEKA REEQREIVKK HEEDLHILHH RLELQADSSL NKFKQTAWDL





1381
MKQSPTPVPT NKHFIRLAEM EQTVAEQDDS LSSLLVKLKK VSQDLERQRE ITELKVKEFE





1441
NIKLQLQENH EDEVKKVKAE VEDLKYLLDQ SQKESQCLKS ELQAQKEANS RAPTITMRNL





1501
VERLKSQLAL KEKQQKALSR ALLELRAEMT AAAEERIISA TSQKEAHLNV QQIVDRHTRE





1561
LKTQVEDLNE NLLKLKEALK TSKNRENSLT DNLNDLNNEL QKKQKAYNKI LREKEEIDQE





1621
NDELKRQIKR LTSGLQGKPL TDNKQSLIEE LQRKVKKLEN QLEGKVEEVD LKPMKEKNAK





1681
EELIRWEEGK KWQAKIEGIR NKLKEKEGEV FTLTKQLNTL KDLFAKADKE KLTLQRKLKT





1741
TGMTVDQVLG IRALESEKEL EELKKRNLDL ENDILYMRAH QALPRDSVVE DLHLQNRYLQ





1801
EKLHALEKQF SKDTYSKPSQ NQISGIESDD HCQREQELQK ENLKLSSENI ELKFQLEQAN





1861
KDLPRLKNQV RDLKEMCEFL KKEKAEVQRK LGHVRGSGRS GKTIPELEKT IGLMKKVVEK





1921
VQRENEQLKK ASGILTSEKM ANIEQENEKL KAELEKLKAH LGHQLSMHYE SKTKGTEKII





1981
AENERLRKEL KKETDAAEKL RIAKNNLEIL NEKMTVQLEE TGKRLQFAES RGPQLEGADS





2041
KSWKSIVVTR MYETKLKELE TDIAKKNQSI TDLKQLVKEA TEREQKVNKY NEDLEQQIKI





2101
LKHVPEGAET EQGLKRELQV LRLANHQLDK EKAELIHQIE ANKDQSGAES TIPDADQLKE





2161
KIKDLETQLK MSDLEKQHLK EEIKKLKKEL ENFDPSFFEE IEDLKYNYKE EVKKNILLEE





2221
KVKKLSEQLG VELTSPVAAS EEFEDEEESP VNFPIY











SEQ ID NO: 77



INOSINE MONOPHOSPHATE DEHYDROGENASE 1 (IMPDH1)



EAL24310.1









1
MEGPLTPPPL QGGGAAAVPE PGARQHPGHE TAAQRYSARL LQAGYEPESP RLDLATHPTT






61
PRSELSSVVL LAGVGVQMDR LRRASMADYL ISGGTGYVPE DGLTAQQLFA SADGLTYNDF





121
LILPGFIDFI ADEVDLTSAL TRKITLKTPL ISSPMDTVTE ADMAIAMALM GGIGFIHHNC





181
TPEFQANEVR KVKKFEQGFI TDPVVLSPSH TVGDVLEAKM RHGFSGIPIT ETGTMGSKLV





241
GIVTSRDIDF LAEKDHTTLL SEVMTPRIEL VVAPAGVTLK EANEILQRSK KGKLPIVNDC





301
DELVAIIART DLKKNRDYPL ASKDSQKQLL CGAAVGTRED DKYRLDLLTQ AGVDVIVLDS





361
SQGNSVYQIA MVHYIKQKYP HLQVIGGNVV TAAQAKNLID AGVDGLRVGM GCGSICITQE





421
VMACGRPQGT AVYKVAEYAR RFGVPIIADG GIQTVGHVVK ALALGASTVM MGSLLAATTE





481
APGEYFFSDG VRLKKYRGMG SLDAMEKSSS SQKRYFSEGD KVKIAQGVSG SIQDKGSIQK





541
FVPYLIAGIQ HGCQDIGARS LSVLRSMMYS GELKFEKRTM SAQIEGGVHG LHSYEKRLY











SEQ ID NO: 78



INOSINE MONOPHOSPHATE DEHYDROGENASE 1 (IMPDH1)



AAH33622.2









1
MEGPLTPPPL QGGGAAAVPE PGARQHPGHE TAAQRYSARL LQAGYEPESM ADYLISGGTG






61
YVPEDGLTAQ QLFASADGLT YNDFLILPGF IDFIADEVDL TSALTRKITL KTPLISSPMD





121
TVTEADMAIA MALMGGIGFI HHNCTPEFQA NEVRKVKKFE QGFITDPVVL SPSHTVGDVL





181
EAKMRHGFSG IPITETGTMG SKLVGIVTSR DIDFLAEKDH TTLLSEVMTP RIELVVAPAG





241
VTLKEANEIL QRSKKGKLPI VNDCDELVAI IARTDLKKNR DYPLASKDSQ KQLLCGAAVG





301
TREDDKYRLD LLTQAGVDVI VLDSSQGNSV YQIAMVHYIK QKYPHLQVIG GNVVTAAQAK





361
NLIDAGVDGL RVGMGCGSIC ITQEVMACGR PQGTAVYKVA EYARRFGVPI IADGGIQTVG





421
HVVKALALGA STVMMGSLLA ATTEAPGEYF FSDGVRLKKY RGMGSLDAME KSSSSQKRYF





481
SEGDKVKIAQ GVSGSIQDKG SIQKFVPYLI AGIQHGCQDI GARSLSVLRS MMYSGELKFE





541
KRTMSAQIEG GVHGLHSYEK RLY











SEQ ID NO: 79



INOSINE MONOPHOSPHATE DEHYDROGENASE 1 (IMPDH1), ISOFORM CRA_A



EAW83649.1









1
MEGPLTPPPL QGGGAAAVPE PGARQHPGHE TAAQRYSARL LQAGYEPESM ADYLISGGTG






61
YVPEDGLTAQ QLFASADGLT YNDFLILPGF IDFIADEVDL TSALTRKITL KTPLISSPMD





121
TVTEADMAIA MALMGGIGFI HHNCTPEFQA NEVRKKFEQG FITDPVVLSP SHTVGDVLEA





181
KMRHGFSGIP ITETGTMGSK LVGIVTSRDI DFLAEKDHTT LLSEVMTPRI ELVVAPAGVT





241
LKEANEILQR SKKGKLPIVN DCDELVAIIA RTDLKKNRDY PLASKDSQKQ LLCGAAVGTR





301
EDDKYRLDLL TQAGVDVIVL DSSQGNSVYQ IAMVHYIKQK YPHLQVIGGN VVTAAQAKNL





361
IDAGVDGLRV GMGCGSICIT QEVMACGRPQ GTAVYKVAEY ARRFGVPIIA DGGIQTVGHV





421
VKALALGAST VMMGSLLAAT TEAPGEYFFS DGVRLKKYRG MGSLDAMEKS SSSQKRYFSE





481
GDKVKIAQGV SGSIQDKGSI QKFVPYLIAG IQHGCQDIGA RSLSVLRSMM YSGELKFEKR





541
TMSAQIEGGV HGLHSYEKRL Y











SEQ ID NO: 80



INOSINE MONOPHOSPHATE DEHYDROGENASE 1 (IMPDH1), ISOFORM CRA_B



EAW83650.1









1
MDRLRRASMA DYLISGGTGY VPEDGLTAQQ LFASADGLTY NDFLILPGFI DFIADEVDLT






61
SALTRKITLK TPLISSPMDT VTEADMAIAM AKFEQGFITD PVVLSPSHTV GDVLEAKMRH





121
GFSGIPITET GTMGSKLVGI VTSRDIDFLA EKDHTTLLSE VMTPRIELVV APAGVTLKEA





181
NEILQRSKKG KLPIVNDCDE LVAIIARTDL KKNRDYPLAS KDSQKQLLCG AAVGTREDDK





241
YRLDLLTQAG VDVIVLDSSQ GNSVYQIAMV HYIKQKYPHL QVIGGNVVTA AQAKNLIDAG





301
VDGLRVGMGC GSICITQEVM ACGRPQGTAV YKVAEYARRF GVPIIADGGI QTVGHVVKAL





361
ALGASTVMMG SLLAATTEAP GEYFFSDGVR LKKYRGMGSL DAMEKSSSSQ KRYFSEGDKV





421
KIAQGVSGSI QDKGSIQKFV PYLIAGIQHG CQDIGARSLS VLRSMMYSGE LKFEKRTMSA





481
QIEGGVHGLH SYEKRLY











SEQ ID NO: 81



INOSINE MONOPHOSPHATE DEHYDROGENASE 1 (IMPDH1), ISOFORM CRA_C



EAW83651.1









1
MRHGFSGIPI TETGTMGSKL VGIVTSRDID FLAEKDHTTL LSEVMTPRIE LVVAPAGVTL






61
KEANEILQRS KKGKLPIVND CDELVAIIAR TDLKKNRDYP LASKDSQKQL LCGAAVGTRE





121
DDKYRLDLLT QAGVDVIVLD SSQGNSVYQI AMVHYIKQKY PHLQVIGGNV VTAAQAKNLI





181
DAGVDGLRVG MGCGSICITQ EVMACGRPQG TAVYKVAEYA RRFGVPIIAD GGIQTVGHVV





241
KALALGASTV MMGSLLAATT EAPGEYFFSD GVRLKKYRGM GSLDAMEKSS SSQKRYFSEG





301
DKVKIAQGVS GSIQDKGSIQ KFVPYLIAGI QHGCQDIGAR SLSVLRSMMY SGELKFEKRT





361
MSAQIEGGVH GLHSYEKRLY











SEQ ID NO: 82



INOSINE MONOPHOSPHATE DEHYDROGENASE 1 (IMPDH1), ISOFORM CRA_D



EAW83652.1









1
MDRLRRASMA DYLISGGTGY VPEDGLTAQQ LFASADGLTY NDFLILPGFI DFIADEVDLT






61
SALTRKITLK TPLISSPMDT VTEADMAIAM ALMGGIGFIH HNCTPEFQAN EVRKVKKFEQ





121
GFITDPVVLS PSHTVGDVLE AKMRHGFSGI PITETGTMGS KLVGIVTSRD IDFLAEKDHT





181
TLLSEVMTPR IELVVAPAGV TLKEANEILQ RSKKGKLPIV NDCDELVAII ARTDLKKNRD





241
YPLASKDSQK QLLCGAAVGT REDDKYRLDL LTQAGVDVIV LDSSQGNSVY QIAMVHYIKQ





301
KYPHLQVIGG NVVTAAQAKN LIDAGVDGLR VGMGCGSICI TQEVMACGRP QGTAVYKVAE





361
YARRFGVPII ADGGIQTVGH VVKALALGAS TVMMGSLLAA TTEAPGEYFF SDGVRLKKYR





421
GMGSLDAMEK SSSSQKRYFS EGDKVKIAQG VSGSIQDKGS IQKFVPYLIA GIQHGCQDIG





481
ARSLSVLRSM MYSGELKFEK RTMSAQIEGG VHGLHSYEKR LY











SEQ ID NO: 83



RETINAL DEGENERATION 3, GUCY2D REGULATOR (RD3)



NP_001158160.1









1
MSLISWLRWN EAPSRLSTRS PAEMVLETLM MELTGQMREA ERQQRERSNA VRKVCTGVDY






61
SWLASTPRST YDLSPIERLQ LEDVCVKIHP SYCGPAILRF RQLLAEQEPE VQEVSQLFRS





121
VLQEVLERMK QEEEAHKLTR QWSLRPRGSL ATFKTRARIS PFASDIRTIS EDVERDTPPP





181
LRSWSMPEFR APKAD











SEQ ID NO: 84



RETINOL DEHYDROGENASE 12 (RDH12)



Q96NR8.3









1
MLVTLGLLTS FFSFLYMVAP SIRKFFAGGV CRTNVQLPGK VVVITGANTG IGKETARELA






61
SRGARVYIAC RDVLKGESAA SEIRVDTKNS QVLVRKLDLS DTKSIRAFAE GFLAEEKQLH





121
ILINNAGVMM CPYSKTADGF ETHLGVNHLG HFLLTYLLLE RLKVSAPARV VNVSSVAHHI





181
GKIPFHDLQS EKRYSRGFAY CHSKLANVLF TRELAKRLQG TGVTTYAVHP GVVRSELVRH





241
SSLLCLLWRL FSPFVKTARE GAQTSLHCAL AEGLEPLSGK YFSDCKRTWV SPRARNNKTA





301
ERLWNVSCEL LGIRWE











SEQ ID NO: 85



RETINOL DEHYDROGENASE 12 (RDH12), ISOFORM 1, PARTIAL



ALQ34323.1









1
MLVTLGLLTS FFSFLYMVAP SIRKFFAGGV CRTNVQLPGK VVVITGANTG IGKETARELA






61
SRGARVYIAC RDVLKGESAA SEIRVDTKNS QVLVRKLDLS DTKSIRAFAE GFLAEEKQLH





121
ILINNAGVMM CPYSKTADGF ETHLGVNHLG HFLLTYLLLE RLKVSAPARV VNVSSVAHHI





181
GKIPFHDLQS EKRYSRGFAY CHSKLANVLF TRELAKRLQG TGVTTYAVHP GVVRSELVRH





241
SSLLCLLWRL FSPFVKTARE GAQTSLHCAL AEGLEPLSGK YFSDCKRTWV SPRARNNKTA





301
ERLWNVSCEL LGIRWE











SEQ ID NO: 86



RETINOL DEHYDROGENASE 12 (RDH12), ISOFORM 4, PARTIAL



ALQ34324.1









1
MLVTLGLLTS FFSFLYMVAP SIRKFFAGGV CRTNVQLPGK VVVITGANTG IGKETARELA






61
SRGARVYIAC RDVLKGESAA SEIRVDTKNS QVLVRKLDLS DTKSIRAFAE GFLAEEKQLH





121
ILINNAGVMM CPYSKTADGF ETHLGVNHLG TGVTTYAVHP GVVRSELVRH SSLLCLLWRL





181
FSPFVKTARE GAQTSLHCAL AEGLEPLSGK YFSDCKRTWV SPRARNNKTA ERLWNVSCEL





241
LGIRWE











SEQ ID NO: 87



RETINOL DEHYDROGENASE 12 (RDH12), PRECURSOR



NP_689656.2









1
MLVTLGLLTS FFSFLYMVAP SIRKFFAGGV CRTNVQLPGK VVVITGANTG IGKETARELA






61
SRGARVYIAC RDVLKGESAA SEIRVDTKNS QVLVRKLDLS DTKSIRAFAE GFLAEEKQLH





121
ILINNAGVMM CPYSKTADGF ETHLGVNHLG HFLLTYLLLE RLKVSAPARV VNVSSVAHHI





181
GKIPFHDLQS EKRYSRGFAY CHSKLANVLF TRELAKRLQG TGVTTYAVHP GVVRSELVRH





241
SSLLCLLWRL FSPFVKTARE GAQTSLHCAL AEGLEPLSGK YFSDCKRTWV SPRARNNKTA





301
ERLWNVSCEL LGIRWE











SEQ ID NO: 88



LECITHIN RETINOL ACYLTRANSFERASE (LRAT)



AAD13529.1









1
MKNPMLEVVS LLLEKLLLIS NFTLFSSGAA GKDKGRNSFY ETSSFHRGDV LEVPRTHLTH






61
YGIYLGDNRV AHMMPDILLA LTDDMGRTQK VVSNKRLILG VIVKVASIRV DTVEDFAYGA





121
NILVNHLDES LQKKALLNEE VARRAEKLLG FTPYSLLWNN CEHFVTYCRY GTPISPQSDK





181
FCETVKIIIR DQRSVLASAV LGLASIVCTG LVSYTTLPAI FIPFFLWMAG











SEQ ID NO: 89



TUBBY LIKE PROTEIN 1 (TULP1)



AAB97966.1









1
MPLRDETLRE VWASDSGHEE ESLSPEAPRR PKQRPAPAQR LRKKRTEAPE SPCPTGSKPR






61
KPGAGRRGRP REEPSPDPAQ ARAPQTVYAR FLRDPEAKKR DPRETFLVAR APDAEDEEEE





121
EEEDEEDEEE EAEEKKEKIL LPPKKPLREK SSADLKERRA KAQGPRGDLG SPDPPPKPLR





181
VRNKEAPAGE GTKMRKTKKK GSGEADKDPS GSPASARKSP AAMFLVGEGS PDKKALKKKG





241
TPKGARKEEE EEEEAATVIK NSNQKGKAKG KGKKKAKEER APSPPVEVDE PREFVLRPAP





301
QGRTVRCRLT RDKKGMDRGM YPSYFLHLDT EKKVFLLAGR KRKRSKTANY LISIDPTNLS





361
RGGENFIGKL RSNLLGNRFT VFDNGQNPQR GYSTNVASLR QELAAVIYET NVLGFRGPRR





421
MTVIIPGMSA ENERVPIRPR NASDGLLVRW QNKTLESLIE LHNKPPVWND DSGSYTLNFQ





481
GRVTQASVKN FQIVHADDPD YIVLQFGRVA EDAFTLDYRY PLCALQAFAI ALSSFDGKLA





541
CE











SEQ ID NO: 90



TUBBY LIKE PROTEIN 1 (TULP1), ISOFORM CRA_A



EAX03839.1









1
MPLRDETLRE VWASDSGHEE ESLSPEAPRR PKQRPAPAQR LRKKRTEAPE SPCPTGSKPR






61
KPGEEEEEEE DEEDEEEEAE EKKEKILLPP KKPLREKSSA DLKERRAKAQ GPRGDLGSPD





121
PPPKPLRVRN KEAPAGEGTK MRKTKKKGSG EADKDPSGSP ASARKSPAAM FLVGEGSPDK





181
KALKKKGTPK GARKEEEEEE EAATVIKNSN QKGKAKGKGK KKEERAPSPP VEVDEPREFV





241
LRPAPQGRTV RCRLTRDKKG MDRGMYPSYF LHLDTEKKVF LLAGRKRKRS KTANYLISID





301
PTNLSRGGEN FIGKLRSNLL GNRFTVFDNG QNPQRGYSTN VASLRQELAA VIYETNVLGF





361
RGPRRMTVII PGMSAENERV PIRPRNASDG LLVRWQNKTL ESLIELHNKP PVWNDDSGSY





421
TLNFQGRVTQ ASVKNFQIVH ADDPDYIVLQ FGRVAEDAFT LDYRYPLCAL QAFAIALSSF





481
DGKLACE











SEQ ID NO: 91



TUBBY LIKE PROTEIN 1 (TULP1), ISOFORM CRA_B



EAX03840.1









1
MPLRDETLRE VWASDSGHEE ESLSPEAPRR PKQRPAPAQR LRKKRTEAPE SPCPTGSKPR






61
KPGAGRRGRP REEPSPDPAQ ARAPQTVYAR FLRDPEAKKR DPRETFLVAR APDAEDEEEE





121
EEEDEEDEEE EAEEKKEKIL LPPKKPLREK SSADLKERRA KAQGPRGDLG SPDPPPKPLR





181
VRNKEAPAGE GTKMRKTKKK GSGEADKDPS GSPASARKSP AAMFLVGEGS PDKKALKKKG





241
TPKGARKEEE EEEEAATVIK NSNQKGKAKG KGKKKEERAP SPPVEVDEPR EFVLRPAPQG





301
RTVRCRLTRD KKGMDRGMYP SYFLHLDTEK KVFLLAGRKR KRSKTANYLI SIDPTNLSRG





361
GENFIGKLRS NLLGNRFTVF DNGQNPQRGY STNVASLRQE LAAVIYETNV LGFRGPRRMT





421
VIIPGMSAEN ERVPIRPRNA SDGLLVRWQN KTLESLIELH NKPPVWNDDS GSYTLNFQGR





481
VTQASVKNFQ IVHADDPDYI VLQFGRVAED AFTLDYRYPL CALQAFAIAL SSFDGKLACE











SEQ ID NO: 92



TUBBY LIKE PROTEIN 1 (TULP1), HOMOLOG ISOFORM A



NP_003311.2









1
MGARTPLPSF WVSFFAETGI LFPGGTPWPM GSQHSKQHRK PGPLKRGHRR DRRTTRRKYW






61
KEGREIARVL DDEGRNLRQQ KLDRQRALLE QKQKKKRQEP LMVQANADGR PRSRRARQSE





121
EQAPLVESYL SSSGSTSYQV QEADSLASVQ LGATRPTAPA SAKRTKAAAT AGGQGGAARK





181
EKKGKHKGTS GPAALAEDKS EAQGPVQILT VGQSDHAQDA GETAAGGGER PSGQDLRATM





241
QRKGISSSMS FDEDEEDEEE NSSSSSQLNS NTRPSSATSR KSVREAASAP SPTAPEQPVD





301
VEVQDLEEFA LRPAPQGITI KCRITRDKKG MDRGMYPTYF LHLDREDGKK VFLLAGRKRK





361
KSKTSNYLIS VDPTDLSRGG DSYIGKLRSN LMGTKFTVYD NGVNPQKASS STLESGTLRQ





421
ELAAVCYETN VLGFKGPRKM SVIVPGMNMV HERVSIRPRN EHETLLARWQ NKNTESIIEL





481
QNKTPVWNDD TQSYVLNFHG RVTQASVKNF QIIHGNDPDY IVMQFGRVAE DVFTMDYNYP





541
LCALQAFAIA LSSFDSKLAC E











SEQ ID NO: 93



TUBBY LIKE PROTEIN 1 (TULP1)



NP_813977.1









1
MTSKPHSDWI PYSVLDDEGR NLRQQKLDRQ RALLEQKQKK KRQEPLMVQA NADGRPRSRR






61
ARQSEEQAPL VESYLSSSGS TSYQVQEADS LASVQLGATR PTAPASAKRT KAAATAGGQG





121
GAARKEKKGK HKGTSGPAAL AEDKSEAQGP VQILTVGQSD HAQDAGETAA GGGERPSGQD





181
LRATMQRKGI SSSMSFDEDE EDEEENSSSS SQLNSNTRPS SATSRKSVRE AASAPSPTAP





241
EQPVDVEVQD LEEFALRPAP QGITIKCRIT RDKKGMDRGM YPTYFLHLDR EDGKKVFLLA





301
GRKRKKSKTS NYLISVDPTD LSRGGDSYIG KLRSNLMGTK FTVYDNGVNP QKASSSTLES





361
GTLRQELAAV CYETNVLGFK GPRKMSVIVP GMNMVHERVS IRPRNEHETL LARWQNKNTE





421
SIIELQNKTP VWNDDTQSYV LNFHGRVTQA SVKNFQIIHG NDPDYIVMQF GRVAEDVFTM





481
DYNYPLCALQ AFAIALSSFD SKLACE











SEQ ID NO: 94



POTASSIUM VOLTAGE-GATED CHANNEL SUBFAMILY J MEMBER 13 (KCNJ13)



O60928.1









1
MDSSNCKVIA PLLSQRYRRM VTKDGHSTLQ MDGAQRGLAY LRDAWGILMD MRWRWMMLVF






61
SASFVVHWLV FAVLWYVLAE MNGDLELDHD APPENHTICV KYITSFTAAF SFSLETQLTI





121
GYGTMFPSGD CPSAIALLAI QMLLGLMLEA FITGAFVAKI ARPKNRAFSI RFTDTAVVAH





181
MDGKPNLIFQ VANTRPSPLT SVRVSAVLYQ ERENGKLYQT SVDFHLDGIS SDECPFFIFP





241
LTYYHSITPS SPLATLLQHE NPSHFELVVF LSAMQEGTGE ICQRRTSYLP SEIMLHHCFA





301
SLLTRGSKGE YQIKMENFDK TVPEFPTPLV SKSPNRTDLD IHINGQSIDN FQISETGLTE











SEQ ID NO: 95



POTASSIUM VOLTAGE-GATED CHANNEL SUBFAMILY J MEMBER 13 (KCNJ13)



AAH37290.1









1
MDSSNCKVIA PLLSQRYRRM VTKDGHSTLQ MDGAQRGLAY LRDAWGILMD MRWRWMMLVF






61
SASFVVHWLV FAVLWYVLAE MNGDLELDHD APPENHTICV KYITSFTAAF SFSLETQLTI





121
GYGTMFPSGD CPSAIALLAI QMLLGLMLEA FITGAFVAKI ARPKNRAFSI RFTDIAVVAH





181
MDGKPNLIFQ VANTRPSPLT SVRVSAVLYQ ERENGKLYQT SVDFHLDGIS SDECPFFIFP





241
LTYYHSITPS SPLATLLQHE NPSHFELVVF LSAMQEGTGE ICQRRTSYLQ SEIMLHHCFA





301
SLLTRGSKCE YQIKMENFDK TVPEFPTPLV SKSPNRTDLD IHINGQSIDN FQISETGLTE











SEQ ID NO: 96



MITOCHONDRIALLY ENCODED NADH DEHYDROGENASE 1 (MT-ND1)



P03886.1









1
MPMANLLLLI VPILIAMAFL MLTERKILGY MQLRKGPNVV GPYGLLQPFA DAMKLFTKEP






61
LKPATSTITL YITAPTLALT IALLLWTPLP MPNPLVNLNL GLLFILATSS LAVYSILWSG





121
WASNSNYALI GALRAVAQTI SYEVTLAIIL LSTLLMSGSF NLSTLITTQE HLWLLLPSWP





181
LAMMWFISTL AETNRTPFDL AEGESELVSG FNIEYAAGPF ALFFMAEYTN IIMMNTLTTT





241
IFLGTTYDAL SPELYTTYFV TKTLLLTSLF LWIRTAYPRF RYDQLMHLLW KNFLPLTLAL





301
LMWYVSMPIT ISSIPPQT











SEQ ID NO: 97



MITOCHONDRIALLY ENCODED NADH DEHYDROGENASE 4 (MT-ND4)



ACT53103.1









1
MLKLIVPTIM LLPLTWLSKK HMIWINTTTH SLIISIIPLL FFNQINNNLF SCSPTFSSDP






61
LTTPLLMLTT WLLPLTIMAS QRHLSSEPLS RKKLYLSMLI SLQISLIMTF TATELIMFYI





121
FFETTLIPTL AIITRWGNQP ERLNAGTYFL FYTLVGSLPL LIALIYTHNT LGSLNILLLT





181
LTAQELSNSW ANNLMWLAYT MAFMVKMPLY GLHLWLPKAH VEAPIAGSMV LAAVLLKLGG





241
YGMMRLTLIL NPLTKHMAYP FLVLSLWGMI MTSSICLRQT DLKSLIAYSS ISHMALVVTA





301
ILIQTPWSFT GAVILMIAHG LTSSLLFCLA NSNYERTHSR IMILSQGLQT LLPLMAFWWL





361
LASLANLALP PTINLLGELS VLVTTFSWSN ITLLLTGLNM LVTALYSLYM FTTTQWGSLT





421
HHINNMKPSF TRENTLMFMH LSPILLLSLN PDIITGFSS











SEQ ID NO: 98



MITOCHONDRIALLY ENCODED NADH DEHYDROGENASE 6 (MT-ND6)



ACT53105.1









1
MMYALFLLSV GLVMGFVGFS SKPSPIYGGL VLIVSGVVGC VIILNFGGGY MGLMVFLIYL






61
GGMMVVFGYT TAMAIEEYPE AWGSGVEVLV SVLVGLAMEV GLVLWVKEYD GVVVVVNFNS





121
VGSWMIYEGE GSGLIREDPI GAGALYDYGR WLVVVTGWTL FVGVYIVIEI ARGN











SEQ ID NO: 99



ANGIOTENSIN I CONVERTING ENZYME (ACE)



P12821.1









1
MGAASGRRGP GLLLPLPLLL LLPPQPALAL DPGLQPGNFS ADEAGAQLFA QSYNSSAEQV






61
LFQSVAASWA HDTNITAENA RRQEEAALLS QEFAEAWGQK AKELYEPIWQ NFTDPQLRRI





121
IGAVRTLGSA NLPLAKRQQY NALLSNMSRI YSTAKVCLPN KTATCWSLDP DLTNILASSR





181
SYAMLLFAWE GWHNAAGIPL KPLYEDFTAL SNEAYKQDGF TDTGAYWRSW YNSPTFEDDL





241
EHLYQQLEPL YLNLHAFVRR ALHRRYGDRY INLRGPIPAH LLGDMWAQSW ENIYDMVVPF





301
PDKPNLDVTS TMLQQGWNAT HMFRVAEEFF TSLELSPMPP EFWEGSMLEK PADGREVVCH





361
ASAWDFYNRK DFRIKQCTRV TMDQLSTVHH EMGHIQYYLQ YKDLPVSLRR GANPGFHEAI





421
GDVLALSVST PEHLHKIGLL DRVTNDTESD INYLLKMALE KIAFLPFGYL VDQWRWGVFS





481
GRTPPSRYNF DWWYLRTKYQ GICPPVTRNE THFDAGAKFH VPNVTPYIRY FVSFVLQFQF





541
HEALCKEAGY EGPLHQCDIY RSTKAGAKLR KVLQAGSSRP WQEVLKDMVG LDALDAQPLL





601
KYFQPVTQWL QEQNQQNGEV LGWPEYQWHP PLPDNYPEGI DLVTDEAEAS KFVEEYDRTS





661
QVVWNEYAEA NWNYNTNITT ETSKILLQKN MQIANHTLKY GTQARKFDVN QLQNTTIKRI





721
IKKVQDLERA ALPAQELEEY NKILLDMETT YSVATVCHPN GSCLQLEPDL TNVMATSRKY





781
EDLLWAWEGW RDKAGRAILQ FYPKYVELIN QAARLNGYVD AGDSWRSMYE TPSLEQDLER





841
LFQELQPLYL NLHAYVRRAL HRHYGAQHIN LEGPIPAHLL GNMWAQTWSN IYDLVVPFPS





901
APSMDTTEAM LKQGWTPRRM FKEADDFFTS LGLLPVPPEF WNKSMLEKPT DGREVVCHAS





961
AWDFYNGKDF RIKQCTTVNL EDLVVAHHEM GHIQYFMQYK DLPVALREGA NPGFHEAIGD





1021
VLALSVSTPK HLHSLNLLSS EGGSDEHDIN FLMKMALDKI AFIPFSYLVD QWRWRVFDGS





1081
ITKENYNQEW WSLRLKYQGL CPPVPRTQGD FDPGAKFHIP SSVPYIRYFV SFIIQFQFHE





1141
ALCQAAGHTG PLHKCDIYQS KEAGQRLATA MKLGFSRPWP EAMQLITGQP NMSASAMLSY





1201
FKPLLDWLRT ENELHGEKLG WPQYNWTPNS ARSEGPLPDS GRVSFLGLDL DAQQARVGQW





1261
LLLFLGIALL VATLGLSQRL FSIRHRSLHR HSHGPQFGSE VELRHS











SEQ ID NO: 100



ANGIOTENSIN I CONVERTING ENZYME (ACE), ISOFORM 1 PRECURSOR



NP_000780.1









1
MGAASGRRGP GLLLPLPLLL LLPPQPALAL DPGLQPGNFS ADEAGAQLFA QSYNSSAEQV






61
LFQSVAASWA HDTNITAENA RRQEEAALLS QEFAEAWGQK AKELYEPIWQ NFTDPQLRRI





121
IGAVRTLGSA NLPLAKRQQY NALLSNMSRI YSTAKVCLPN KTATCWSLDP DLTNILASSR





181
SYAMLLFAWE GWHNAAGIPL KPLYEDFTAL SNEAYKQDGF TDTGAYWRSW YNSPTFEDDL





241
EHLYQQLEPL YLNLHAFVRR ALHRRYGDRY INLRGPIPAH LLGDMWAQSW ENIYDMVVPF





301
PDKPNLDVTS TMLQQGWNAT HMFRVAEEFF TSLELSPMPP EFWEGSMLEK PADGREVVCH





361
ASAWDFYNRK DFRIKQCTRV TMDQLSTVHH EMGHIQYYLQ YKDLPVSLRR GANPGFHEAI





421
GDVLALSVST PEHLHKIGLL DRVTNDTESD INYLLKMALE KIAFLPFGYL VDQWRWGVFS





481
GRTPPSRYNF DWWYLRTKYQ GICPPVTRNE THFDAGAKFH VPNVTPYIRY FVSFVLQFQF





541
HEALCKEAGY EGPLHQCDIY RSTKAGAKLR KVLQAGSSRP WQEVLKDMVG LDALDAQPLL





601
KYFQPVTQWL QEQNQQNGEV LGWPEYQWHP PLPDNYPEGI DLVTDEAEAS KFVEEYDRTS





661
QVVWNEYAEA NWNYNTNITT ETSKILLQKN MQIANHTLKY GTQARKFDVN QLQNTTIKRI





721
IKKVQDLERA ALPAQELEEY NKILLDMETT YSVATVCHPN GSCLQLEPDL TNVMATSRKY





781
EDLLWAWEGW RDKAGRAILQ FYPKYVELIN QAARLNGYVD AGDSWRSMYE TPSLEQDLER





841
LFQELQPLYL NLHAYVRRAL HRHYGAQHIN LEGPIPAHLL GNMWAQTWSN IYDLVVPFPS





901
APSMDTTEAM LKQGWTPRRM FKEADDFFTS LGLLPVPPEF WNKSMLEKPT DGREVVCHAS





961
AWDFYNGKDF RIKQCTTVNL EDLVVAHHEM GHIQYFMQYK DLPVALREGA NPGFHEAIGD





1021
VLALSVSTPK HLHSLNLLSS EGGSDEHDIN FLMKMALDKI AFIPFSYLVD QWRWRVFDGS





1081
ITKENYNQEW WSLRLKYQGL CPPVPRTQGD FDPGAKFHIP SSVPYIRYFV SFIIQFQFHE





1141
ALCQAAGHTG PLHKCDIYQS KEAGQRLATA MKLGFSRPWP EAMQLITGQP NMSASAMLSY





1201
FKPLLDWLRT ENELHGEKLG WPQYNWTPNS ARSEGPLPDS GRVSFLGLDL DAQQARVGQW





1261
LLLFLGIALL VATLGLSQRL FSIRHRSLHR HSHGPQFGSE VELRHS











SEQ ID NO: 101



ANGIOTENSIN I CONVERTING ENZYME (ACE), ISOFORM 2 PRECURSOR



NP_690043.1









1
MGQGWATAGL PSLLFLLLCY GHPLLVPSQE ASQQVTVTHG TSSQATTSSQ TTTHQATAHQ






61
TSAQSPNLVT DEAEASKFVE EYDRTSQVVW NEYAEANWNY NTNITTETSK ILLQKNMQIA





121
NHTLKYGTQA RKFDVNQLQN TTIKRIIKKV QDLERAALPA QELEEYNKIL LDMETTYSVA





181
TVCHPNGSCL QLEPDLTNVM ATSRKYEDLL WAWEGWRDKA GRAILQFYPK YVELINQAAR





241
LNGYVDAGDS WRSMYETPSL EQDLERLFQE LQPLYLNLHA YVRRALHRHY GAQHINLEGP





301
IPAHLLGNMW AQTWSNIYDL VVPFPSAPSM DTTEAMLKQG WTPRRMFKEA DDFFTSLGLL





361
PVPPEFWNKS MLEKPTDGRE VVCHASAWDF YNGKDFRIKQ CTTVNLEDLV VAHHEMGHIQ





421
YFMQYKDLPV ALREGANPGF HEAIGDVLAL SVSTPKHLHS LNLLSSEGGS DEHDINFLMK





481
MALDKIAFIP FSYLVDQWRW RVFDGSITKE NYNQEWWSLR LKYQGLCPPV PRTQGDFDPG





541
AKFHIPSSVP YIRYFVSFII QFQFHEALCQ AAGHTGPLHK CDIYQSKEAG QRLATAMKLG





601
FSRPWPEAMQ LITGQPNMSA SAMLSYFKPL LDWLRTENEL HGEKLGWPQY NWTPNSARSE





661
GPLPDSGRVS FLGLDLDAQQ ARVGQWLLLF LGIALLVATL GLSQRLFSIR HRSLHRHSHG





721
PQFGSEVELR HS











SEQ ID NO: 102



INTERLEUKIN 10 (IL10)



CAG46790.1









1
MHSSALLCCL VLLTGVRASP GQGTQSENSC THFPGNLPNM LRDLRDAFSR VKTFFQMKDQ






61
LDNLLLKESL LEDFKGYLGC QALSEMIQFY LEEVMPQAEN QDPDIKAHVN SLGENLKTLR





121
LRLRRCHRFL PCENKSKAVE QVKNAFNKLQ EKGIYKAMSE FDIFINYIEA YMTMKIRN











SEQ ID NO: 103



RAB ESCORT PROTEIN 1 (CHM)



EAW98559.1









1
MADTLPSEFD VIVIGTGLPE SIIAAACSRS GRRVLHVDSR SYYGGNWASF SFSGLLSWLK






61
EYQENSDIVS DSPVWQDQIL ENEEAIALSR KDKTIQHVEV FCYASQDLHE DVEEAGALQK





121
NHALVTSANS TEAADSAFLP TEDESLSTMS CEMLTEQTPS SDPENALEVN GAEVTGEKEN





181
HCDDKTCVPS TSAEDMSENV PIAEDTTEQP KKNRITYSQI IKEGRRFNID LVSKLLYSRG





241
LLIDLLIKSN VSRYAEFKNI TRILAFREGR VEQVPCSRAD VFNSKQLTMV EKRMLMKFLT





301
FCMEYEKYPD EYKGYEEITF YEYLKTQKLT PNLQYIVMHS IAMTSETASS TIDGLKATKN





361
FLHCLGRYGN TPFLFPLYGQ GELPQCFCRM CAVFGGIYCL RHSVQCLVVD KESRKCKAII





421
DQFGQRIISE HFLVEDSYFP ENMCSRVQYR QISRAVLITD RSVLKTDSDQ QISILTVPAE





481
EPGTFAVRVI ELCSSTMTCM KGTYLVHLTC TSSKTAREDL ESVVQKLFVP YTEMEIENEQ





541
VEKPRILWAL YFNMRDSSDI SRSCYNDLPS NVYVCSGPDC GLGNDNAVKQ AETLFQEICP





601
NEDFCPPPPN PEDIILDGDS LQPEASESSA IPEANSETFK ESTNLGNLEE SSE











SEQ ID NO: 104



RETINOSCHISIN (RS1)



NP_000321.1









1
MSRKIEGFLL LLLFGYEATL GLSSTEDEGE DPWYQKACKC DCQGGPNALW SAGATSLDCI






61
PECPYHKPLG FESGEVTPDQ ITCSNPEQYV GWYSSWTANK ARLNSQGFGC AWLSKFQDSS





121
QWLQIDLKEI KVISGILTQG RCDIDEWMTK YSVQYRTDER LNWIYYKDQT GNNRVFYGNS





181
DRTSTVQNLL RPPIISRFIR LIPLGWHVRI AIRMELLECV SKCA











SEQ ID NO: 105



RETINOSCHISIN (RS1), PARTIAL



ABK40506.1









1
VFYGNSDRTS TVQNLLRPPI ISRFIRLIPL GCHVRIAIRM ELLECVSKCA












SEQ ID NO: 106



BARDET-BIEDL SYNDROME 1 (BBS1)



AAM92770.1









1
MAAASSSDSD ACGAESNEAN SKWLDAHYDP MANIHTFSAC LALADLHGDG EYKLVVGDLG






61
PGGQQPRLKV LKGPLVMTES PLPALPAAAA TFLMEQHEPR TPALALASGP CVYVYKNLRP





121
YFKFSLPQLP PNPLEQDLWN QAKEDRIDPL TLKEMLESIR ETAEEPLSIQ SLRFLQLELS





181
EMEAFVNQHK SNSIKRQTVI TTMTTLKKNL ADEDAVSCLV LGTENKELLV LDPEAFTILA





241
KMSLPSVPVF LEVSGQFDVE FRLAAACRNG NIYILRRDSK HPKYCIELSA QPVGLIRVHK





301
VLVVGSTQDS LHGFTHKGKK LWTVQMPAAI LTMNLLEQHS RGLQAVMAGL ANGEVRIYRD





361
KALLNVIHTP DAVTSLCFGR YGREDNTLIM TTRGGGLIIK ILKRTAVFVE GGSEVGPPPA





421
QAMKLNVPRK TRLYVDQTLR EREAGTAMHR AFQTDLYLLR LRAARAYLQA LESSLSPLST





481
TAREPLKLHA VVQGLGPTFK LTLHLQNTST TRPVLGLLVC FLYNEALYSL PRAFFKVPLL





541
VPGLNYPLET FVESLSNKGI SDIIKVLVLR EGQSAPLLSA HVNMPGSEGL AAA











SEQ ID NO: 107



BARDET-BIEDL SYNDROME 2 (BBS2)



AAH14140.1









1
MLLPVFTLKL RHKISPRMVA IGRYDGTHPC LAAATQTGKV FIHNPHTRNQ HVSASRVFQS






61
PLESDVSLLN INQAVSCLTA GVLNPELGYD ALLVGTQTNL LAYDVYNNSD LFYREVADGA





121
NVVVLGTLGD ISSPLAIIGG NCALQGFNHE GSDLFWTVTG DNVNSLALCD FDGDGKKELL





181
VGSEDFDIRV FKEDEIVAEM TETEIVTSLC PMYGSRFGYA LSNGTVGVYD KTSRYWRIKS





241
KNHAMSIHAF DLNSDGVNEL ITGWSNGKVD ARSDRTGEVI FKDNFSSAIA GVVEGDYRMD





301
GHIQLICCSV DGEIRGYLPG TAEMRGNLMD TSAEQDLIRE LSQKKQNLLL ELRNYEENAK





361
AELASPLNEA DGHRGIIPAN TRLHTTLSVS LGNETQTAHT ELRISTSNDT IIRAVLIFAE





421
GIFTGESHVV HPSIHNLSSS ICIPIVPPKD VPVDLHLKAF VGYRSSTQFH VFESTRQLPR





481
FSMYALTSLD PASEPISYVN FTIAERAQRV VVWLGQNFLL PEDTHIQNAP FQVCFTSLRN





541
GGHLHIKIKL SGEITINTDD IDLAGDIIQS MASFFAIEDL QVEADFPVYF EELRKVLVKV





601
DEYHSVHQKL SADMADHSNL IRSLLVGAED ARLMRDMKTM KSRYMELYDL NRDLLNGYKI





661
RCNNHTELLG NLKAVNQAIQ RAGRLRVGKP KNQVITACRD AIRSNNINTL FKIMRVGTAS





721
S











SEQ ID NO: 108



ADP RIBOSYLATION FACTOR LIKE GTPASE 6 (ARL6), ISOFORM BB3SL



NP_001310442.1









1
MGLLDRLSVL LGLKKKEVHV LCLGLDNSGK TTIINKLKPS NAQSQNILPT IGFSIEKFKS






61
SSLSFTVFDM SGQGRYRNLW EHYYKEGQAI IFVIDSSDRL RMVVAKEELD TLLNHPDIKH





121
RRIPILFFAN KMDLRDAVTS VKVSQLLCLE NIKDKPWHIC ASDAIKGEGL QEGVDWLQEK





181
TIQSDPDCED MKR











SEQ ID NO: 109



ADP RIBOSYLATION FACTOR LIKE GTPASE 6 (ARL6), ISOFORM 1



NP_001265222.1









1
MGLLDRLSVL LGLKKKEVHV LCLGLDNSGK TTIINKLKPS NAQSQNILPT IGFSIEKFKS






61
SSLSFTVFDM SGQGRYRNLW EHYYKEGQAI IFVIDSSDRL RMVVAKEELD TLLNHPDIKH





121
RRIPILFFAN KMDLRDAVTS VKVSQLLCLE NIKDKPWHIC ASDAIKGEGL QEGVDWLQDQ





181
IQTVKT











SEQ ID NO: 110



ADP RIBOSYLATION FACTOR LIKE GTPASE 6 (ARL6), ISOFORM 2



NP_001310443.1









1
MGLLDRLSVL LGLKKKEVHV LCLGLDNSGK TTIINKLKPS NAQSQNILPT IGFSIEKFKS






61
SSLSFTVFDM SGQGRYRNLW EHYYKEGQAI IFVIDSSDRL RMVVAKEELD TLLNHPDIKH





121
RRIPILFFAN KMDLRDAVTS VKVSQLLCLE NIKDKPWHI











SEQ ID NO: 111



BARDET-BIEDL SYNDROME 4 (BBS4)



AAH27624.1









1
MAEERVATRT QFPVSTESQK PRQKKAPEFP ILEKQNWLIH LHYIRKDYEA CKAVIKEQLQ






61
ETQGLCEYAI YVQALIFRLE GNIQESLELF QTCAVLSPQS ADNLKQVARS LFLLGKHKAA





121
IEVYNEAAKL NQKDWEISHN LGVCYIYLKQ FNKAQDQLHN ALNLNRHDLT YIMLGKIHLL





181
EGDLDKAIEV YKKAVEFSPE NTELLTTLGL LYLQLGIYQK AFEHLGNALT YDPTNYKAIL





241
AAGSMMQTHG DFDVALTKYR VVACAVPESP PLWNNIGMCF FGKKKYVAAI SCLKRANYLA





301
PFDWKILYNL GLVHLTMQQY ASAFHFLSAA INFQPKMGEL YMLLAVALTN LEDTENAKRA





361
YAEAVHLDKC NPLVNLNYAV LLYNQGEKKN ALVQYQEMEK KVSLLKDNSS LEFDSEMVEM





421
AQKLGAALQV GEALVWTKPV KDPKSKHQTT STSKPASFQQ PLGSNQALGQ AMSSAAAYRT





481
LPSGAGGTSQ FTKPPSLPLE PEPAVESSPT ETSEQIREK











SEQ ID NO: 112



BARDET-BIEDL SYNDROME 4 (BBS4), ISOFORM 1



NP_149017.2









1
MAEERVATRT QFPVSTESQK PRQKKAPEFP ILEKQNWLIH LHYIRKDYEA CKAVIKEQLQ






61
ETQGLCEYAI YVQALIFRLE GNIQESLELF QTCAVLSPQS ADNLKQVARS LFLLGKHKAA





121
IEVYNEAAKL NQKDWEISHN LGVCYIYLKQ FNKAQDQLHN ALNLNRHDLT YIMLGKIHLL





181
EGDLDKAIEV YKKAVEFSPE NTELLTTLGL LYLQLGIYQK AFEHLGNALT YDPTNYKAIL





241
AAGSMMQTHG DFDVALTKYR VVACAVPESP PLWNNIGMCF FGKKKYVAAI SCLKRANYLA





301
PFDWKILYNL GLVHLTMQQY ASAFHFLSAA INFQPKMGEL YMLLAVALTN LEDIENAKRA





361
YAEAVHLDKC NPLVNLNYAV LLYNQGEKKN ALAQYQEMEK KVSLLKDNSS LEFDSEMVEM





421
AQKLGAALQV GEALVWTKPV KDPKSKHQTT STSKPASFQQ PLGSNQALGQ AMSSAAAYRT





481
LPSGAGGTSQ FTKPPSLPLE PEPAVESSPT ETSEQIREK











SEQ ID NO: 113



BARDET-BIEDL SYNDROME 4 (BBS4), ISOFORM 2



NP_001239607.1









1
MLGKIHLLEG DLDKAIEVYK KAVEFSPENT ELLTTLGLLY LQLGIYQKAF EHLGNALTYD






61
PTNYKAILAA GSMMQTHGDF DVALTKYRVV ACAVPESPPL WNNIGMCFFG KKKYVAAISC





121
LKRANYLAPF DWKILYNLGL VHLTMQQYAS AFHFLSAAIN FQPKMGELYM LLAVALTNLE





181
DIENAKRAYA EAVHLDKCNP LVNLNYAVLL YNQGEKKNAL AQYQEMEKKV SLLKDNSSLE





241
FDSEMVEMAQ KLGAALQVGE ALVWTKPVKD PKSKHQTTST SKPASFQQPL GSNQALGQAM





301
SSAAAYRTLP SGAGGTSQFT KPPSLPLEPE PAVESSPTET SEQIREK











SEQ ID NO: 114



BARDET-BIEDL SYNDROME 4 (BBS4), ISOFORM 3



NP_001307594.1









1
MAEERVATRT QFPVSTESQK PRQKKAPEFP ILEKQNWLIH LHYIRKDYEA CKAVIKEQLQ






61
ETQGLCEYAI YVQALIFRLE GNIQESLELF QTCAVLSPQS ADNLKQVARS LFLLGKHKAA





121
IEVYNEAAKL NQKDWEISHN LGVCYIYLKQ FNKAQDQLHN ALNLNRHDLT YIMLGKIHLL





181
EGDLDKAIEV YKKAVEFSPE NTELLTTLGL LYLQAILAAG SMMQTHGDFD VALTKYRVVA





241
CAVPESPPLW NNIGMCFFGK KKYVAAISCL KRANYLAPFD WKILYNLGLV HLTMQQYASA





301
FHFLSAAINF QPKMGELYML LAVALTNLED IENAKRAYAE AVHLDKCNPL VNLNYAVLLY





361
NQGEKKNALA QYQEMEKKVS LLKDNSSLEF DSEMVEMAQK LGAALQVGEA LVWTKPVKDP





421
KSKHQTTSTS KPASFQQPLG SNQALGQAMS SAAAYRTLPS GAGGTSQFTK PPSLPLEPEP





481
AVESSPTETS EQIREK











SEQ ID NO: 115



BARDET-BIEDL SYNDROME 5 (BBS5)



NP_689597.1









1
MSVLDALWED RDVRFDLSAQ QMKTRPGEVL IDCLDSIEDT KGNNGDRGRL LVTNLRILWH






61
SLALSRVNVS VGYNCILNIT TRTANSKLRG QTEALYILTK CNSTRFEFIF TNLVPGSPRL





121
FTSVMAVHRA YETSKMYRDF KLRSALIQNK QLRLLPQEHV YDKINGVWNL SSDQGNLGTF





181
FITNVRIVWH ANMNDSFNVS IPYLQIRSIK IRDSKFGLAL VIESSQQSGG YVLGFKIDPV





241
EKLQESVKEI NSLHKVYSAS PIFGVDYEME EKPQPLEALT VEQIQDDVEI DSDGHTDAFV





301
AYFADGNKQQ DREPVFSEEL GLAIEKLKDG FTLQGLWEVM S











SEQ ID NO: 116



BARDET-BIEDL SYNDROME 5 (BBS5), ISOFORM 1



AAT08182.1









1
MSVLDALWED RDVRFDLSAQ QMKTRPGEVL IDCLDSIEDT KGNNGDRGRL LVTNLRILWH






61
SLALSRVNVS VGYNCILNIT TRTANSKLRG QTEALYILTK CNSTRFEFIF TNLVPGSPRL





121
FTSVMAVHRA YETSKMYRDF KLRSALIQNK QLRLLPQEHV YDKINGVWNL SSDQGNLGTF





181
FITNVRIVWH ANMNDSFNVS IPYLQIRSIK IRDSKFGLAL VIESSQQSGG YVLGFKIDPV





241
EKLQESVKEI NSLHKVYSAS PIFGVDYEME EKPQPLEALT VEQIQDDVEI DSDGHTDAFV





301
AYFADGNKQQ DREPVFSEEL GLAIEKLKDG FTLQGLWEVM S











SEQ ID NO: 117



BARDET-BIEDL SYNDROME 5 (BBS5), ISOFORM 2



AAT08183.1









1
MSVLDALWED RDVRFDLSAQ QMKTRPGEVL IDCLDSIEDT KGNNGDRGRL LVTNLRILWH






61
SLALSRVNVS VGYNCILNIT TRTANSKLRG QTEALYILTK CNSTRFEFIF TNLVPGSPRL





121
FTSVMAVHRA YETSKMYRDF KLRSALIQNK QLRLLPQEHV YDKINGVWNL SSDQGNLGTF





181
FITNVRIVWH ANMNDSFNVS IPYLQISGGY VLGFKIDPVE KLQESVKEIN SLHKVYSASP





241
IFGVDYEMEE KPQPLEALTV EQIQDDVEID SDGHTDAFVA YFADGNKQQD REPVFSEELG





301
LAIEKLKDGF TLQGLWEVMS











SEQ ID NO: 118



MCKUSICK-KAUFMAN SYNDROME (MKKS)



AAH28973.1









1
MSRLEAKKPS LCKSEPLTTE RVRTTLSVLK RIVTSCYGPS GRLKQLHNGF GGYVCTTSQS






61
SALLSHLLVT HPILKILTAS IQNHVSSFSD CGLFTAILCC NLIENVQRLG LIPTIVIRLN





121
KHLLSLCISY LKSETCGCRI PVDFSSTQIL LCLVRSILTS KPACMLTRKE TEHVSALILR





181
AFLLTIPENA EGHIILGKSL IVPLKGQRVI DSTVLPGILI EMSEVQLMRL LPIKKSTALK





241
VALFCTTLSG DTSDTGEGTV VVSYGVSLEN AVLDQLLNLG RQLISDHVDL VLCQKVIHPS





301
LKQFLNMHRI IAIDRIGVTL MEPLTKMTGT QPIGSLGSIC PNSYGSVKDV CTAKFGSKHF





361
FHLIPNEATI CSLLLCNRND TAWDELKLTC QTALHVLQLT LKEPWALLGG GCTETHLAAY





421
IRHKTHNDPE SILKDDECTQ TELQLIAEAF CSALESVVGS LEHDGGEILT DMKYGHLWSV





481
QADSPCVANW PDLLSQCGCG LYNSQEELNW SFLRSTCRPF VPQSCLPHEA VVSASNLTLD





541
CLTAKLSGLQ VAVETANLIL DLSYVIEDKN











SEQ ID NO: 119



MCKUSICK-KAUFMAN SYNDROME (MKKS), ISOFORM CRA_A



EAX10343.1









1
MSLRNLWRDY KVLVVMVPLV GLIHLGWYRI KSSPVFQIPK NDDIPEQDSL GLSNLQKSQI






61
QGK











SEQ ID NO: 120



MCKUSICK-KAUFMAN SYNDROME (MKKS), ISOFORM CRA_B



EAX10344.1









1
MSRLEAKKPS LCKSEPLTTE RVRTTLSVLK RIVTSCYGPS GRLKQLHNGF GGYVCTTSQS






61
SALLSHLLVT HPILKILTAS IQNHVSSFSD CGLFTAILCC NLIENVQRLG LIPTIVIRLN





121
KHLLSLCISY LKSETCGCRI PVDFSSTQIL LCLVRSILTS KPACMLTRKE TEHVSALILR





181
AFLLTIPENA EGHIILGKSL IVPLKGQRVI DSTVLPGILI EMSEVQLMRL LPIKKSTALK





241
VALFCTTLSG DTSDTGEGTV VVSYGVSLEN AVLDQLLNLG RQLISDHVDL VLCQKVIHPS





301
LKQFLNMHRI IAIDRIGVTL MEPLTKMTGT QPIGSLGSIC PNSYGSVKDV CTAKFGSKHF





361
FHLIPNEATI CSLLLCNRND TAWDELKLTC QTALHVLQLT LKEPWALLGG GCTETHLAAY





421
IRHKTHNDPE SILKDDECTQ TELQLIAEAF CSALESVVGS LEHDGGEILT DMKYGHLWSV





481
QADSPCVANW PDLLSQCGCG LYNSQEELNW SFLRSTRRPF VPQSCLPHEA VGSASNLTLD





541
CLTAKLSGLQ VAVETANLIL DLSYVIEDKN











SEQ ID NO: 121



BARDET-BIEDL SYNDROME 7 (BBS7)



AAH32691.1









1
MDLILNRMDY LQVGVTSQKT MKLIPASRHR ATQKVVIGDH DGVVMCFGMK KGEAAAVFKT






61
LPGPKIARLE LGGVINTPQE KIFIAAASEI RGFTKRGKQF LSFETNLTES IKAMHISGSD





121
LFLSASYIYN HYCDCKDQHY YLSGDKINDV ICLPVERLSR ITPVLACQDR VLRVLQGSDV





181
MYAVEVPGPP TVLALHNGNG GDSGEDLLFG TSDGKLALIQ ITTSKPVRKW EIQNEKKRGG





241
ILCIDSFDIV GDGVKDLLVG RDDGMVEVYS FDNANEPVLR FDQMLSESVT SIQGGCVGKD





301
SYDEIVVSTY SGWVTGLTTE PIHKESGPGE ELKINQEMQN KISSLRNELE HLQYKVLQER





361
ENYQQSSQSS KAKSAVPSFG INDKFTLNKD DASYSLILEV QTAIDNVLIQ SDVPIDLLDV





421
DKNSAVVSFS SCDSESNDNF LLATYRCQAD TTRLELKIRS IEGQYGTLQA YVTPRIQPKT





481
CQVRQYHIKP LSLHQRTHFI DHDRPMNTLT LTGQFSFAEV HSWVVFCLPE VPEKPPAGEC





541
VTFYFQNTFL DTQLESTYRK GEGVFKSDNI STISILKDVL SKEATKRKIN LNISYEINEV





601
SVKHTLKLIH PKLEYQLLLA KKVQLIDALK ELQIHEGNTN FLIPEYHCIL EEADHLQEEY





661
KKQPAHLERL YG











SEQ ID NO: 122



BARDET-BIEDL SYNDROME 7 (BBS7), ISOFORM A



NP_789794.1









1
MDLILNRMDY LQVGVTSQKT MKLIPASRHR ATQKVVIGDH DGVVMCFGMK KGEAAAVFKT






61
LPGPKIARLE LGGVINTPQE KIFIAAASEI RGFTKRGKQF LSFETNLTES IKAMHISGSD





121
LFLSASYIYN HYCDCKDQHY YLSGDKINDV ICLPVERLSR ITPVLACQDR VLRVLQGSDV





181
MYAVEVPGPP TVLALHNGNG GDSGEDLLFG TSDGKLALIQ ITTSKPVRKW EIQNEKKRGG





241
ILCIDSFDIV GDGVKDLLVG RDDGMVEVYS FDNANEPVLR FDQMLSESVT SIQGGCVGKD





301
SYDEIVVSTY SGWVTGLTTE PIHKESGPGE ELKINQEMQN KISSLRNELE HLQYKVLQER





361
ENYQQSSQSS KAKSAVPSFG INDKFTLNKD DASYSLILEV QTAIDNVLIQ SDVPIDLLDV





421
DKNSAVVSFS SCDSESNDNF LLATYRCQAD TTRLELKIRS IEGQYGTLQA YVTPRIQPKT





481
CQVRQYHIKP LSLHQRTHFI DHDRPMNTLT LTGQFSFAEV HSWVVFCLPE VPEKPPAGEC





541
VTFYFQNTFL DTQLESTYRK GEGVFKSDNI STISILKDVL SKEATKRKIN LNISYEINEV





601
SVKHTLKLIH PKLEYQLLLA KKVQLIDALK ELQIHEGNTN FLIPEYHCIL EEADHLQEEY





661
KKQPAHLERL YGMITDLFID KFKFKGTNVK TKVPLLLEIL DSYDQNALIS FFDAA











SEQ ID NO: 123



BARDET-BIEDL SYNDROME 7 (BBS7), ISOFORM B



NP_060660.2









1
MDLILNRMDY LQVGVTSQKT MKLIPASRHR ATQKVVIGDH DGVVMCFGMK KGEAAAVFKT






61
LPGPKIARLE LGGVINTPQE KIFIAAASEI RGFTKRGKQF LSFETNLTES IKAMHISGSD





121
LFLSASYIYN HYCDCKDQHY YLSGDKINDV ICLPVERLSR ITPVLACQDR VLRVLQGSDV





181
MYAVEVPGPP TVLALHNGNG GDSGEDLLFG TSDGKLALIQ ITTSKPVRKW EIQNEKKRGG





241
ILCIDSFDIV GDGVKDLLVG RDDGMVEVYS FDNANEPVLR FDQMLSESVT SIQGGCVGKD





301
SYDEIVVSTY SGWVTGLTTE PIHKESGPGE ELKINQEMQN KISSLRNELE HLQYKVLQER





361
ENYQQSSQSS KAKSAVPSFG INDKFTLNKD DASYSLILEV QTAIDNVLIQ SDVPIDLLDV





421
DKNSAVVSFS SCDSESNDNF LLATYRCQAD TTRLELKIRS IEGQYGTLQA YVTPRIQPKT





481
CQVRQYHIKP LSLHQRTHFI DHDRPMNTLT LTGQFSFAEV HSWVVFCLPE VPEKPPAGEC





541
VTFYFQNTFL DTQLESTYRK GEGVFKSDNI STISILKDVL SKEATKRKIN LNISYEINEV





601
SVKHTLKLIH PKLEYQLLLA KKVQLIDALK ELQIHEGNTN FLIPEYHCIL EEADHLQEEY





661
KKQPAHLERL YG











SEQ ID NO: 124



TETRATRICOPEPTIDE REPEAT DOMAIN 8 (TTC8)



AAH95433.1









1
MSSEMEPLLL AWSYFRRRKF QLCADLCTQM LEKSPYDQAA WILKARALTE MVYIDEIDVD






61
QEGIAEMMLD ENAIAQVPRP GTSLKLPGTN QTGGPSQAVR PITQAGRPIT GFLRPSTQSG





121
RPGTMEQAIR TPRTAYTARP ITSSSGRFVR LGTASMLTSP DGPFINLSRL NLTKYSQKPK





181
LAKALFEYIF HHENDVKTAL DLAALSTEHS QYKDWWWKVQ IGKCYYRLGM YREAEKQFKS





241
ALKQQEMVDT FLYLAKVYVS LDQPVTALNL FKQGLDKFPG EVTLLCGIAR IYEEMNNMSS





301
AAEYYKEVLK QDNTHVEAIA CIGSNHFYSD QPEIALRFYR RLLQMGIYNG QLFNNLGLCC





361
FYAQQYDMTL TSFERALSLA ENEEEAADVW YNLGHVAVGI GDTNLAHQCF RLALVNNNNH





421
AEAYNNLAVL EMRKGHVEQA RALLQTASSL APHMYEPHFN FATISDKIGD LQRSYVAAQK





481
SEAAFPDHVD TQHLIKQLRQ HFAML











SEQ ID NO: 125



TETRATRICOPEPTIDE REPEAT DOMAIN 8 (TTC8), ISOFORM A



NP_653197.2









1
MSSEMEPLLL AWSYFRRRKF QLCADLCTQM LEKSPYDQEP DPELPVHQAA WILKARALTE






61
MVYIDEIDVD QEGIAEMMLD ENAIAQVPRP GTSLKLPGTN QTGGPSQAVR PITQAGRPIT





121
GFLRPSTQSG RPGTMEQAIR TPRTAYTARP ITSSSGRFVR LGTASMLTSP DGPFINLSRL





181
NLTKYSQKPK LAKALFEYIF HHENDVKTAL DLAALSTEHS QYKDWWWKVQ IGKCYYRLGM





241
YREAEKQFKS ALKQQEMVDT FLYLAKVYVS LDQPVTALNL FKQGLDKFPG EVTLLCGIAR





301
IYEEMNNMSS AAEYYKEVLK QDNTHVEAIA CIGSNHFYSD QPEIALRFYR RLLQMGIYNG





361
QLFNNLGLCC FYAQQYDMTL TSFERALSLA ENEEEAADVW YNLGHVAVGI GDTNLAHQCF





421
RLALVNNNNH AEAYNNLAVL EMRKGHVEQA RALLQTASSL APHMYEPHFN FATISDKIGD





481
LQRSYVAAQK SEAAFPDHVD TQHLIKQLRQ HFAML











SEQ ID NO: 126



TETRATRICOPEPTIDE REPEAT DOMAIN 8 (TTC8), ISOFORM B



NP_938051.1









1
MSSEMEPLLL AWSYFRRRKF QLCADLCTQM LEKSPYDQAA WILKARALTE MVYIDEIDVD






61
QEGIAEMMLD ENAIAQVPRP GTSLKLPGTN QTGGPSQAVR PITQAGRPIT GFLRPSTQSG





121
RPGTMEQAIR TPRTAYTARP ITSSSGRFVR LGTASMLTSP DGPFINLSRL NLTKYSQKPK





181
LAKALFEYIF HHENDVKTAL DLAALSTEHS QYKDWWWKVQ IGKCYYRLGM YREAEKQFKS





241
ALKQQEMVDT FLYLAKVYVS LDQPVTALNL FKQGLDKFPG EVTLLCGIAR IYEEMNNMSS





301
AAEYYKEVLK QDNTHVEAIA CIGSNHFYSD QPEIALRFYR RLLQMGIYNG QLFNNLGLCC





361
FYAQQYDMTL TSFERALSLA ENEEEAADVW YNLGHVAVGI GDTNLAHQCF RLALVNNNNH





421
AEAYNNLAVL EMRKGHVEQA RALLQTASSL APHMYEPHFN FATISDKIGD LQRSYVAAQK





481
SEAAFPDHVD TQHLIKQLRQ HFAML











SEQ ID NO: 127



BARDET-BIEDL SYNDROME 9 (BBS9)



AAI03832.1









1
MSLFKARDWW STILGDKEEF DQGCLCLANV DNSGNGQDKI IVGSFMGYLR IFSPHPAKTG






61
DGAQAEDLLL EVDLRDPVLQ VEVGKFVSGT EMLHLAVLHS RKLCVYSVSG TLGNVEHGNQ





121
CQMKLMYEHN LQRTACNMTY GSFGGVKGRD LICIQSMDGM LMVFEQESYA FGRFLPGFLL





181
PGPLAYSSRT DSFLTVSSCQ QVESYKYQVL AFATDADKRQ ETEQQKLGSG KRLVVDWTLN





241
IGEQALDICI VSFNQSASSV FVLGERNFFC LKDNGQIRFM KKLDWSPSCF LPYCSVSEGT





301
INTLIGNHNN MLHIYQDVTL KWATQLPHIP VAVRVGCLHD LKGVIVTLSD DGHLQCSYLG





361
TDPSLFQAPN VQSRELNYDE LDVEMKELQK IIKDVNKSQG VWPMTEREDD LNVSVVVSPN





421
FDSVSQATDV EVGTDLVPSV TVKVTLQNRV ILQKAKLSVY VQPPLELTCD QFTFEFMTPD





481
LTRTVSFSVY LKRSYTPSEL EGNAVVSYSR PTDRNPDGIP RVIQCKFRLP LKLICLPGQP





541
SKTASHKITI DTNKSPVSLL SLFPGFASQS DDDQVNVMGF HFLGGARITV LASKTSQRYR





601
IQSEQFEDLW LITNELILRL QEYFEKQGVK DFACSFSGSI PLQEYFELID HHFELRINGE





661
KLEELLSERA VQFRAIQRRL LARFKDKTPA PLQHLDTLLD GTYKQVIALA DAVEENQGNL





721
FQSFTRLKSA THLVILLIAL WQKLSADQVA ILEAAFLPLQ EDTQELGWEE TVDAAISHLL





781
KTCLSKSSKE QALNLNSQLN IPKDTSQLKK HITLLCDRLS KGGRLCLSTD AAAPQTMVMP





841
GGCTTIPESD LEERSVEQDS TELFTNHRHL TAETPRPEVS PLQGVSE











SEQ ID NO: 128



BARDET-BIEDL SYNDROME 10 (BBS10)



AAH26355.2









1
MLSSMAAAGS VKAALQVAEV LEAIVSCCVG PEGRQVLCTK PTGEVLLSRN GGRLLEALHL






61
EHPIARMIVD CVSSHLKKTG DGAKTFIIFL CHLLRGLHAI TDREKDPLMC ENIQTHGRHW





121
KNCSRWKFIS QALLTFQTQI LDGIMDQYLS RHFLSIFSSA KERTLCRSSL ELLLEAYFCG





181
RVGRNNHKFI SQLMCDYFFK CMTCKSGIGV FELVDDHFVE LNVGVTGLPV SDSRIIAGLV





241
LQKDFSVYRP ADGDMRMVIV TETIQPLFST SGSEFILNSE AQFQTSQFWI MEKTKAIMKH





301
LHSQNVKLLI SSVKQPDLVS YYAGVNGISV VECLSSEEVS LIRRIIGLSP FVPPQAFSQC





361
EIPNTALVKF CKPLILRSKR YVHLGLISTC AFIPHSIVLC GPVHGLIEQH EDALHGALKM





421
LRQLFKDLDL NYMTQTNDQN GTSSLFIYKN SGESYQAPDP GNGSIQRPYQ DTVAENKDAL





481
EKTQTYLKVH SNLVIPDVEL ETYIPYSTPT LTPTDTFQTV ETLTCLSLER NRLTDYYEPL





541
LKNNSTAYST RGNRIEISYE NLQVTNITRK GSMLPVSCKL PNMGTSQSYL SSSMPAGCVL





601
PVGGNFDILL HYYLLNYAKK CHQSEETMVS MIIANALLGI PKVLYKSKTG KYSFPHTYIR





661
AVHALQTNQP LVSSQTGLES VMGKYQLLTS VLQCLTKILT IDMVITVKRH PQKVHNQDSE





721
DEL











SEQ ID NO: 129



TRIPARTITE MOTIF CONTAINING 32 (TRIM32)



AAH03154.1









1
MAAAAASHLN LDALREVLEC PICMESFTEE QLRPKLLHCG HTICRQCLEK LLASSINGVR






61
CPFCSKITRI TSLTQLTDNL TVLKIIDTAG LSEAVGLLMC RSCGRRLPRQ FCRSCGLVLC





121
EPCREADHQP PGHCTLPVKE AAEERRRDFG EKLTRLRELM GELQRRKAAL EGVSKDLQAR





181
YKAVLQEYGH EERRVQDELA RSRKFFTGSL AEVEKSNSQV VEEQSYLLNI AEVQAVSRCD





241
YFLAKIKQAD VALLEETADE EEPELTASLP RELTLQDVEL LKVGHVGPLQ IGQAVKKPRT





301
VNVEDSWAME ATASAASTSV TFREMDMSPE EVVASPRASP AKQRGPEAAS NIQQCLFLKK





361
MGAKGSTPGM FNLPVSLYVT SQGEVLVADR GNYRIQVFTR KGFLKEIRRS PSGIDSFVLS





421
FLGADLPNLT PLSVAMNCQG LIGVTDSYDN SLKVYTLDGH CVACHRSQLS KPWGITALPS





481
GQFVVTDVEG GKLWCFTVDR GSGVVKYSCL CSAVRPKFVT CDAEGTVYFT QGLGLNLENR





541
QNEHHLEGGF SIGSVGPDGQ LGRQISHFFS ENEDFRCIAG MCVDARGDLI VADSSRKEIL





601
HFPKGGGYSV LIREGLTCPV GIALTPKGQL LVLDCWDHCI KIYSYHLRRY STP











SEQ ID NO: 130



TRIPARTITE MOTIF CONTAINING 32 (TRIM32), ISOFORM CRA_A



EAW87447.1









1
MAAAAASHLN LDALREVLEC PICMESFTEE QLRPKLLHCG HTICRQCLEK LLASSINGVR






61
CPFCSKITRI TSLTQLTDNL TVLKIIDTAG LSEAVGLLMC RSCGRRLPRQ FCRSCGLVLC





121
EPCREADHQP PGHCTLPVKE AAEERRRDFG EKLTRLRELM GELQRRKAAL EGVSKDLQAR





181
YKAVLQEYGH EERRVQDELA RSRKFFTGSL AEVEKSNSQV VEEQSYLLNI AEVQAVSRCD





241
YFLAKIKQAD VALLEETADE EEPELTASLP RELTLQDVEL LKVGHVGPLQ IGQAVKKPRT





301
VNVEDSWAME ATASAASTSV TFREMDMSPE EVVASPRASP AKQRGPEAAS NIQQCLFLKK





361
MGAKGSTPGM FNLPVSLYVT SQGEVLVADR GNYRIQVFTR KGFLKEIRRS PSGIDSFVLS





421
FLGADLPNLT PLSVAMNCQG LIGVTDSYDN SLKVYTLDGH CVACHRSQLS KPWGITALPS





481
GQFVVTDVEG GKLWCFTVDR GSGVVKYSCL CSAVRPKFVT CDAEGTVYFT QGLGLNLENR





541
QNEHHLEGGF SIGSVGPDGQ LGRQISHFFS ENEDFRCIAG MCVDARGDLI VADSSRKEIL





601
HFPKGGGYSV LIREGLTCPV GIALTPKGQL LVLDCWDHCI KIYSYHLRRY STP











SEQ ID NO: 131



BARDET-BIEDL SYNDROME 12 (BBS12)



AAH55426.1









1
MVMACRVVNK RRHMGLQQLS SFAETGRTFL GPLKSSKFII DEECHESVLI SSTVRLLESL






61
DLTSAVGQLL NEAVQAQNNT YRTGISTLLF LVGAWSSAVE ECLHLGVPIS IIVSVMSEGL





121
NFCSEEVVSL HVPVHNIFDC MDSTKTFSQL ETFSVSLCPF LQVPSDTDLI EELHGLKDVA





181
SQTLTISNLS GRPLRSYELF KPQTKVEADN NTSRTLKNSL LADTCCRQSI LIHSRHFNRT





241
DNTEGVSKPD GFQEHVTATH KTYRCNDLVE LAVGLSHGDH SSMKLVEEAV QLQYQNACVQ





301
QGNCTKPFMF DISRIFTCCL PGLPETSSCV CPGYITVVSV SNNPVIKELQ NQPVRIVLIE





361
GDLTENYRHL GFNKSANIKT VLDSMQLQED SSEELWANHV LQVLIQFKVN LVLVQGNVSE





421
RLIEKCINSK RLVIGSVNGS VMQAFAEAAG AVQVAYITQV NEDCVGNGVC VTFWRSSPLD





481
VVDRNNRIAI LLKTEGINLV TAVLTNPVTA QMQIKEDRFW TCAYRLYYAL KEEKVFLGGG





541
AVEFLCLSCL HILAEQSLKK ENHACSGWLH NTSSWLASSL AIYRPTVLKF LANGWQKYLS





601
TLLYNTANYS SEFEVSTYIQ HHLQNATDSG SPSSYILNEY SKLNSRIFNS DISNKLEQIP





661
RVYDVVTPKI EAWRRALDLV LLVLQTDSEI ITGHGHTQIN SQELTGFLFL











SEQ ID NO: 132



MKS TRANSITION ZONE COMPLEX SUBUNIT 1 (MKS1)



NP_060247.2









1
MAETVWSTDT GEAVYRSRDP VRNLRLRVHL QRITSSNFLH YQPAAELGKD LIDLATFRPQ






61
PTASGHRPEE DEEEEIVIGW QEKLFSQFEV DLYQNETACQ SPLDYQYRQE ILKLENSGGK





121
KNRRIFTYTD SDRYTNLEEH CQRMTTAASE VPSFLVERMA NVRRRRQDRR GMEGGILKSR





181
IVTWEPSEEF VRNNHVINTP LQTMHIMADL GPYKKLGYKK YEHVLCTLKV DSNGVITVKP





241
DFTGLKGPYR IETEGEKQEL WKYTIDNVSP HAQPEEEERE RRVFKDLYGR HKEYLSSLVG





301
TDFEMTVPGA LRLFVNGEVV SAQGYEYDNL YVHFFVELPT AHWSSPAFQQ LSGVTQTCTT





361
KSLAMDKVAH FSYPFTFEAF FLHEDESSDA LPEWPVLYCE VLSLDFWQRY RVEGYGAVVL





421
PATPGSHTLT VSTWRPVELG TVAELRRFFI GGSLELEDLS YVRIPGSFKG ERLSRFGLRT





481
ETTGTVTFRL HCLQQSRAFM ESSSLQKRMR SVLDRLEGFS QQSSIHNVLE AFRRARRRMQ





541
EARESLPQDL VSPSGTLVS











SEQ ID NO: 133



WD REPEAT CONTAINING PLANAR CELL POLARITY EFFECTOR (WDPCP), HOMOLOG ISOFORM 1



NP_001036157.1









1
MFSSLHSALL TDSFIILSFL AQNKLCFIQF TKKMESSDVN KRLEKLSALD YKIFYYEIPG






61
PINKTTERHL AINCVHDRVV CWWPLVNDDA WPWAPISSEK DRANLLLLGY AQGRLEVLSS





121
VRTEWDPLDV RFGTKQPYQV FTVEHSVSVD KEPMADSCIY ECIRNKIQCV SVTRIPLKSK





181
AISCCRNVTE DKLILGCEDS SLILYETHRR VTLLAQTELL PSLISCHPSG AILLVGSNQG





241
ELQIFDMALS PINIQLLAED RLPRETLQFS KLFDASSSLV QMQWIAPQVV SQKGEGSDIY





301
DLLFLRFERG PLGVLLFKLG VFTRGQLGLI DIIFQYIHCD EIYEAINILS SMNWDTLGHQ





361
CFISMSAIVN HLLRQKLTPE REAQLETSLG TFYAPTRPLL DSTILEYRDQ ISKYARRFFH





421
HLLRYQRFEK AFLLAVDVGA RDLFMDIHYL ALDKGELALA EVARKRASDI DAESITSGVE





481
LLGPLDRGDM LNEAFIGLSL APQGEDSFPD NLPPSCPTHR HILQQRILNG SSNRQIIDRR





541
NELEKDICSG FLMTNTCNAE DGELREDGRE QEIRDGGSLK MIHFGLV











SEQ ID NO: 134



WD REPEAT CONTAINING PLANAR CELL POLARITY EFFECTOR (WDPCP), HOMOLOG ISOFORM 2



NP_056994.3









1
MRREFCWDAY SKAAGSRASS PLPRQDRDSF CHQMSFCLTE LHLWSLKNTL HIADRDIGIY






61
QYYDKKDPPA TEHGNLEKKQ KLAESRDYPW TLKNRRPEKL RDSLKELEEL MQNSRCVLSK





121
WKNKYVCQLL FGSGVLVSLS LSGPQLEKVV IDRSLVGKLI SDTISDALLT DSFIILSFLA





181
QNKLCFIQFT KKMESSDVNK RLEKLSALDY KIFYYEIPGP INKTTERHLA INCVHDRVVC





241
WWPLVNDDAW PWAPISSEKD RANLLLLGYA QGRLEVLSSV RTEWDPLDVR FGTKQPYQVF





301
TVEHSVSVDK EPMADSCIYE CIRNKIQCVS VTRIPLKSKA ISCCRNVTED KLILGCEDSS





361
LILYETHRRV TLLAQTELLP SLISCHPSGA ILLVGSNQGE LQIFDMALSP INIQLLAEDR





421
LPRETLQFSK LFDASSSLVQ MQWIAPQVVS QKGEGSDIYD LLFLRFERGP LGVLLFKLGV





481
FTRGQLGLID IIFQYIHCDE IYEAINILSS MNWDTLGHQC FISMSAIVNH LLRQKLTPER





541
EAQLETSLGT FYAPTRPLLD STILEYRDQI SKYARRFFHH LLRYQRFEKA FLLAVDVGAR





601
DLFMDIHYLA LDKGELALAE VARKRASDID AESITSGVEL LGPLDRGDML NEAFIGLSLA





661
PQGEDSFPDN LPPSCPTHRH ILQQRILNGS SNRQIIDRRN ELEKDICSGF LMTNTCNAED





721
GELREDGREQ EIRDGGSLKM IHFGLV











SEQ ID NO: 135



WD REPEAT CONTAINING PLANAR CELL POLARITY EFFECTOR (WDPCP), HOMOLOG ISOFORM 3



NP_001340973.1









1
MDRDSFCHQM SFCLTELHLW SLKNTLHIAD RDIGIYQYYD KKDPPATEHG NLEKKQKLAE






61
SRDYPWTLKN RRPEKLRDSL KELEELMQNS RCVLSKWKNK YVCQLLFGSG VLVSLSLSGP





121
QLEKVVIDRS LVGKLISDTI SDALLTDSFI ILSFLAQNKL CFIQFTKKME SSDVNKRLEK





181
LSALDYKIFY YEIPGPINKT TERHLAINCV HDRVVCWWPL VNDDAWPWAP ISSEKDRANL





241
LLLGYAQGRL EVLSSVRTEW DPLDVRFGTK QPYQVFTVEH SVSVDKEPMA DSCIYECIRN





301
KIQCVSVTRI PLKSKAISCC RNVTEDKLIL GCEDSSLILY ETHRRVTLLA QTELLPSLIS





361
CHPSGAILLV GSNQGELQIF DMALSPINIQ LLAEDRLPRE TLQFSKLFDA SSSLVQMQWI





421
APQVVSQKGE GSDIYDLLFL RFERGPLGVL LFKLGVFTRG QLGLIDIIFQ YIHCDEIYEA





481
INILSSMNWD TLGHQCFISM SAIVNHLLRQ KLTPEREAQL ETSLGTFYAP TRPLLDSTIL





541
EYRDQISKYA RRFFHHLLRY QRFEKAFLLA VDVGARDLFM DIHYLALDKG ELALAEVARK





601
RASDIDAESI TSGVELLGPL DRGDMLNEAF IGLSLAPQGE DSFPDNLPPS CPTHRHILQQ





661
RILNGSSNRQ IIDRRNELEK DICSGFLMTN TCNAEDGELR EDGREQEIRD GGSLKMIHFG





721
LV











SEQ ID NO: 136



WD REPEAT CONTAINING PLANAR CELL POLARITY EFFECTOR (WDPCP), HOMOLOG ISOFORM 4



NP_001340974.1









1
MRREFCWDAY SKAAGSRASS PLPRQDRDSF CHQMSFCLTE LHLWSLKNTL HIADRDIGIY






61
QYYDKKDPPA TEHGNLEKKQ KLAESRDYPW TLKNRRPEKL RDSLKELEEL MQNSRCVLSK





121
WKNKYVCQLL FGSGVLVSLS LSGPQLEKVV IDRSLVGKLI SDTISDALLT DSFIILSFLA





181
QNKLCFIQFT KKMESSDVNK RLEKLSALDY KIFYYEIPGP INKTTERHLA INCVHDRVVC





241
WWPLVNDDAW PWAPISSEKD RANLLLLGYA QGRLEVLSSV RTEWDPLDVR FGTKQPYQVF





301
TVEHSVSVDK EPMADSCIYE CIRNKIQCVS VTRIPLKSKA ISCCRNVTED KLILGCEDSS





361
LILYETHRRV TLLAQTELLP SLISCHPSGA ILLVGSNQGE LQIFDMALSP INIQLLAEDR





421
LPRETLQFSK LFDASSSLVQ MQWIAPQVVS QKGEGSDIYD LLFLRFERGP LGVLLFKLGV





481
FTRGQLGLID IIFQYIHCDE IYEAINILSS MNWDTLGHQC FISMSAIVNH LLRQKLTPER





541
EAQLETSLGT FYAPTRPLLD STILEYRDQI SKYARRFFHH LLRWSLALSP RLECSDVIAV





601
HCHLHLLGSS DSSASASRVA GTTGMCHHTQ LIFVVFSRDG ISPCWPGWS











SEQ ID NO: 137



SEROLOGICALLY DEFINED COLON CANCER ANTIGEN 8 (SDCCAG8)



Q86SQ7.1









1
MAKSPENSTL EEILGQYQRS LREHASRSIH QLTCALKEGD VTIGEDAPNL SFSTSVGNED






61
ARTAWPELQQ SHAVNQLKDL LRQQADKESE VSPSRRRKMS PLRSLEHEET NMPTMHDLVH





121
TINDQSQYIH HLEAEVKFCK EELSGMKNKI QVVVLENEGL QQQLKSQRQE ETLREQTLLD





181
ASGNMHNSWI TTGEDSGVGE TSKRPFSHDN ADFGKAASAG EQLELEKLKL TYEEKCEIEE





241
SQLKFLRNDL AEYQRTCEDL KEQLKHKEFL LAANTCNRVG GLCLKCAQHE AVLSQTHTNV





301
HMQTIERLVK ERDDLMSALV SVRSSLADTQ QREASAYEQV KQVLQISEEA NFEKTKALIQ





361
CDQLRKELER QAERLEKELA SQQEKRAIEK DMMKKEITKE REYMGSKMLI LSQNIAQLEA





421
QVEKVTKEKI SAINQLEEIQ SQLASREMDV TKVCGEMRYQ LNKTNMEKDE AEKEHREFRA





481
KTNRDLEIKD QEIEKLRIEL DESKQHLEQE QQKAALAREE CLRLTELLGE SEHQLHLTRQ





541
EKDSIQQSFS KEAKAQALQA QQREQELTQK IQQMEAQHDK TENEQYLLLT SQNTFLTKLK





601
EECCTLAKKL EQISQKTRSE IAQLSQEKRY TYDKLGKLQR RNEELEEQCV QHGRVHETMK





661
QRLRQLDKHS QATAQQLVQL LSKQNQLLLE RQSLSEEVDR LRTQLPSMPQ SDC











SEQ ID NO: 138



LEUCINE ZIPPER TRANSCRIPTION FACTOR LIKE 1 (LZTFL1)



CAB95836.1









1
MAELGLNEHH QNEVINYMRF ARSKRGLRLK TVDSCFQDLK ESRLVEDTFT IDEVSEVLNG






61
LQAVVHSEVE SELINTAYTN VLLLRQLFAQ AEKWYLKLQT DISELENREL LEQVAEFEKA





121
EITSSNKKPI LDVTKPKLAP LNEGGTAELL NKEILRLQEE NEKLKSRLKT IEIQATNALD





181
EKSKLEKALQ DLQLDQGNQK DFIKAQDLSN LENTVAALKS EFQKTLNDKT ENQKSLEENL





241
ATAKHDLLRV QEQLHMAEKE LEKKFQQTAA YRNMKEILTK KNDQIKDLRK RLAQYEPED











SEQ ID NO: 139



BBSOME INTERACTING PROTEIN 1 (BBIP1), ISOFORM 1



NP_001182233.1









1
MLKAAAKRPE LSGLLKFNNY GILSESPLTS QRTTWLLYQS PSFIPGFAYP SRCLKTIGGV






61
YKQARKKHYI QQLRYGRSEV NVPGSSSKAR ATVCGRYNDN GAV











SEQ ID NO: 140



BBSOME INTERACTING PROTEIN 1 (BBIP1), ISOFORM 2



NP_001182234.1









1
MLKAAAKRPE LSGKNTISNN SDMAEVKSMF REVLPKQGPL FVEDIMTMVL CKPKLLPLKS






61
LTLEKLEKMH QAAQNTIRQQ EMAEKDQRQI TH











SEQ ID NO: 141



INTRAFLAGELLAR TRANSPORT 27 (IFT27), HOMOLOG ISOFORM 1



NP_001349932.1









1
MVKLAAKCIL AGDPAVGKTA LAQIFRSDGA HFQKSYTLTT GMDLVVKTVP VPDTGDSVEL






61
FIFDSAGKEL FSEMLDKLWE SPNVLCLVYD VTNEESFNNC SKWLEKARSQ APGISLPGVL





121
VGNKTDLAGR RAVDSAEARA WALGQGLECF ETSVKEMENF EAPFHCLAKQ FHQLYREKVE





181
VFRALA











SEQ ID NO: 142



INTRAFLAGELLAR TRANSPORT 27 (IFT27), HOMOLOG ISOFORM 2



NP_006851.1









1
MVKLAAKCIL ADPAVGKTAL AQIFRSDGAH FQKSYTLTTG MDLVVKTVPV PDTGDSVELF






61
IFDSAGKELF SEMLDKLWES PNVLCLVYDV TNEESFNNCS KWLEKARSQA PGISLPGVLV





121
GNKTDLAGRR AVDSAEARAW ALGQGLECFE TSVKEMENFE APFHCLAKQF HQLYREKVEV





181
FRALA











SEQ ID NO: 143



GUANYLATE CYCLASE ACTIVATOR 1A (GUCA1A)



EAX04084.1









1
MGNVMEGKSV EELSSTECHQ WYKKFMTECP SGQLTLYEFR QFFGLKNLSP SASQYVEQMF






61
ETFDFNKDGY IDFMEYVAAL SLVLKGKVEQ KLRWYFKLYD VDGNGCIDRD ELLTIIQAIR





121
AINPCSDTTM TAEEFTDTVF SKIDVNGDGE LSLEEFIEGV QKDQMLLDTL TRSLDLTRIV





181
RRLQNGEQDE EGADEAAEAA G











SEQ ID NO: 144



OPA1 MITOCHONDRIAL DYNAMIN LIKE GTPASE (OPA1);



AAH58013.1









1
MTEPKGKEHD DIFDKLKEAV KEESIKRHKW NDFAEDSLRV IQHNALEDRS ISDKQQWDAA






61
IYFMEEALQA RLKDTENAIE NMVGPDWKKR WLYWKNRTQE QCVHNETKNE LEKMLKCNEE





121
HPAYLASDEI TTVRKNLESR GVEVDPSLIK DTWHQVYRRH FLKTALNHCN LCRRGFYYYQ





181
RHFVDSELEC NDVVLFWRIQ RMLAITANTL RQQLTNTEVR RLEKNVKEVL EDFAEDGEKK





241
IKLLTGKRVQ LAEDLKKVRE IQEKLDAFIE ALHQEK











SEQ ID NO: 145



RP1 AXONEMAL MICROTUBULE ASSOCIATED (RP1)



AAA20120.1









1
MQKWFSAFDD AIIQRQWRAN PSRGGGGVSF TKEVDTNVAT GAPPRRQRVP GRACPWREPI






61
RGRRGARPGG GDAGGTPGET VRHCSAPEDP IFRFSSLHSY PFPGTIKSRD MSWKRHHLIP





121
ETFGVKRRRK RGPVESDPLR GEPGSARAAV SELMQLFPRG LFEDALPPIV LRSQVYSLVP





181
DRTVADRQLK ELQEQGEIRI VQLGFDLDAH GIIFTEDYRT RVLKACDGRP YAGAVQKFLA





241
SVLPACGDLS FQQDQMTQTF GFRDSEITHL VNAGVLTVRD AGSWWLAVPG AGRFIKYFVK





301
GRQAVLSMVR KAKYRELLLS ELLGRRAPVV VRLGLTYHVH DLIGAQLVDC ISTTSGTLLR





361
LPET











SEQ ID NO: 146



RP2 ACTIVATOR OF ARL3 GTPASE (RP2)



ANZ79619.1









1
MGCFFSKRRK ADKESRPENE EERPKQYSWD QREKVDPKDY MFSGLKDETV GRLPGTVAGQ






61
QFLIQDCENC NIYIFDHSAT VTIDDCTNCI IFLGPVKGSV FFRNCRDCKC TLACQQFRVR





121
DCRKLEVFLC CATQPIIESS SNIKFGCFQW YYPELAFQFK DAGLSIFNNT WSNIHDFTPV





181
SGELNWSLLP EDAVVQDYVP IPTTEELKAV RVSTEANRSI VPISRGQRQK SSDESCLVVL





241
FAGDYTIANA RKLIDEMVGK GFFLVQTKEV SMKAEDAQRV FREKAPDFLP LLNKGPVIAL





301
EFNGDGAVEV CQLIVNEIFN GTKMFVSESK ETASGDVDSF YNFADIQMGI











SEQ ID NO: 147



PERIPHERIN 2 (PRPH2)



NP_000313.2









1
MALLKVKFDQ KKRVKLAQGL WLMNWFSVLA GIIIFSLGLF LKIELRKRSD VMNNSESHFV






61
PNSLIGMGVL SCVFNSLAGK ICYDALDPAK YARWKPWLKP YLAICVLFNI ILFLVALCCF





121
LLRGSLENTL GQGLKNGMKY YRDTDTPGRC FMKKTIDMLQ IEFKCCGNNG FRDWFEIQWI





181
SNRYLDFSSK EVKDRIKSNV DGRYLVDGVP FSCCNPSSPR PCIQYQITNN SAHYSYDHQT





241
EELNLWVRGC RAALLSYYSS LMNSMGVVTL LIWLFEVTIT IGLRYLQTSL DGVSNPEESE





301
SESQGWLLER SVPETWKAFL ESVKKLGKGN QVEAEGADAG QAPEAG











SEQ ID NO: 148



PRE-MRNA PROCESSING FACTOR 31 (PRPF31)



AAI17390.1









1
MSLADELLAD LEEAAEEEEG GSYGEEEEEP AIEDVQEETQ LDLSGDSVKT IAKLWDSKMF






61
AEIMMKIEEY ISKQAKASEV MGPVEAAPEY RVIVDANNLT VEIENELNII HKFIRDKYSK





121
RFPELESLVP NALDYIRTVK ELGNSLDKCK NNENLQQILT NATIMVVSVT ASTTQGQQLS





181
EEELERLEEA CDMALELNAS KHRIYEYVES RMSFIAPNLS IIIGASTAAK IMGVAGGLTN





241
LSKMPACNIM LLGAQRKTLS GFSSTSVLPH TGYIYHSDIV QSLPPDLRRK AARLVAAKCT





301
LAARVDSFHE STEGKVGYEL KDEIERKFDK WQEPPPVKQV KPLPAPLDGQ RKKRGGRRYR





361
KMKERLGLTE IRKQANRMSF GEIEEDAYQE DLGFSLGHLG KSGSGRVRQT QVNEATKARI





421
SKTLQRTLQK QSVVYGGKST IRDRSSGTAS SVAFTPLQGL EIVNPQAAEK KVAEANQKYF





481
SSMAEFLKVK GEKSGLMST











SEQ ID NO: 149



PRE-MRNA PROCESSING FACTOR 31 (PRPF31), ISOFORM CRA_A



EAW72190.1









1
MSLADELLAD LEEAAEEEEG GSYGEEEEEP AIEDVQEETQ LDLSGDSVKT IAKLWDSKMF






61
AEIMMKIEEY ISKQAKASEV MGPVEAAPEY RVIVDANNLT VEIENELNII HKFIRDKYSK





121
RFPELESLVP NALDYIRTVK ELGNSLDKCK NNENLQQILT NATIMVVSVT ASTTQGQQLS





181
EEELERLEEA CDMALELNAS KHRIYEYVES RMSFIAPNLS IIIGASTAAK IMGVAGGLTN





241
LSKMPACNIM LLGAQRKTLS GFSSTSVLPH TGYIYHSDIV QSLPPDLRRK AARLVAAKCT





301
LAARVDSFHE STEGKVGYEL KDEIERKFDK WQEPPPVKQV KPLPAPLDGQ RKKRGGRRYR





361
KMKERLGLTE IRKQANRMSF GEIEEDAYQE DLGFSLGHLG KSGSGRVRQT QVNEATKARI





421
SKTLQRTLQK QSVVYGGKST IRDRSSGTAS SVAFTPLQGL EIVNPQAAEK KVAEANQKYF





481
SSMAEFLKVK GEKSGLMST











SEQ ID NO: 150



PRE-MRNA PROCESSING FACTOR 31 (PRPF31), ISOFORM CRA_A



EAW72191.1









1
MFAEIMMKIE EYISKQAKAS EVMGPVEAAP EYRVIVDANN LTVEIENELN IIHKFIRDKY






61
SKRFPELESL VPNALDYIRT VKELGNSLDK CKNNENLQQI LTNATIMVVS VTASTTQGQQ





121
LSEEELERLE EACDMALELN ASKHRIYEYV ESRMSFIAPN LSIIIGASTA AKIMGVAGGL





181
TNLSKMPACN IMLLGAQRKT LSGFSSTSVL PHTGYIYHSD IVQSLPPDLR RKAARLVAAK





241
CTLAARVDSF HESTEGKVGY ELKDEIERKF DKWQEPPPVK QVKPLPAPLD GQRKKRGGRR











SEQ ID NO: 151



PRE-MRNA PROCESSING FACTOR 8 (PRPF8)



AAH64370.1









1
MAGVFPYRGP GNPVPGPLAP LPDYMSEEKL QEKARKWQQL QAKRYAEKRK FGFVDAQKED






61
MPPEHVRKII RDHGDMTNRK FRHDKRVYLG ALKYMPHAVL KLLENMPMPW EQIRDVPVLY





121
HITGAISFVN EIPWVIEPVY ISQWGSMWIM MRREKRDRRH FKRMRFPPFD DEEPPLDYAD





181
NILDVEPLEA IQLELDPEED APVLDWFYDH QPLRDSRKYV NGSTYQHWQF TLPMMSTLYR





241
LANQLLTDLV DDNYFYLFDL KAFFTSKALN MAIPGGPKFE PLVRDINLQD EDWNEFNDIN





301
KIIIRQPIRT EYKIAFPYLY NNLPHHVHLT WYHTPNVVFI KTEDPDLPAF YFDPLINPIS





361
HRHSVKSQEP LPDDDEEFEL PEFVEPFLKD TPLYTDNTAN GIALLWAPRP FNLRSGRTRR





421
ALDIPLVKNW YREHCPAGQP VKVRVSYQKL LKYYVLNALK HRPPKAQKKR YLFRSFKATK





481
FFQSTKLDWV EVGLQVCRQG YNMLNLLIHR KNLNYLHLDY NFNLKPVKTL TTKERKKSRF





541
GNAFHLCREV LRLTKLVVDS HVQYRLGNVD AFQLADGLQY IFAHVGQLTG MYRYKYKLMR





601
QIRMCKDLKH LIYYRFNTGP VGKGPGCGFW AAGWRVWLFF MRGITPLLER WLGNLLARQF





661
EGRHSKGVAK TVTKQRVESH FDLELRAAVM HDILDMMPEG IKQNKARTIL QHLSEAWRCW





721
KANIPWKVPG LPTPIENMIL RYVKAKADWW TNTAHYNRER IRRGATVDKT VCKKNLGRLT





781
RLYLKAEQER QHNYLKDGPY ITAEEAVAVY TTTVHWLESR RFSPIPFPPL SYKHDTKLLI





841
LALERLKEAY SVKSRLNQSQ REELGLIEQA YDNPHEALSR IKRHLLTQRA FKEVGIEFMD





901
LYSHLVPVYD VEPLEKITDA YLDQYLWYEA DKRRLFPPWI KPADTEPPPL LVYKWCQGIN





961
NLQDVWETSE GECNVMLESR FEKMYEKIDL TLLNRLLRLI VDHNIADYMT AKNNVVINYK





1021
DMNHTNSYGI IRGLQFASFI VQYYGLVMDL LVLGLHRASE MAGPPQMPND FLSFQDIATE





1081
AAHPIRLFCR YIDRIHIFFR FTADEARDLI QRYLTEHPDP NNENIVGYNN KKCWPRDARM





1141
RLMKHDVNLG RAVFWDIKNR LPRSVTTVQW ENSFVSVYSK DNPNLLFNMC GFECRILPKC





1201
RTSYEEFTHK DGVWNLQNEV TKERTAQCFL RVDDESMQRF HNRVRQILMA SGSTIFTKIV





1261
NKWNTALIGL MTYFREAVVN TQELLDLLVK CENKIQTRIK IGLNSKMPSR FPPVVFYTPK





1321
ELGGLGMLSM GHVLIPQSDL RWSKQTDVGI THFRSGMSHE EDQLIPNLYR YIQPWESEFI





1381
DSQRVWAEYA LKRQEAIAQN RRLTLEDLED SWDRGIPRIN TLFQKDRHTL AYDKGWRVRT





1441
DFKQYQVLKQ NPFWWTHQRH DGKLWNLNNY RTDMIQALGG VEGILEHTLF KGTYFPTWEG





1501
LFWEKASGFE ESMKWKKLTN AQRSGLNQIP NRRFTLWWSP TINRANVYVG FQVQLDLTGI





1561
FMHGKIPTLK ISLIQIFRAH LWQKIHESIV MDLCQVFDQE LDALEIETVQ KETIHPRKSY





1621
KMNSSCADIL LFASYKWNVS RPSLLADSKD VMDSTTTQKY WIDIQLRWGD YDSHDIERYA





1681
RAKFLDYTTD NMSIYPSPTG VLIAIDLAYN LHSAYGNWFP GSKPLIQQAM AKIMKANPAL





1741
YVLRERIRKG LQLYSSEPTE PYLSSQNYGE LFSNQIIWFV DDINVYRVII HKTFEGNLTT





1801
KPINGAIFIF NPRTGQLFLK IIHTSVWAGQ KRLGQLAKWK TAEEVAALIR SLPVEEQPKQ





1861
IIVTRKGMLD PLEVHLLDFP NIVIKGSELQ LPFQACLKVE KFGDLILKAT EPQMVLFNLY





1921
DDWLKTISSY TAFSRLILIL RALHVNNDRA KVILKPDKTT ITEPHHIWPT LTDEEWIKVE





1981
VQLKDLILAD YGKKNNVNVA SLTQSEIRDI ILGMEISAPS QQRQQIAEIE KQTKEQSQLT





2041
ATQTRTVNKH GDEIITSTTS NYETQTFSSK TEWRVRAISA ANLHLRTNHI YVSSDDIKET





2101
GYTYILPKNV LKKFICISDL RAQIAGYLYG VSPPDNPQVK EIRCIVMVPQ WGTHQTVHLP





2161
GQLPQHEYLK EMEPLGWIHT QPNESPQLSP QDVTTHAKIM ADNPSWDGEK TIIITCSFTP





2221
GSCTLTAYKL TPSGYEWGRQ NTDKGNNPKG YLPSHYERVQ MLLSDRFLGF FMVPAQSSWN





2281
YNFMGVRHDP NMKYELQLAN PKEFYHEVHR PSHFLNFALL QEGEVYSADR EDLYA











SEQ ID NO: 152



PRE-MRNA PROCESSING FACTOR 8 (PRPF8), ISOFORM CRA_A



EAW90588.1









1
MAGVFPYRGP GNPVPGPLAP LPDYMSEEKL QEKARKWQQL QAKRYAEKRK FGFVDAQKED






61
MPPEHVRKII RDHGDMTNRK FRHDKRVYLG ALKYMPHAVL KLLENMPMPW EQIRDVPVLY





121
HITGAISFVN EIPWVIEPVY ISQWGSMWIM MRREKRDRRH FKRMRFPPFD DEEPPLDYAD





181
NILDVEPLEA IQLELDPEED APVLDWFYDH QPLRDSRKYV NGSTYQRWQF TLPMMSTLYR





241
LANQLLTDLV DDNYFYLFDL KAFFTSKALN MAIPGGPKFE PLVRDINLQD EDWNEFNDIN





301
KIIIRQPIRT EYKIAFPYLY NNLPHHVHLT WYHTPNVVFI KTEDPDLPAF YFDPLINPIS





361
HRHSVKSQEP LPDDDEEFEL PEFVEPFLKD TPLYTDNTAN GIALLWAPRP FNLRSGRTRR





421
ALDIPLVKNW YREHCPAGQP VKVRVSYQKL LKYYVLNALK HRPPKAQKKR YLFRSFKATK





481
FFQSTKLDWV EVGLQVCRQG YNMLNLLIHR KNLNYLHLDY NFNLKPVKTL TTKERKKSRF





541
GNAFHLCREV LRLTKLVVDS HVQYRLGNVD AFQLADGLQY IFAHVGQLTG MYRYKYKLMR





601
QIRMCKDLKH LIYYRFNTGP VGKGPGCGFW AAGWRVWLFF MRGITPLLER WLGNLLARQF





661
EGRHSKGVAK TVTKQRVESH FDLELRAAVM HDILDMMPEG IKQNKARTIL QHLSEAWRCW





721
KANIPWKVPG LPTPIENMIL RYVKAKADWW TNTAHYNRER IRRGATVDKT VCKKNLGRLT





781
RLYLKAEQER QHNYLKDGPY ITAEEAVAVY TTTVHWLESR RFSPIPFPPL SYKHDTKLLI





841
LALERLKEAY SVKSRLNQSQ REELGLIEQA YDNPHEALSR IKRHLLTQRA FKEVGIEFMD





901
LYSHLVPVYD VEPLEKITDA YLDQYLWYEA DKRRLFPPWI KPADTEPPPL LVYKWCQGIN





961
NLQDVWETSE GECNVMLESR FEKMYEKIDL TLLNRLLRLI VDHNIADYMT AKNNVVINYK





1021
DMNHTNSYGI IRGLQFASFI VQYYGLVMDL LVLGLHRASE MAGPPQMPND FLSFQDIATE





1081
AAHPIRLFCR YIDRIHIFFR FTADEARDLI QRYLTEHPDP NNENIVGYNN KKCWPRDARM





1141
RLMKHDVNLG RAVFWDIKNR LPRSVTTVQW ENSFVSVYSK DNPNLLFNMC GFECRILPKC





1201
RTSYEEFTHK DGVWNLQNEV TKERTAQCFL RVDDESMQRF HNRVRQILMA SGSTIFTKIV





1261
NKWNTALIGL MTYFREAVVN TQELLDLLVK CENKIQTRIK IGLNSKMPSR FPPVVFYTPK





1321
ELGGLGMLSM GHVLIPQSDL RWSKQTDVGI THFRSGMSHE EDQLIPNLYR YIQPWESEFI





1381
DSQRVWAEYA LKRQEAIAQN RRLTLEDLED SWDRGIPRIN TLFQKDRHTL AYDKGWRVRT





1441
DFKQYQVLKQ NPFWWTHQRH DGKLWNLNNY RTDMIQALGG VEGILEHTLF KGTYFPTWEG





1501
LFWEKASGFE ESMKWKKLTN AQRSGLNQIP NRRFTLWWSP TINRANVYVG FQVQLDLTGI





1561
FMHGKIPTLK ISLIQIFRAH LWQKIHESIV MDLCQVFDQE LDALEIETVQ KETIHPRKSY





1621
KMNSSCADIL LFASYKWNVS RPSLLADSKD VMDSTTTQKY WIDIQLRWGD YDSHDIERYA





1681
RAKFLDYTTD NMSIYPSPTG VLIAIDLAYN LHSAYGNWFP GSKPLIQQAM AKIMKANPAL





1741
YVLRERIRKG LQLYSSEPTE PYLSSQNYGE LFSNQIIWFV DDINVYRVII HKTFEGNLTT





1801
KPINGAIFIF NPRTGQLFLK IIHTSVWAGQ KRLGQLAKWK TAEEVAALIR SLPVEEQPKQ





1861
IIVTRKGMLD PLEVHLLDFP NIVIKGSELQ LPFQACLKVE KFGDLILKAT EPQMVLFNLY





1921
DDWLKTISSY TAFSRLILIL RALHVNNDRA KVILKPDKTT ITEPHHIWPT LTDEEWIKVE





1981
VQLKDLILAD YGKKNNVNVA SLTQSEIRDI ILGMEISAPS QQRQQIAEIE KQTKEQSQLT





2041
ATQTRTVNKH GDEIITSTTS NYETQTFSSK TEWRVRAISA ANLHLRTNHI YVSSDDIKET





2101
GYTYILPKNV LKKFICISDL RAQVSKWTQL GHSVCPTHFV PKTQT











SEQ ID NO: 153



PRE-MRNA PROCESSING FACTOR 8 (PRPF8), ISOFORM CRA_B



EAW90589.1









1
MAGVFPYRGP GNPVPGPLAP LPDYMSEEKL QEKARKWQQL QAKRYAEKRK FGFVDAQKED






61
MPPEHVRKII RDHGDMTNRK FRHDKRVYLG ALKYMPHAVL KLLENMPMPW EQIRDVPVLY





121
HITGAISFVN EIPWVIEPVY ISQWGSMWIM MRREKRDRRH FKRMRFPPFD DEEPPLDYAD





181
NILDVEPLEA IQLELDPEED APVLDWFYDH QPLRDSRKYV NGSTYQRWQF TLPMMSTLYR





241
LANQLLTDLV DDNYFYLFDL KAFFTSKALN MAIPGGPKFE PLVRDINLQD EDWNEFNDIN





301
KIIIRQPIRT EYKIAFPYLY NNLPHHVHLT WYHTPNVVFI KTEDPDLPAF YFDPLINPIS





361
HRHSVKSQEP LPDDDEEFEL PEFVEPFLKD TPLYTDNTAN GIALLWAPRP FNLRSGRTRR





421
ALDIPLVKNW YREHCPAGQP VKVRVSYQKL LKYYVLNALK HRPPKAQKKR YLFRSFKATK





481
FFQSTKLDWV EVGLQVCRQG YNMLNLLIHR KNLNYLHLDY NFNLKPVKTL TTKERKKSRF





541
GNAFHLCREV LRLTKLVVDS HVQYRLGNVD AFQLADGLQY IFAHVGQLTG MYRYKYKLMR





601
QIRMCKDLKH LIYYRFNTGP VGKGPGCGFW AAGWRVWLFF MRGITPLLER WLGNLLARQF





661
EGRHSKGVAK TVTKQRVESH FDLELRAAVM HDILDMMPEG IKQNKARTIL QHLSEAWRCW





721
KANIPWKVPG LPTPIENMIL RYVKAKADWW TNTAHYNRER IRRGATVDKT VCKKNLGRLT





781
RLYLKAEQER QHNYLKDGPY ITAEEAVAVY TTTVHWLESR RFSPIPFPPL SYKHDTKLLI





841
LALERLKEAY SVKSRLNQSQ REELGLIEQA YDNPHEALSR IKRHLLTQRA FKEVGIEFMD





901
LYSHLVPVYD VEPLEKITDA YLDQYLWYEA DKRRLFPPWI KPADTEPPPL LVYKWCQGIN





961
NLQDVWETSE GECNVMLESR FEKMYEKIDL TLLNRLLRLI VDHNIADYMT AKNNVVINYK





1021
DMNHTNSYGI IRGLQFASFI VQYYGLVMDL LVLGLHRASE MAGPPQMPND FLSFQDIATE





1081
AAHPIRLFCR YIDRIHIFCR FTADEARDLI QRYLTEHPDP NNENIVGYNN KKCWPRDARM





1141
RLMKHDVNLG RAVFWDIKNR LPRSVTTVQW ENSFVSVYSK DNPNLLFNMC GFECRILPKC





1201
RTSYEEFTHK DGVWNLQNEV TKERTAQCFL RVDDESMQRF HNRVRQILMA SGSTIFTKIV





1261
NKWNTALIGL MTYFREAVVN TQELLDLLVK CENKIQTRIK IGLNSKMPSR FPPVVFYTPK





1321
ELGGLGMLSM GHVLIPQSDL RWSKQTDVGI THFRSGMSHE EDQLIPNLYR YIQPWESEFI





1381
DSQRVWAEYA LKRQEAIAQN RRLTLEDLED SWDRGIPRIN TLFQKDRHTL AYDKGWRVRT





1441
DFKQYQVLKQ NPFWWTHQRH DGKLWNLNNY RTDMIQALGG VEGILEHTLF KGTYFPTWEG





1501
LFWEKASGFE ESMKWKKLTN AQRSGLNQIP NRRFTLWWSP TINRANVYVG FQVQLDLTGI





1561
FMHGKIPTLK ISLIQIFRAH LWQKIHESIV MDLCQVFDQE LDALEIETVQ KETIHPRKSY





1621
KMNSSCADIL LFASYKWNVS RPSLLADSKD VMDSTTTQKY WIDIQLRWGD YDSHDIERYA





1681
RAKFLDYTTD NMSIYPSPTG VLIAIDLAYN LHSAYGNWFP GSKPLIQQAM AKIMKANPAL





1741
YVLRERIRKG LQLYSSEPTE PYLSSQNYGE LFSNQIIWFV DDINVYRVII HKTFEGNLTT





1801
KPINGAIFIF NPRTGQLFLK IIHTSVWAGQ KRLGQLAKWK TAEEVAALIR SLPVEEQPKQ





1861
IIVTRKGMLD PLEVHLLDFP NIVIKGSELQ LPFQACLKVE KFGDLILKAT EPQMVLFNLY





1921
DDWLKTISSY TAFSRLILIL RALHVNNDRA KVILKPDKTT ITEPHHIWPT LTDEEWIKVE





1981
VQLKDLILAD YGKKNNVNVA SLTQSEIRDI ILGMEISAPS QQRQQIAEIE KQTKEQSQLT





2041
ATQTRTVNKH GDEIITSTTS NYETQTFSSK TEWRVRAISA ANLHLRTNHI YVSSDDIKET





2101
GYTYILPKNV LKKFICISDL RAQIAGYLYG VSPPDNPQVK EIRCIVMVPQ WGTHQTVHLP





2161
GQLPQHEYLK EMEPLGWIHT QPNESPQLSP QDVTTHAKIM ADNPSWDGEK TIIITCSFTP





2221
GSCTLTAYKL TPSGYEWGRQ NTDKGNNPKG YLPSHYERVQ MLLSDRFLGF FMVPAQSSWN





2281
YNFMGVRHDP NMKYELQLAN PKEFYHEVHR PSHFLNFALL QEGEVYSADR EDLYA











SEQ ID NO: 154



PRE-MRNA PROCESSING FACTOR 8 (PRPF8), ISOFORM CRA_C



EAW90590.1









1
MMSTLYRQNT DKGNNPKGYL PSHYERVQML LSDRFLGFFM VPAQSSWNYN FMGVRHDPNM






61
KYELQLANPK EFYHEVHRPS HFLNFALLQE GEVYSADRED LYA











SEQ ID NO: 155



PRE-MRNA PROCESSING FACTOR 8 (PRPF8), ISOFORM CRA_D



EAW90591.1









1
MAGVFPYRGP GNPVPGPLAP LPDYMSEEKL QEKARKWQQL QAKRYAEKRK FGFVDAQKED






61
MPPEHVRKII RDHGDMTNRK FRHDKRVYLG ALKYMPHAVL KLLENMPMPW EQIRDVPVLY





121
HITGAISFVN EIPWVIEPVY ISQWGSMWIM MRREKRDRRH FKRMRFPPFD DEEPPLDYAD





181
NILDVEPLEA IQLELDPEED APVLDWFYDH QPLRDSRKYV NGSTYQRWQF TLPMMSTLYR





241
LANQLLTDLV DDNYFYLFDL KAFFTSKALN MAIPGGPKFE PLVRDINLQD EDWNEFNDIN





301
KIIIRQPIRT EYKIAFPYLY NNLPHHVHLT WYHTPNVVFI KTEDPDLPAF YFDPLINPIS





361
HRHSVKSQEP LPDDDEEFEL PEFVEPFLKD TPLYTDNTAN GIALLWAPRP FNLRSGRTRR





421
ALDIPLVKNW YREHCPAGQP VKVRVSYQKL LKYYVLNALK HRPPKAQKKR YLFRSFKATK





481
FFQSTKLDWV EVGLQVCRQG YNMLNLLIHR KNLNYLHLDY NFNLKPVKTL TTKERKKSRF





541
GNAFHLCREV LRLTKLVVDS HVQYRLGNVD AFQLADGLQY IFAHVGQLTG MYRYKYKLMR





601
QIRMCKDLKH LIYYRFNTGP VGKGPGCGFW AAGWRVWLFF MRGITPLLER WLGNLLARQF





661
EGRHSKGVAK TVTKQRVESH FDLELRAAVM HDILDMMPEG IKQNKARTIL QHLSEAWRCW





721
KANIPWKVPG LPTPIENMIL RYVKAKADWW TNTAHYNRER IRRGATVDKT VCKKNLGRLT





781
RLYLKAEQER QHNYLKDGPY ITAEEAVAVY TTTVHWLESR RFSPIPFPPL SYKHDTKLLI





841
LALERLKEAY SVKSRLNQSQ REELGLIEQA YDNPHEALSR IKRHLLTQRA FKEVGIEFMD





901
LYSHLVPVYD VEPLEKITDA YLDQYLWYEA DKRRLFPPWI KPADTEPPPL LVYKWCQGIN





961
NLQDVWETSE GECNVMLESR FEKMYEKIDL TLLNRLLRLI VDHNIADYMT AKNNVVINYK





1021
DMNHTNSYGI IRGLQFASFI VQYYGLVMDL LVLGLHRASE MAGPPQMPND FLSFQDIATE





1081
AAHPIRLFCR YIDRIHIFFR FTADEARDLI QRYLTEHPDP NNENIVGYNN KKCWPRDARM





1141
RLMKHDVNLG RAVFWDIKNR LPRSVTTVQW ENSFVSVYSK DNPNLLFNMC GFECRILPKC





1201
RTSYEEFTHK DGVWNLQNEV TKERTAQCFL RVDDESMQRF HNRVRQILMA SGSTIFTKIV





1261
NKWNTALIGL MTYFREAVVN TQELLDLLVK CENKIQTRIK IGLNSKMPSR FPPVVFYTPK





1321
ELGGLGMLSM GHVLIPQSDL RWSKQTDVGI THFRSGMSHE EDQLIPNLYR YIQPWESEFI





1381
DSQRVWAEYA LKRQEAIAQN RRLTLEDLED SWDRGIPRIN TLFQKDRHTL AYDKGWRVRT





1441
DFKQYQVLKQ NPFWWTHQRH DGKLWNLNNY RTDMIQALGG VEGILEHTLF KGTYFPTCEQ





1501
RSGKSDPEAR QDYYYRTTPH LAHSD











SEQ ID NO: 156



PRE-MRNA PROCESSING FACTOR 8 (PRPF8), ISOFORM CRA_E



EAW90592.1









1
MEISAPSQQR QQIAEIEKQT KEQSQLTATQ TRTVNKHGDE IITSTISNYE TQTFSSKTEW






61
RVRAISAANL HLRTNHIYVS SDDIKETGYT YILPKNVLKK FICISDLRAQ VSKWTQLGHS





121
VCPTHFVPKT QT











SEQ ID NO: 157



PRE-MRNA PROCESSING FACTOR 8 (PRPF8), ISOFORM CRA_F



EAW90593.1









1
MAGVFPYRGP GNPVPGPLAP LPDYMSEEKL QEKARKWQQL QAKRYAEKRK FGFVDAQKED






61
MPPEHVRKII RDHGDMTNRK FRHDKRVYLG ALKYMPHAVL KLLENMPMPW EQIRDVPVLY





121
HITGAISFVN EIPWVIEPVY ISQWGSMWIM MRREKRDRRH FKRMRFPPFD DEEPPLDYAD





181
NILDVEPLEA IQLELDPEED APVLDWFYDH QPLRDSRKYV NGSTYQRWQF TLPMMSTLYR





241
LANQLLTDLV DDNYFYLFDL KAFFTSKALN MAIPGGPKFE PLVRDINLQD EDWNEFNDIN





301
KIIIRQPIRT EYKIAFPYLY NNLPHHVHLT WYHTPNVVFI KTEDPDLPAF YFDPLINPIS





361
HRHSVKSQEP LPDDDEEFEL PEFVEPFLKD TPLYTDNTAN GIALLWAPRP FNLRSGRTRR





421
ALDIPLVKNW YREHCPAGQP VKVRVSYQKL LKYYVLNALK HRPPKAQKKR YLFRSFKATK





481
FFQSTKLDWV EVGLQVCRQG YNMLNLLIHR KNLNYLHLDY NFNLKPVKTL TTKERKKSRF





541
GNAFHLCREV LRLTKLVVDS HVQYRLGNVD AFQLADGLQY IFAHVGQLTG MYRYKYKLMR





601
QIRMCKDLKH LIYYRFNTGP VGKGPGCGFW AAGWRVWLFF MRGITPLLER WLGNLLARQF





661
EGRHSKGVAK TVTKQRVESH FDLELRAAVM HDILDMMPEG IKQNKARTIL QHLSEAWRCW





721
KANIPWKVPG LPTPIENMIL RYVKAKADWW TNTAHYNRER IRRGATVDKT VCKKNLGRLT





781
RLYLKAEQER QHNYLKDGPY ITAEEAVAVY TTTVHWLESR RFSPIPFPPL SYKHDTKLLI





841
LALERLKEAY SVKSRLNQSQ REELGLIEQA YDNPHEALSR IKRHLLTQRA FKEVGIEFMD





901
LYSHLVPVYD VEPLEKITDA YLDQYLWYEA DKRRLFPPWI KPADTEPPPL LVYKWCQGIN





961
NLQDVWETSE GECNVMLESR FEKMYEKIDL TLLNRLLRLI VDHNIADYMT AKNNVVINYK





1021
DMNHTNSYGI IRGLQFASFI VQYYGLVMDL LVLGLHRASE MAGPPQMPND FLSFQDIATE





1081
AAHPIRLFCR YIDRIHIFFR FTADEARDLI QRYLTEHPDP NNENIVGYNN KKCWPRDARM





1141
RLMKHDVNLG RAVFWDIKNR LPRSVTTVQW ENSFVSVYSK DNPNLLFNMC GFECRILPKC





1201
RTSYEEFTHK DGVWNLQNEV TKERTAQCFL RVDDESMQRF HNRVRQILMA SGSTIFTKIV





1261
NKWNTALIGL MTYFREAVVN TQELLDLLVK CENKIQTRIK IGLNSKMPSR FPPVVFYTPK





1321
ELGGLGMLSM GHVLIPQSDL RWSKQTDVGI THFRSGMSHE EDQLIPNLYR YIQPWESEFI





1381
DSQRVWAEYA LKRQEAIAQN RRLTLEDLED SWDRGIPRIN TLFQKDRHTL AYDKGWRVRT





1441
DFKQYQVLKQ NPFWWTHQRH DGKLWNLNNY RTDMIQALGG VEGILEHTLF KGTYFPTWEG





1501
LFWEKASGFE ESMKWKKLTN AQRSGLNQIP NRRFTLWWSP TINRANVYVG FQVQLDLTGI





1561
FMHGKIPTLK ISLIQIFRAH LWQKIHESIV MDLCQVFDQE LDALEIETVQ KETIHPRKSY





1621
KMNSSCADIL LFASYKWNVS RPSLLADSKD VMDSTTTQKY WIDIQLRWGD YDSHDIERYA





1681
RAKFLDYTTD NMSIYPSPTG VLIAIDLAYN LHSAYGNWFP GSKPLIQQAM AKIMKANPAL





1741
YVLRERIRKG LQLYSSEPTE PYLSSQNYGE LFSNQIIWFV DDINVYRVII HKTFEGNLTT





1801
KPINGAIFIF NPRTGQLFLK IIHTSVWAGQ KRLGQLAKWK TAEEVAALIR SLPVEEQPKQ





1861
IIVTRKGMLD PLEVHLLDFP NIVIKGSELQ LPFQACLKVE KFGDLILKAT EPQMVLFNLY





1921
DDWLKTISSY TAFSRLILIL RALHVNNDRA KVILKPDKTT ITEPHHIWPT LTDEEWIKVE





1981
VQLKDLILAD YGKKNNVNVA SLTQSEIRDI ILGMEISAPS QQRQQIAEIE KQTKEQSQLT





2041
ATQTRTVNKH GDEIITSTTS NYETQTFSSK TEWRVRAISA ANLHLRTNHI YVSSDDIKET





2101
GYTYILPKNV LKKFICISDL RAQIAGYLYG VSPPDNPQVK EIRCIVMVPQ WGTHQTVHLP





2161
GQLPQHEYLK EMEPLGWIHT QPNESPQLSP QDVTTHAKIM ADNPSWDGEK TIIITCSFTP





2221
GSCTLTAYKL TPSGYEWGRQ NTDKGNNPKG YLPSHYERVQ MLLSDRFLGF FMVPAQSSWN





2281
YNFMGVRHDP NMKYELQLAN PKEFYHEVHR PSHFLNFALL QEGEVYSADR EDLYA











SEQ ID NO: 158



PRE-MRNA PROCESSING FACTOR 8 (PRPF8), ISOFORM CRA_G



EAW90594.1









1
MAGVFPYRGP GNPVPGPLAP LPDYMSEEKL QEKARKWQQL QAKRYAEKRK FGFVDAQKED






61
MPPEHVRKII RDHGDMTNRK FRHDKRVYLG ALKYMPHAVL KLLENMPMPW EQIRDVPVLY





121
HITGAISFVN EIPWVIEPVY ISQWGSMWIM MRREKRDRRH FKRMRFPPFD DEEPPLDYAD





181
NILDVEPLEA IQLELDPEED APVLDWFYDH QPLRDSRKYV NGSTYQRWQF TLPMMMSPPM





241
PRSWLTTHLG MARRPLSSHA ASRQAPVH











SEQ ID NO: 159



EYES SHUT HOMOLOG (EYS)



CAR64275.1









1
MTDKSIVILS LMVFHSSFIN GKTCRRQLVE EWHPQPSSYV VNWILTENIC LDFYRDCWFL






61
GVNTKIDTSG NQAVPQICPL QIQLGDILVI SSEPSLQFPE INLMNVSETS FVGCVQNTTT





121
EDQLLFGCRL KGMHTVNSKW LSVGTHYFIT VMASGPSPCP LGLRLNVTVK QQFCQESLSS





181
EFCSGHGKCL SEAWSKTYSC HCQPPFSGKY CQELDACSFK PCKNNGSCIN KRENWDEQAY





241
ECVCHPPFTG KNCSEIIGQC QPHVCFHGNC SNITSNSFIC ECDEQFSGPF CEVSAKPCVS





301
LLFWKRGICP NSSSAYTYEC PKGSSSQNGE TDVSEFSLVP CQNGTDCIKI SNDVMCICSP





361
IFTDLLCKSI QTSCESFPLR NNATCKKCEK DYPCSCISGF TEKNCEKAID HCKLLSINCL





421
NEEWCFNIIG RFKYVCIPGC TKNPCWFLKN VYLIHQHLCY CGVTFHGICQ DKGPAQFEYV





481
WQLGFAGSEG EKCQGVIDAY FFLAANCTED ATYVNDPEDN NSSCWFPHEG TKEICANGCS





541
CLSEEDSQEY RYLCFLRWAG NMYLENTTDD QENECQHEAV CKDEINRPRC SCSLSYIGRL





601
CVVNVDYCLG NHSISVHGLC LALSHNCNCS GLQRYERNIC EIDTEDCKSA SRKNGTTSTH





661
LRGYFFRKCV PGFKGTQCEI DIDECASHPC KNGATCIDQP GNYFCQCVPP FKVVDGFSCL





721
CNPGYVGIRC EQDIDDCILN ACEHNSTCKD LHLSYQCVCL SDWEGNFCEQ ESNECKMNPC





781
KNNSTCTDLY KSYRCECTSG WTGQNCSEEI NECDSDPCMN GGLCHESTIP GQFVCLCPPL





841
YTGQFCHQRY NLCDLLHNPC RNNSTCLALV DANQHCICRE EFEGKNCEID VKDCLFLSCQ





901
DYGDCEDMVN NFRCICRPGF SGSLCEIEIN ECSSEPCKNN GTCVDLTNRF FCNCEPEYHG





961
PFCELDVNKC KISPCLDEEN CVYRTDGYNC LCAPGYTGIN CEINLDECLS EPCLHDGVCI





1021
DGINHYTCDC KSGFFGTHCE TNANDCLSNP CLHGRYTELI NEYPCSCDAD GTSTQCKIKI





1081
NDCTSIPCMN EGFCQKSAHG FICICPRGYT GAYCEKSIDN CAEPELNSVI CLNGGICVDG





1141
PGHTFDCRCL PGFSGQFCEI NINECSSSPC LHGADCEDHI NGHVCKCQPG WSGHHCENEL





1201
ECIPNSCVHE LCMENEPGST CLCTPGFMTC SIGLLCGDEI RRITCLTPIF QRTDPISTQT





1261
YTIPPSETLV SSFPSIKATR IPAIMDTYPV DQGPKQTGIV KHDILPTTGL ATLRISTPLE





1321
SYLLQELIVT RELSAKHSLL SSADVSSSRF LNFGIRDPAQ IVQDKTSVSH MPIRTSAATL





1381
GFFFPDRRAR TPFIMSSLMS DFIFPTQSLL FENCQTVALS ATPTTSVIRS IPGADIELNR





1441
QSLLSRGFLL IAASISATPV VSRGAQEDIE EYSADSLISR REHWRLLSPS MSPIFPAKVI





1501
ISKQVTILNS SALHRFSTKA FNPSEYQAIT EASSNQRLTN IKSQAADSLR ELSQTCATCS





1561
MTEIKSSREF SDQVLHSKQS HFYETFWMNS AILASWYALM GAQTITSGHS FSSATEITPS





1621
VAFTEVPSLF PSKKSAKRTI LSSSLEESIT LSSNLDVNLC LDKTCLSIVP SQTISSDLMN





1681
SDLTSKMTTD ELSVSENILK LLKIRQYGIT MGPTEVLNQE SLLDMEKSKG SHTLFKLHPS





1741
DSSLDFELNL QIYPDVTLKT YSEITHANDF KNNLPPLTGS VPDFSEVTTN VAFYTVSATP





1801
ALSIQTSSSM SVIRPDWPYF TDYMTSLKKE VKTSSEWSKW ELQPSVQYQE FPTASRHLPF





1861
TRSLTLSSLE SILAPQRLMI SDFSCVRYYG DSYLEFQNVA LNPQNNISLE FQTFSSYGLL





1921
LHVKQDSNLV DGFFIQLFIE NGTLKYHFYC PGEAKFKSIN TTVRVDNGQK YTLLIRQELD





1981
PCNAELTILG RNTQICESIN HVLGKPLPKS GSVFIGGFPD LHGKIQMPVP VKNFTGCIEV





2041
IEINNWRSFI PSKAVKNYHI NNCRSQGFML SPTASFVDAS DVTQGVDTMW TSVSPSVAAP





2101
SVCQQDVCHN GGTCHAIFLS SGIVSFQCDC PLHFTGRFCE KDAGLFFPSF NGNSYLELPF





2161
LKFVLEKEHN RTVTIYLTIK TNSLNGTILY SNGNNCGKQF LHLFLVEGRP SVKYGCGNSQ





2221
NILTVSANYS INTNAFTPIT IRYTTPVGSP GVVCMIEMTA DGKPPVQKKD TEISHASQAY





2281
FESMFLGHIP ANVQIHKKAG PVYGFRGCIL DLQVNNKEFF IIDEARHGKN IENCHVPWCA





2341
HHLCRNNGTC ISDNENLFCE CPRLYSGKLC QFASCENNPC GNGATCVPKS GTDIVCLCPY





2401
GRSGPLCTDA INITQPRFSG TDAFGYTSFL AYSRISDISF RYEFHLKFQL ANNHSALQNN





2461
LIFFTEQKGH GLNGDDFLAV GLLNGSVVYS YNLGSGIASI RSEPLNLSLG VHTVHLGKFF





2521
QEGWLKVDDH KNKSIIAPGR LVGLNVFSQF YVGGYSEYTP DLLPNGADFK NGFQGCIFTL





2581
QVRTEKDGHF RGLGNPEGHP NAGRSVGQCH ASPCSLMKCG NGGTCIESGT SVYCNCTTGW





2641
KGSFCTETVS TCDPEHDPPH HCSRGATCIS LPHGYTCFCP LGTTGIYCEQ ALILIVILEK





2701
PKPAERKVKK EALSISDPSF RSNELSWMSF ASFHVRKKTH IQLQFQPLAA DGILFYAAQH





2761
LKAQSGDFLC ISLVNSSVQL RYNLGDRTII LETLQKVTIN GSTWHIIKAG RVGAEGYLDL





2821
DGINVTEKAS TKMSSLDTNT DFYIGGVSSL NLVNPMAIEN EPVGFQGCIR QVIINNQELQ





2881
LTEFGAKGGS NVGDCDGTAC GYNTCRNGGE CTVNGTTFSC RCLPDWAGNT CNQSVSCLNN





2941
LCLHQSLCIP DQSFSYSCLC TLGWVGRYCE NKTSFSTAKF MGNSYIKYID PNYRMRNLQF





3001
TTISLNFSTT KTEGLIVWMG IAQNEENDFL AIGLHNQTLK IAVNLGERIS VPMSYNNGTF





3061
CCNKWHHVVV IQNQTLIKAY INNSLILSED IDPHKNFVAL NYDGICYLGG FEYGRKVNIV





3121
TQEIFKTNFV GKIKDVVFFQ EPKNIELIKL EGYNVYDGDE QNEVT











SEQ ID NO: 160



FAM161 CENTROSOMAL PROTEIN A (FAM161A), ISOFORM 1



NP_001188472.1









1
MATSHRVAKL VASSLQTPVN PITGARVAQY EREDPLKALA AAEAILEDEE EEKVAQPAGA






61
SADLNTSFSG VDEHAPISYE DFVNFPDIHH SNEEYFKKVE ELKAAHIETM AKLEKMYQDK





121
LHLKEVQPVV IREDSLSDSS RSVSEKNSYH PVSLMTSFSE PDLGQSSSLY VSSSEEELPN





181
LEKEYPRKNR MMTYAKELIN NMWTDFCVED YIRCKDTGFH AAEKRRKKRK EWVPTITVPE





241
PFQMMIREQK KKEESMKSKS DIEMVHKALK KQEEDPEYKK KFRANPVPAS VFLPLYHDLV





301
KQKEERRRSL KEKSKEALLA SQKPFKFIAR EEQKRAAREK QLRDFLKYKK KTNRFKARPI





361
PRSTYGSTTN DKLKEEELYR NLRTQLRAQE HLQNSSPLPC RSACGCRNPR CPEQAVKLKC





421
KHKVRCPTPD FEDLPERYQK HLSEHKSPKL LTVCKPFDLH ASPHASIKRE KILADIEADE





481
ENLKETRWPY LSPRRKSPVR CAGVNPVPCN CNPPVPTVSS RGREQAVRRS LEEKKMLEEE





541
RNRILTKQKQ RMKELQKLLT TRAKAYDSHQ SLAQISKSRV KCLRKSEKER MREYQRELEE





601
REEKLKKRPL LFERVAQKNA RMAAEKHYSN TLKALGISDE FVSKKGQSGK VLEYFNNQET





661
KSVTEDKESF NEEEKIEERE NGEENYFIDT NSQDSYKEKD EANEESEEEK SVEESH











SEQ ID NO: 161



FAM161 CENTROSOMAL PROTEIN A (FAM161A), ISOFORM 2



NP_115556.2









1
MATSHRVAKL VASSLQTPVN PITGARVAQY EREDPLKALA AAEAILEDEE EEKVAQPAGA






61
SADLNTSFSG VDEHAPISYE DFVNFPDIHH SNEEYFKKVE ELKAAHIETM AKLEKMYQDK





121
LHLKEVQPVV IREDSLSDSS RSVSEKNSYH PVSLMTSFSE PDLGQSSSLY VSSSEEELPN





181
LEKEYPRKNR MMTYAKELIN NMWTDFCVED YIRCKDTGFH AAEKRRKKRK EWVPTITVPE





241
PFQMMIREQK KKEESMKSKS DIEMVHKALK KQEEDPEYKK KFRANPVPAS VFLPLYHDLV





301
KQKEERRRSL KEKSKEALLA SQKPFKFIAR EEQKRAAREK QLRDFLKYKK KTNRFKARPI





361
PRSTYGSTTN DKLKEEELYR NLRTQLRAQE HLQNSSPLPC RSACGCRNPR CPEQAVKLKC





421
KHKVRCPTPD FEDLPERYQK HLSEHKSPKL LTVCKPFDLH ASPHASIKRE KILADIEADE





481
ENLKETRWPY LSPRRKSPVR CAGVNPVPCN CNPPVPTVSS RGREQAVRKS EKERMREYQR





541
ELEEREEKLK KRPLLFERVA QKNARMAAEK HYSNTLKALG ISDEFVSKKG QSGKVLEYFN





601
NQETKSVTED KESFNEEEKI EERENGEENY FIDTNSQDSY KEKDEANEES EEEKSVEESH











SEQ ID NO: 162



MER PROTO-ONCOGENE, TYROSINE KINASE (MERTK);



Q12866.2









1
MGPAPLPLLL GLFLPALWRR AITEAREEAK PYPLFPGPFP GSLQTDHTPL LSLPHASGYQ






61
PALMFSPTQP GRPHTGNVAI PQVTSVESKP LPPLAFKHTV GHIILSEHKG VKFNCSISVP





121
NIYQDTTISW WKDGKELLGA HHAITQFYPD DEVTAIIASF SITSVQRSDN GSYICKMKIN





181
NEEIVSDPIY IEVQGLPHFT KQPESMNVTR NTAFNLTCQA VGPPEPVNIF WVQNSSRVNE





241
QPEKSPSVLT VPGLTEMAVF SCEAHNDKGL TVSKGVQINI KAIPSPPTEV SIRNSTAHSI





301
LISWVPGFDG YSPFRNCSIQ VKEADPLSNG SVMIFNISAL PHLYQIKQLQ ALANYSIGVS





361
CMNEIGWSAV SPWILASTTE GAPSVAPLNV TVFLNESSDN VDIRWMKPPT KQQDGELVGY





421
RISHVWQSAG ISKELLEEVG QNGSRARISV QVHNATCTVR IAAVTRGGVG PFSDPVKIFI





481
PAHGWVDYAP SSTPAPGNAD PVLIIFGCFC GFILIGLILY ISLAIRKRVQ ETKFGNAFTE





541
EDSELVVNYI AKKSFCRRAI ELTLHSLGVS EELQNKLEDV VIDRNLLILG KILGEGEFGS





601
VMEGNLKQED GTSLKVAVKT MKLDNSSQRE IEEFLSEAAC MKDFSHPNVI RLLGVCIEMS





661
SQGIPKPMVI LPFMKYGDLH TYLLYSRLET GPKHIPLQTL LKFMVDIALG MEYLSNRNFL





721
HRDLAARNCM LRDDMTVCVA DFGLSKKIYS GDYYRQGRIA KMPVKWIAIE SLADRVYTSK





781
SDVWAFGVTM WEIATRGMTP YPGVQNHEMY DYLLHGHRLK QPEDCLDELY EIMYSCWRTD





841
PLDRPTFSVL RLQLEKLLES LPDVRNQADV IYVNTQLLES SEGLAQGSTL APLDLNIDPD





901
SIIASCTPRA AISVVTAEVH DSKPHEGRYI LNGGSEEWED LTSAPSAAVT AEKNSVLPGE





961
RLVRNGVSWS HSSMLPLGSS LPDELLFADD SSEGSEVLM











SEQ ID NO: 163



PHOSPHODIESTERASE 6B (PDE6B)



AAH00249.1









1
MSLSEEQARS FLDQNPDFAR QYFGKKLSPE NVAAACEDGC PPDCDSLRDL CQVEESTALL






61
ELVQDMQESI NMERVVFKVL RRLCTLLQAD RCSLFMYRQR NGVAELATRL FSVQPDSVLE





121
DCLVPPDSEI VFPLDIGVVG HVAQTKKMVN VEDVAECPHF SSFADELTDY KTKNMLATPI





181
MNGKDVVAVI MAVNKLNGPF FTSEDEDVFL KYLNFATLYL KIYHLSYLHN CETRRGQVLL





241
WSANKVFEEL TDIERQFHKA FYTVRAYLNC ERYSVGLLDM TKEKEFFDVW SVLMGESQPY





301
SGPRTPDGRE IVFYKVIDYI LHGKEEIKVI PTPSADHWAL ASGLPSYVAE SGFICNIMNA





361
SADEMFKFQE GALDDSGWLI KNVLSMPIVN KKEEIVGVAT FYNRKDGKPF DEQDEVLMES





421
LTQFLGWSVM NTDTYDKMNK LENRKDIAQD MVLYHVKCDR DEIQLILPTR ARLGKEPADC





481
DEDELGEILK EELPGPTTFD IYEFHFSDLE CTELDLVKCG IQMYYELGVV RKFQIPQEVL





541
VRFLFSISKG YRRITYHNWR HGFNVAQTMF TLLMTGKLKS YYTDLEAFAM VTAGLCHDID





601
HRGTNNLYQM KSQNPLAKLH GSSILERHHL EFGKFLLSEE TLNIYQNLNR RQHDHVIHLM





661
DIAIIATDLA LYFKKRAMFQ KIVDESKNYQ DKKSWVEYLS LETTRKEIVM AMMMTACDLS





721
AITKPWEVQS KVALLVAAEF WEQGDLERTV LDQQPIPMMD RNKAAELPKL QVGFIDFVCT





781
FVYKEFSRFH EEILPMFDRL QNNRKEWKAL ADEYEAKVKA LEEKEEEERV AAKKGTEICN





841
GGPAPKSSTC CIL











SEQ ID NO: 164



PHOSPHODIESTERASE 6B (PDE6B), ISOFORM CRA_A



EAW82661.1









1
MSLSEEQARS FLDQNPDFAR QYFGKKLSPE NVAAACEDGC PPDCDSLRDL CQVEESTALL






61
ELVQDMQESI NMERVVFKVL RRLCTLLQAD RCSLFMYRQR NGVAELATRL FSVQPDSVLE





121
DCLVPPDSEI VFPLDIGVVG HVAQTKKMVN VEDVAECPHF SSFADELTDY KTKNMLATPI





181
MNGKDVVAVI MAVNKLNGPF FTSEDEDVFL KYLNFATLYL KIYHLSYLHN CETRRGQVLL





241
WSANKVFEEL TDIERQFHKA FYTVRAYLNC ERYSVGLLDM TKEKEFFDVW SVLMGESQPY





301
SGPRTPDGRE IVFYKVIDYI LHGKEEIKVI PTPSADHWAL ASGLPSYVAE SGFICNIMNR





361
SADEMFKFQE GALDDSGWLI KNVLSMPIVN KKEEIVGVAT FYNRKDGKPF DEQDEVLMES





421
LTQFLGWSVM NTDTYDKMNK LENRKDIAQD MVLYHVKCDR DEIQLILPTR ARLGKEPADC





481
DEDELGEILK EELPGPTTFD IYEFHFSDLE CTELDLVKCG IQMYYELGVV RKFQIPQEVL





541
VRFLFSISKG YRRITYHNWR HGFNVAQTMF TLLMTGKLKS YYTDLEAFAM VTAGLCHDID





601
HRGTNNLYQM KSQNPLAKLH GSSILERHHL EFGKFLLSEE TLNIYQNLNR RQHEHVIHLM





661
DIAIIATDLA LYFKKRAMFQ KIVDESKNYQ DKKSWVEYLS LETTRKEIVM AMMMTACDLS





721
AITKPWEVQS KVALLVAAEF WEQGDLERTV LDQQPIPMMD RNKAAELPKL QVGFIDFVCT





781
FVYKAILSFP RRDPAHVRPT AEQ











SEQ ID NO: 165



PHOSPHODIESTERASE 6B (PDE6B), ISOFORM CRA_B



EAW82662.1









1
MSLSEEQARS FLDQNPDFAR QYFGKKLSPE NVAAACEDGC PPDCDSLRDL CQVEESTALL






61
ELVQDMQESI NMERVVFKVL RRLCTLLQAD RCSLFMYRQR NGVAELATRL FSVQPDSVLE





121
DCLVPPDSEI VFPLDIGVVG HVAQTKKMVN VEDVAECPHF SSFADELTDY KTKNMLATPI





181
MNGKDVVAVI MAVNKLNGPF FTSEDEDVFL KYLNFATLYL KIYHLSYLHN CETRRGQVLL





241
WSANKVFEEL TDIERQFHKA FYTVRAYLNC ERYSVGLLDM TKEKEFFDVW SVLMGESQPY





301
SGPRTPDGRE IVFYKVIDYI LHGKEEIKVI PTPSADHWAL ASGLPSYVAE SGFVLVRFLF





361
SISKGYRRIT YHNWRHGFNV AQTMFTLLMT GKLKSYYTDL EAFAMVTAGL CHDIDHRGTN





421
NLYQMKSQNP LAKLHGSSIL ERHHLEFGKF LLSEETLNIY QNLNRRQHEH VIHLMDIAII





481
ATDLALYFKK RAMFQKIVDE SKNYQDKKSW VEYLSLETTR KEIVMAMMMT ACDLSAITKP





541
WEVQSKVALL VAAEFWEQGD LERTVLDQQP IPMMDRNKAA ELPKLQVGFI DEVCIFVYKA





601
SGSRVRHRNL QWRPSTQVFN LLYPVSTVPW DPMAPSIFTH











SEQ ID NO: 166



PROMININ 1 (PROM1)



O43490.1









1
MALVLGSLLL LGLCGNSFSG GQPSSTDAPK AWNYELPATN YETQDSHKAG PIGILFELVH






61
IFLYVVQPRD FPEDTLRKFL QKAYESKIDY DKPETVILGL KIVYYEAGII LCCVLGLLFI





121
ILMPLVGYFF CMCRCCNKCG GEMHQRQKEN GPFLRKCFAI SLLVICIIIS IGIFYGFVAN





181
HQVRTRIKRS RKLADSNFKD LRTLLNETPE QIKYILAQYN TTKDKAFTDL NSINSVLGGG





241
ILDRLRPNII PVLDEIKSMA TAIKETKEAL ENMNSTLKSL HQQSTQLSSS LTSVKTSLRS





301
SLNDPLCLVH PSSETCNSIR LSLSQLNSNP ELRQLPPVDA ELDNVNNVLR TDLDGLVQQG





361
YQSLNDIPDR VQRQTTTVVA GIKRVLNSIG SDIDNVTQRL PIQDILSAFS VYVNNTESYI





421
HRNLPTLEEY DSYWWLGGLV ICSLLTLIVI FYYLGLLCGV CGYDRHATPT TRGCVSNTGG





481
VFLMVGVGLS FLFCWILMII VVLTFVFGAN VEKLICEPYT SKELFRVLDT PYLLNEDWEY





541
YLSGKLFNKS KMKLTFEQVY SDCKKNRGTY GTLHLQNSFN ISEHLNINEH TGSISSELES





601
LKVNLNIFLL GAAGRKNLQD FAACGIDRMN YDSYLAQTGK SPAGVNLLSF AYDLEAKANS





661
LPPGNLRNSL KRDAQTIKTI HQQRVLPIEQ SLSTLYQSVK ILQRTGNGLL ERVTRILASL





721
DFAQNFITNN TSSVIIEETK KYGRTIIGYF EHYLQWIEFS ISEKVASCKP VATALDTAVD





781
VFLCSYIIDP LNLFWFGIGK ATVFLLPALI FAVKLAKYYR RMDSEDVYDD VETIPMKNME





841
NGNNGYHKDH VYGIHNPVMT SPSQH











SEQ ID NO: 167



PROMININ 1 (PROM1), ISOFORM CRA_A



EAW92750.1









1
MALVLGSLLL LGLCGNSFSG GQPSSTDAPK AWNYELPATN YETQDSHKAG PIGILFELVH






61
IFLYVVQPRD FPEDTLRKFL QKAYESKIDY DKIVYYEAGI ILCCVLGLLF IILMPLVGYF





121
FCMCRCCNKC GGEMHQRQKE NGPFLRKCFA ISLLVICIII SIGIFYGFVA NHQVRTRIKR





181
SRKLADSNFK DLRTLLNETP EQIKYILAQY NTIKDKAFTD LNSINSVLGG GILDRLRPNI





241
IPVLDEIKSM ATAIKETKEA LENMNSTLKS LHQQSTQLSS SLTSVKTSLR SSLNDPLCLV





301
HPSSETCNSI RLSLSQLNSN PELRQLPPVD AELDNVNNVL RTDLDGLVQQ GYQSLNDIPD





361
RVQRQTTTVV AGIKRVLNSI GSDIDNVTQR LPIQDILSAF SVYVNNTESY IHRNLPTLEE





421
YDSYWWLGGL VICSLLTLIV IFYYLGLLCG VCGYDRHATP TTRGCVSNTG GVFLMVGVGL





481
SFLFCWILMI IVVLTFVFGA NVEKLICEPY TSKELFRVLD TPYLLNEDWE YYLSGKLFNK





541
SKMKLTFEQV YSDCKKNRGT YGTLHLQNSF NISEHLNINE HTGSISSELE SLKVNLNIFL





601
LGAAGRKNLQ DFAACGIDRM NYDSYLAQTG KSPAGVNLLS FAYDLEAKAN SLPPGNLRNS





661
LKRDAQTIKT IHQQRVLPIE QSLSTLYQSV KILQRTGNGL LERVTRILAS LDFAQNFITN





721
NTSSVIIEET KKYGRTIIGY FEHYLQWIEF SISEKVASCK PVATALDTAV DVFLCSYIID





781
PLNLFWFGIG KATVFLLPAL IFAVKLAKYY RRMDSEDVYD DVETIPMKNM ENGNNGYHKD





841
HVYGIHNPVM TSPSQH











SEQ ID NO: 168



PROMININ 1 (PROM1), ISOFORM CRA_B



EAW92751.1









1
MFHLEMACKS NHRETCVTPS DKFKREREIL REKCCSFKSG VVLTDANYGV QFNRVFCCIR






61
ININWSAANM SIIRLVSSVL K











SEQ ID NO: 169



PROMININ 1 (PROM1), ISOFORM CRA_C



EAW92752.1









1
MALVLGSLLL LGLCGNSFSG GQPSSTDAPK AWNYELPATN YETQDSHKAG PIGILFELVH






61
IFLYVVQPRD FPEDTLRKFL QKAYESKIDY DKPETVILGL KIVYYEAGII LCCVLGLLFI





121
ILMPLVGYFF CMCRCCNKCG GEMHQRQKEN GPFLRKCFAI SLLVICIIIS IGIFYGFVAN





181
HQVRTRIKRS RKLADSNFKD LRTLLNETPE QIKYILAQYN TIKDKAFTDL NSINSVLGGG





241
ILDRLRPNII PVLDEIKSMA TAIKETKEAL ENMNSTLKSL HQQSTQLSSS LTSVKTSLRS





301
SLNDPLCLVH PSSETCNSIR LSLSQLNSNP ELRQLPPVDA ELDNVNNVLR TDLDGLVQQG





361
YQSLNDIPDR VQRQTTTVVA GIKRVLNSIG SDIDNVTQRL PIQDILSAFS VYVNNTESYI





421
HRNLPTLEEY DSYWWLGGLV ICSLLTLIVI FYYLGLLCGV CGYDRHATPT TRGCVSNTGG





481
VFLMVGVGLS FLFCWILMII VVLTFVFGAN VEKLICEPYT SKELFRVLDT PYLLNEDWEY





541
YLSGKLFNKS KMKLTFEQVY SDCKKNRGTY GTLHLQNSFN ISEHLNINEH TGSISSELES





601
LKVNLNIFLL GAAGRKNLQD FAACGIDRMN YDSYLAQTGK SPAGVNLLSF AYDLEAKANS





661
LPPGNLRNSL KRDAQTIKTI HQQRVLPIEQ SLSTLYQSVK ILQRTGNGLL ERVTRILASL





721
DFAQNFITNN TSSVIIEETK KYGRTIIGYF EHYLQWIEFS ISEKVASCKP VATALDTAVD





781
VFLCSYIIDP LNLFWFGIGK ATVFLLPALI FAVKLAKYYR RMDSEDVYDD VETIPMKNME





841
NGNNGYHKDH VYGIHNPVMT SPSQH











SEQ ID NO: 170



PHOSPHODIESTERASE 6A (PDE6A)



AAH35909.1









1
MGEVTAEEVE KFLDSNIGFA KQYYNLHYRA KLISDLLGAK EAAVDFSNYH SPSSMEESEI






61
IFDLLRDFQE NLQTEKCIFN VMKKLCFLLQ ADRMSLFMYR TRNGIAELAT RLFNVHKDAV





121
LEDCLVMPDQ EIVFPLDMGI VGHVAHSKKI ANVPNTEEDE HFCDFVDILT EYKTKNILAS





181
PIMNGKDVVA IIMAVNKVDG SHFTKRDEEI LLKYLNFANL IMKVYHLSYL HNCETRRGQI





241
LLWSGSKVFE ELTDIERQFH KALYTVRAFL NCDRYSVGLL DMTKQKEFFD VWPVLMGEVP





301
PYSGPRTPDG REINFYKVID YILHGKEDIK VIPNPPPDHW ALVSGLPAYV AQNGLICNIM





361
NAPAEDFFAF QKEPLDESGW MIKNVLSMPI VNKKEEIVGV ATFYNRKDGK PFDEMDETLM





421
ESLTQFLGWS VLNPDTYESM NKLENRKDIF QDIVKYHVKC DNEEIQKILK TREVYGKEPW





481
ECEEEELAEI LQAELPDADK YEINKFHFSD LPLTELELVK CGIQMYYELK VVDKFHIPQE





541
ALVRFMYSLS KGYRKITYHN WRHGFNVGQT MFSLLVTGKL KRYFTDLEAL AMVTAAFCHD





601
IDHRGTNNLY QMKSQNPLAK LHGSSILERH HLEFGKTLLR DESLNIFQNL NRRQHEHAIH





661
MMDIAIIATD LALYFKKRTM FQKIVDQSKT YESEQEWTQY MMLEQTRKEI VMAMMMTACD





721
LSAITKPWEV QSQVALLVAA EFWEQGDLER TVLQQNPIPM MDRNKADELP KLQVGFIDFV





781
CTFVYKEFSR FHEEITPMLD GITNNRKEWK ALADEYDAKM KVQEEKKQKQ QSAKSAAAGN





841
QPGGNPSPGG ATTSKSCCIQ











SEQ ID NO: 171



PHOSPHODIESTERASE 6A (PDE6A), ISOFORM CRA_A



EAW61756.1









1
MVTAAFCHDI DHRGTNNLYQ MKSQNPLAKL HGSSILERHH LEFGKTLLRD ESLNIFQNLN






61
RRQHEHAIHM MDIAIIATDL ALYFKKRTMF QKIVDQSKTY ESEQEWTQYM MLEQTRKEIV





121
MAMMMTACDL SAITKPWEVQ SQVALLVAAE FWEQGDLERT VLQQNPIPMM DRNKADELPK





181
LQVGFIDFVC TFVYKEFSRF HEEITPMLDG ITNNRKEWKA LADEYDAKMK VQEEKKQKQQ





241
SAKSAAAGNQ PGGNPSPGGA TTSKSCCIQ











SEQ ID NO: 172



PHOSPHODIESTERASE 6A (PDE6A), ISOFORM CRA_B



EAW61757.1









1
MGEVTAEEVE KFLDSNIGFA KQYYNLHYRA KLISDLLGAK EAAVDFSNYH SPSSMEESEI






61
IFDLLRDFQE NLQTEKCIFN VMKKLCFLLQ ADRMSLFMYR TRNGIAELAT RLFNVHKDAV





121
LEDCLVMPDQ EIVFPLDMGI VGHVAHSKKI ANVPNTEEDE HFCDFVDILT EYKTKNILAS





181
PIMNGKDVVA IIMAVNKVDG SHFTKRDEEI LLKYLNFANL IMKVYHLSYL HNCETRRGQI





241
LLWSGSKVFE ELTDIERQFH KALYTVRAFL NCDRYSVGLL DMTKQKEFFD VWPVLMGEVP





301
PYSGPRTPDG REINFYKVID YILHGKEDIK VIPNPPPDHW ALVSGLPAYV AQNGLICNIM





361
NAPAEDFFAF QKEPLDESGW MIKNVLSMPI VNKKEEIVGV ATFYNRKDGK PFDEMDETLM





421
ESLTQFLGWS VLNPDTYESM NKLENRKDIF QDIVKYHVKC DNEEIQKILK TREVYGKEPW





481
ECEEEELAEI LQAELPDADK YEINKFHFSD LPLTELELVK CGIQMYYELK VVDKFHIPQE





541
ALVRFMYSLS KGYRKITYHN WRHGFNVGQT MFSLLVTGKL KRYFTDLEAL AMVTAAFCHD





601
IDHRGTNNLY QMKSQNPLAK LHGSSILERH HLEFGKTLLR DESLNIFQNL NRRQHEHAIH





661
MMDIAIIATD LALYFKKRTM FQKIVDQSKT YESEQEWTQY MMLEQTRKEI VMAMMMTACD





721
LSAITKPWEV QSQVALLVAA EFWEQGDLER TVLQQNPIPM MDRNKADELP KLQVGFIDFV





781
CTFVYKEFSR FHEEITPMLD GITNNRKEWK ALADEYDAKM KVQEEKKQKQ QSAKSAAAGN





841
QPGGNPSPGG ATTSKSCCIQ











SEQ ID NO: 173



INTERPHOTORECEPTOR MATRIX PROTEOGLYCAN 2 (IMPG2)



EAW79803.1









1
MIMFPLFGKI SLGILIFVLI EGDFPSLTAQ TYLSIEEIQE PKSAVSFLLP EESTDLSLAT






61
KKKQPLDRRE TERQWLIRRR RSILFPNGVK ICPDESVAEA VANHVKYFKV RVCQEAVWEA





121
FRTFWDRLPG REEYHYWMNL CEDGVTSIFE MGTNFSESVE HRSLIMKKLT YAKETVSSSE





181
LSSPVPVGDT STLGDTTLSV PHPEVDAYEG ASESSLERPE ESISNEIENV IEEATKPAGE





241
QIAEFSIHLL GKQYREELQD SSSFHHQHLE EEFISEVENA FTGLPGYKEI RVLEFRSPKE





301
NDSGVDVYYA VTFNGEAISN TTWDLISLHS NKVENHGLVE LDDKPTVVYT ISNFRDYIAE





361
TLQQNFLLGN SSLNPDPDSL QLINVRGVLR HQTEDLVWNT QSSSLQATPS SILDNTFQAA





421
WPSADESITS SIPPLDFSSG PPSATGRELW SESPLGDLVS THKLAFPSKM GLSSSPEVLE





481
VSSLTLHSVT PAVLQTGLPV ASEERTSGSH LVEDGLANVE ESEDFLSIDS LPSSSFTQPV





541
PKETIPSMED SDVSLTSSPY LTSSIPFGLD SLTSKVKDQL KVSPFLPDAS MEKELIFDGG





601
LGSGSGQKVD LITWPWSETS SEKSAEPLSK PWLEDDDSLL PAEIEDKKLV LVDKMDSTDQ





661
ISKHSKYEHD DRSIHFPEEE PLSGPAVPIF ADTAAESASL TLPKHISEVP GVDDYSVTKA





721
PLILTSVAIS ASTDKSDQAD AILREDMEQI TESSNYEWFD SEVSMVKPDM QTLWTILPES





781
ERVWTRTSSL EKLSRDILAS TPQSADRLWL SVTQSTKLPP TTISTLLEDE VIMGVQDISL





841
ELDRIGTDYY QPEQVQEQNG KVGSYVEMST SVHSTEMVSV AWPTEGGDDL SYTQTSGALV





901
VFFSLRVTNM MFSEDLFNKN SLEYKALEQR FLELLVPYLQ SNLTGFQNLE ILNFRNGSIV





961
VNSRMKFANS VPPNVNNAVY MILEDFCTTA YNTMNLAIDK YSLDVESGDE ANPCKFQACN





1021
EFSECLVNPW SGEAKCRCFP GYLSVEERPC QSLCDLQPDF CLNDGKCDIM PGHGAICRCR





1081
VGENWWYRGK HCEEFVSEPV IIGITIASVV GLLVIFSAII YFFIRTLQAH HDRSERESPF





1141
SGSSRQPDSL SSIENAVKYN PVYESHRAGC EKYEGPYPQH PFYSSASGDV IGGLSREEIR





1201
QMYESSELSR EEIQERMRVL ELYANDPEFA AFVREQQVEE V











SEQ ID NO: 174



MALE GERM CELL ASSOCIATED KINASE (MAK)



AAN16405.1









1
MNRYTTMRQL GDGTYGSVLM GKSNESGELV AIKRMKRKFY SWDECMNLRE VKSLKKLNHA






61
NVIKLKEVIR ENDHLYFIFE YMKENLYQLM KDRNKLFPES VIRNIMYQIL QGLAFIHKHG





121
FFHRDMKPEN LLCMGPELVK IADFGLAREL RSQPPYTDYV STRWYRAPEV LLRSSVYSSP





181
IDVWAVGSIM AELYMLRPLF PGTSEVDEIF KICQVLGTPK KSDWPEGYQL ASSMNFRFPQ





241
CVPINLKTLI PNASNEAIQL MTEMLNWDPK KRPTASQALK HPYFQVGQVL GPSSNHLESK





301
QSLNKQLQPL ESKPSLVEVE PKPLPDIIDQ VVGQPQPKTS QQPLQPIQPP QNLSVQQPPK





361
QQSQEKPPQT LFPSIVKNMP TKPNGTLSHK SGRRRWGQTI FKSGDSWEEL EDYDFGASHS





421
KKPSMGVFKE KRKKDSPFRL PEPVPSGSNH STGENKSLPA VTSLKSDSEL STAPTSKQYY





481
LKQSRYLPGV NPKKVSLIAS GKEINPHTWS NQLFPKSLGP VGAELAFKRS NAGNLGSYAT





541
YNQSGYIPSF LKKEVQSAGQ RIHLAPLNAT ASEYTWNTKT GRGQFSGRTY NPTAKNLNIV





601
NRAQPIPSVH GRTDWVAKYG GHR











SEQ ID NO: 175



MALE GERM CELL ASSOCIATED KINASE (MAK); RETINAL-ENRICHED ISOFORM



AEL29206.1









1
MNRYTTMRQL GDGTYGSVLM GKSNESGELV AIKRMKRKFY SWDECMNLRE VKSLKKLNHA






61
NVIKLKEVIR ENDHLYFIFE YMKENLYQLM KDRNKLFPES VIRNIMYQIL QGLAFIHKHG





121
FFHRDMKPEN LLCMGPELVK IADFGLAREL RSQPPYTDYV STRWYRAPEV LLRSSVYSSP





181
IDVWAVGSIM AELYMLRPLF PGTSEVDEIF KICQVLGTPK KSDWPEGYQL ASSMNFRFPQ





241
CVPINLKTLI PNASNEAIQL MTEMLNWDPK KRPTASQALK HPYFQVGQVL GPSSNHLESK





301
QSLNKQLQPL ESKPSLVEVE PKPLPDIIDQ VVGQPQPKTS QQPLQPIQPP QNLSVQQPPK





361
QQSQEKPPQT LFPSIVKNMP TKPNGTLSHK SGRRRWGQTI FKSGDSWEEL EDYDFGASHS





421
KKPSMGVFKE KRKKDSPFRL PEPVPSGSNH STGENKSLPA VTSLKSDSEL STAPTSKQYY





481
LKQSRYLPGV NPKKVSLIAS GKEINPHTWS NQLFPKSLGP VGAELAFKRS NAEESIIKPI





541
EKLSCNETFP EKLEDPQGNL GSYATYNQSG YIPSFLKKEV QSAGQRIHLA PLNATASEYT





601
WNTKTGRGQF SGRTYNPTAK NLNIVNRAQP IPSVHGRTDW VAKYGGHR











SEQ ID NO: 176



INTRAFLAGELLAR TRANSPORT 140 (IFT140)



NP_055529.2









1
MALYYDHQIE APDAAGSPSF ISWHPVHPFL AVAYISTTST GSVDIYLEQG ECVPDTHVER






61
PFRVASLCWH PTRLVLAVGW ETGEVTVFNK QDKEQHTMPL THTADITVLR WSPSGNCLLS





121
GDRLGVLLLW RLDQRGRVQG TPLLKHEYGK HLTHCIFRLP PPGEDLVQLA KAAVSGDEKA





181
LDMFNWKKSS SGSLLKMGSH EGLLFFVSLM DGTVHYVDEK GKTTQVVSAD STIQMLFYME





241
KREALVVVTE NLRLSLYTVP PEGKAEEVMK VKLSGKTGRR ADIALIEGSL LVMAVGEAAL





301
RFWDIERGEN YILSPDEKFG FEKGENMNCV CYCKVKGLLA AGTDRGRVAM WRKVPDFLGS





361
PGAEGKDRWA LQTPTELQGN ITQIQWGSRK NLLAVNSVIS VAILSERAMS SHFHQQVAAM





421
QVSPSLLNVC FLSTGVAHSL RTDMHISGVF ATKDAVAVWN GRQVAIFELS GAAIRSAGTF





481
LCETPVLAMH EENVYTVESN RVQVRTWQGT VKQLLLFSET EGNPCFLDIC GNFLVVGTDL





541
AHFKSFDLSR REAKAHCSCR SLAELVPGVG GIASLRCSSS GSTISILPSK ADNSPDSKIC





601
FYDVEMDTVT VFDFKTGQID RRETLSFNEQ ETNKSHLFVD EGLKNYVPVN HFWDQSEPRL





661
FVCEAVQETP RSQPQSANGQ PQDGRAGPAA DVLILSFFIS EEHGFLLHES FPRPATSHSL





721
LGMEVPYYYF TRKPEEADRE DEVEPGCHHI PQMVSRRPLR DFVGLEDCDK ATRDAMLHFS





781
FFVTIGDMDE AFKSIKLIKS EAVWENMARM CVKTQRLDVA KVCLGNMGHA RGARALREAE





841
QEPELEARVA VLATQLGMLE DAEQLYRKCK RHDLLNKFYQ AAGRWQEALQ VAEHHDRVHL





901
RSTYHRYAGH LEASADCSRA LSYYEKSDTH RFEVPRMLSE DLPSLELYVN KMKDKTLWRW





961
WAQYLESQGE MDAALHYYEL ARDHFSLVRI HCFQGNVQKA AQIANETGNL AASYHLARQY





1021
ESQEEVGQAV HFYTRAQAFK NAIRLCKENG LDDQLMNLAL LSSPEDMIEA ARYYEEKGVQ





1081
MDRAVMLYHK AGHFSKALEL AFATQQFVAL QLIAEDLDET SDPALLARCS DFFIEHSQYE





1141
RAVELLLAAR KYQEALQLCL GQNMSITEEM AEKMTVAKDS SDLPEESRRE LLEQIADCCM





1201
RQGSYHLATK KYTQAGNKLK AMRALLKSGD TEKITFFASV SRQKEIYIMA ANYLQSLDWR





1261
KEPEIMKNII GFYTKGRALD LLAGFYDACA QVEIDEYQNY DKAHGALTEA YKCLAKAKAK





1321
SPLDQETRLA QLQSRMALVK RFIQARRTYT EDPKESIKQC ELLLEEPDLD STIRIGDVYG





1381
FLVEHYVRKE EYQTAYRFLE EMRRRLPLAN MSYYVSPQAV DAVHRGLGLP LPRTVPEQVR





1441
HNSMEDAREL DEEVVEEADD DP











SEQ ID NO: 177



HTRA SERINE PEPTIDASE 1 (HTRA1)



EAW49312.1









1
MQIPRAALLP LLLLLLAAPA SAQLSRAGRS APLAAGCPDR CEPARCPPQP EHCEGGRARD






61
ACGCCEVCGA PEGAACGLQE GPCGEGLQCV VPFGVPASAT VRRRAQAGLC VCASSEPVCG





121
SDANTYANLC QLRAASRRSE RLHRPPVIVL QRGACGQGQE DPNSLRHKYN FIADVVEKIA





181
PAVVHIELFR KLPFSKREVP VASGSGFIVS EDGLIVTNAH VVTNKHRVKV ELKNGATYEA





241
KIKDVDEKAD IALIKIDHQG KLPVLLLGRS SELRPGEFVV AIGSPFSLQN TVTTGIVSTT





301
QRGGKELGLR NSDMDYIQTD AIINYGNSGG PLVNLDGEVI GINTLKVTAG ISFAIPSDKI





361
KKFLTESHDR QAKGKAITKK KYIGIRMMSL TSSKAKELKD RHRDFPDVIS GAYIIEVIPD





421
TPAEAGGLKE NDVIISINGQ SVVSANDVSD VIKRESTLNM VVRRGNEDIM ITVIPEEIDP











SEQ ID NO: 178



BESTROPHIN 1 (BEST1), ISOFORM 1



NP_004174.1









1
MTITYTSQVA NARLGSFSRL LLCWRGSIYK LLYGEFLIFL LCYYIIRFIY RLALTEEQQL






61
MFEKLTLYCD SYIQLIPISF VLGFYVTLVV TRWWNQYENL PWPDRLMSLV SGFVEGKDEQ





121
GRLLRRTLIR YANLGNVLIL RSVSTAVYKR FPSAQHLVQA GFMTPAEHKQ LEKLSLPHNM





181
FWVPWVWFAN LSMKAWLGGR IRDPILLQSL LNEMNTLRTQ CGHLYAYDWI SIPLVYTQVV





241
TVAVYSFFLT CLVGRQFLNP AKAYPGHELD LVVPVFTFLQ FFFYVGWLKV AEQLINPFGE





301
DDDDFETNWI VDRNLQVSLL AVDEMHQDLP RMEPDMYWNK PEPQPPYTAA SAQFRRASFM





361
GSTFNISLNK EEMEFQPNQE DEEDAHAGII GRFLGLQSHD HHPPRANSRT KLLWPKRESL





421
LHEGLPKNHK AAKQNVRGQE DNKAWKLKAV DAFKSAPLYQ RPGYYSAPQT PLSPTPMFFP





481
LEPSAPSKLH SVTGIDTKDK SLKTVSSGAK KSFELLSESD GALMEHPEVS QVRRKTVEFN





541
LTDMPEIPEN HLKEPLEQSP TNIHTTLKDH MDPYWALENR DEAHS











SEQ ID NO: 179



BESTROPHIN 1 (BEST1), ISOFORM 2



NP_001132915.1









1
MFEKLTLYCD SYIQLIPISF VLGFYVTLVV TRWWNQYENL PWPDRLMSLV SGFVEGKDEQ






61
GRLLRRTLIR YANLGNVLIL RSVSTAVYKR FPSAQHLVQA GFMTPAEHKQ LEKLSLPHNM





121
FWVPWVWFAN LSMKAWLGGR IRDPILLQSL LNEMNTLRTQ CGHLYAYDWI SIPLVYTQVV





181
TVAVYSFFLT CLVGRQFLNP AKAYPGHELD LVVPVFTFLQ FFFYVGWLKV AEQLINPFGE





241
DDDDFETNWI VDRNLQVSLL AVDEMHQDLP RMEPDMYWNK PEPQPPYTAA SAQFRRASFM





301
GSTFNISLNK EEMEFQPNQE DEEDAHAGII GRFLGLQSHD HHPPRANSRT KLLWPKRESL





361
LHEGLPKNHK AAKQNVRGQE DNKAWKLKAV DAFKSAPLYQ RPGYYSAPQT PLSPTPMFFP





421
LEPSAPSKLH SVTGIDTKDK SLKTVSSGAK KSFELLSESD GALMEHPEVS QVRRKTVEFN





481
LTDMPEIPEN HLKEPLEQSP TNIHTTLKDH MDPYWALENR SVLHLNQGHC IALCPTPASL





541
ALSLPFLHNF LGFHHCQSTL DLRPALAWGI YLATFTGILG KCSGPFLTSP WYHPEDFLGP





601
GEGR











SEQ ID NO: 180



BESTROPHIN 1 (BEST1), ISOFORM 3



ALQ33849.1









1
MFEKLTLYCD SYIQLIPISF VLGFYVTLVV TRWWNQYENL PWPDRLMSLV SGFVEGKDEQ






61
GRLLRRTLIR YANLGNVLIL RSVSTAVYKR FPSAQHLVQA GFMTPAEHKQ LEKLSLPHNM





121
FWVPWVWFAN LSMKAWLGGR IRDPILLQSL LNEMNTLRTQ CGHLYAYDWI SIPLVYTQVV





181
TVAVYSFFLT CLVGRQFLNP AKAYPGHELD LVVPVFTFLQ FFFYVGWLKV AEQLINPFGE





241
DDDDFETNWI VDRNLQVSLL AVDEMHQDLP RMEPDMYWNK PEPQPPYTAA SAQFRRASFM





301
GSTFNISLNK EEMEFQPNQE DEEDAHAGII GRFLGLQSHD HHPPRANSRT KLLWPKRESL





361
LHEGLPKNHK AAKQNVRGQE DNKAWKLKAV DAFKSAPLYQ RPGYYSAPQT PLSPTPMFFP





421
LEPSAPSKLH SVTGIDTKDK SLKTVSSGAK KSFELLSESD GALMEHPEVS QVRRKTVEFN





481
LTDMPEIPEN HLKEPLEQSP TNIHTTLKDH MDPYWALENR DEAHS











SEQ ID NO: 181



BESTROPHIN 1 (BEST1), ISOFORM 4



NP_001287716.1









1
MFEKLTLYCD SYIQLIPISF VLGFYVTLVV TRWWNQYENL PWPDRLMSLV SGFVEGKDEQ






61
GRLLRRTLIR YANLGNVLIL RSVSTAVYKR FPSAQHLVQA GFMTPAEHKQ LEKLSLPHNM





121
FWVPWVWFAN LSMKAWLGGR IRDPILLQSL LNEMNTLRTQ CGHLYAYDWI SIPLVYTQVA





181
EQLINPFGED DDDFETNWIV DRNLQVSLLA VDEMHQDLPR MEPDMYWNKP EPQPPYTAAS





241
AQFRRASFMG STFNISLNKE EMEFQPNQED EEDAHAGIIG RFLGLQSHDH HPPRANSRTK





301
LLWPKRESLL HEGLPKNHKA AKQNVRGQED NKAWKLKAVD AFKSAPLYQR PGYYSAPQTP





361
LSPTPMFFPL EPSAPSKLHS VTGIDTKDKS LKTVSSGAKK SFELLSESDG ALMEHPEVSQ





421
VRRKTVEFNL TDMPEIPENH LKEPLEQSPT NIHTTLKDHM DPYWALENRD EAHS











SEQ ID NO: 182



BESTROPHIN 1 (BEST1), ISOFORM 5



NP_001350520.1









1
MSLVSGFVEG KDEQGRLLRR TLIRYANLGN VLILRSVSTA VYKRFPSAQH LVQAGFMTPA






61
EHKQLEKLSL PHNMFWVPWV WFANLSMKAW LGGRIRDPIL LQSLLNEMNT LRTQCGHLYA





121
YDWISIPLVY TQVVTVAVYS FFLTCLVGRQ FLNPAKAYPG HELDLVVPVF TFLQFFFYVG





181
WLKVAEQLIN PFGEDDDDFE TNWIVDRNLQ VSLLAVDEMH QDLPRMEPDM YWNKPEPQPP





241
YTAASAQFRR ASFMGSTFNI SLNKEEMEFQ PNQEDEEDAH AGIIGRFLGL QSHDHHPPRA





301
NSRTKLLWPK RESLLHEGLP KNHKAAKQNV RGQEDNKAWK LKAVDAFKSA PLYQRPGYYS





361
APQTPLSPTP MFFPLEPSAP SKLHSVTGID TKDKSLKTVS SGAKKSFELL SESDGALMEH





421
PEVSQVRRKT VEFNLTDMPE IPENHLKEPL EQSPTNIHTT LKDHMDPYWA LENRSVLHLN





481
QGHCIALCPT PASLALSLPF LHNFLGFHHC QSTLDLRPAL AWGIYLATFT GILGKCSGPF





541
LTSPWYHPED FLGPGEGR











SEQ ID NO: 183



BESTROPHIN 1 (BEST1), ISOFORM 6



NP_001350521.1









1
MTITYTSQVA NARLGSFSRL LLCWRGSIYK LLYGEFLIFL LCYYIIRFIY RLALTEEQQL






61
MFEKLTLYCD SYIQLIPISF VLGFYVTLVV TRWWNQYENL PWPDRLMSLV SGFVEGKDEQ





121
GRLLRRTLIR YANLGNVLIL RSVSTAVYKR FPSAQHLVQA GFMTPAEHKQ LEKLSLPHNM





181
FWVPWVWFAN LSMKAWLGGR IRDPILLQSL LNEMNTLRTQ CGHLYAYDWI SIPLVYTQVV





241
TVAVYSFFLT CLVGRQFLNP AKAYPGHELD LVVPVFTFLQ FFFYVGWLKV GLSRALLGWR





301
HGQRGHGQQL PETRMQCQER KVSRVESSQA WWRTPVIPAT REAEAGESLE PGRRRLWWQS





361
SSSTPLERMM MILRPTGLST GICRCPCWLW MRCTRTCLGW SRTCTGISPS HSPPTQLLPP





421
SSVEPPLWAP PSTSA











SEQ ID NO: 184



BESTROPHIN 1 (BEST1), ISOFORM 7



NP_001350522.1









1
MHQDLPRMEP DMYWNKPEPQ PPYTAASAQF RRASFMGSTF NISLNKEEME FQPNQEDEED






61
AHAGIIGRFL GLQSHDHHPP RANSRTKLLW PKRESLLHEG LPKNHKAAKQ NVRGQEDNKA





121
WKLKAVDAFK SAPLYQRPGY YSAPQTPLSP TPMFFPLEPS APSKLHSVTG IDTKDKSLKT





181
VSSGAKKSFE LLSESDGALM EHPEVSQVRR KTVEFNLTDM PEIPENHLKE PLEQSPTNIH





241
TTLKDHMDPY WALENRSVLH LNQGHCIALC PTPASLALSL PFLHNFLGFH HCQSTLDLRP





301
ALAWGIYLAT FTGILGKCSG PFLTSPWYHP EDFLGPGEGR











SEQ ID NO: 185



BESTROPHIN 1 (BEST1), ISOFORM 8



ALQ33852.1









1
MFEKLTLYCD SYIQLIPISF VLGDEHLAYS VWTPVCLRLD












SEQ ID NO: 186



COMPLEMENT FACTOR B



AAA16820.1









1
MGSNLSPQLC LMPFILGLLS GGVTTTPWSL AQPQGSCSLE GVEIKGGSFR LLQEGQALEY






61
VCPSGFYPYP VQTRTCRSTG SWSTLKTQDQ KTVRKAECRA IHCPRPHDFE NGEYWPRSPY





121
YNVSDEISFH CYDGYTLRGS ANRTCQVNGR WSGQTAICDN GAGYCSNPGI PIGTRKVGSQ





181
YRLEDSVTYH CSRGLTLRGS QRRTCQEGGS WSGTEPSCQD SFMYDTPQEV AEAFLSSLTE





241
TIEGVDAEDG HGPGEQQKRK IVLDPSGSMN IYLVLDGSDS IGASNFTGAK KCLVNLIEKV





301
ASYGVKPRYG LVTYATYPKI WVKVSEADSS NADWVTKQLN EINYEDHKLK SGTNTKKALQ





361
AVYSMMSWPD DVPPEGWNRT RHVIILMTDG LHNMGGDPIT VIDEIRDLLY IGKDRKNPRE





421
DYLDVYVFGV GPLVNQVNIN ALASKKDNEQ HVFKVKDMEN LEDVFYQMID ESQSLSLCGM





481
VWEHRKGTDY HKQPWQAKIS VIRPSKGHES CMGAVVSEYF VLTAAHCFTV DDKEHSIKVS





541
VGGEKRDLEI EVVLFHPNYN INGKKEAGIP EFYDYDVALI KLKNKLKYGQ TIRPICLPCT





601
EGTTRALRLP PTTTCQQQKE ELLPAQDIKA LFVSEEEKKL TRKEVYIKNG DKKGSCERDA





661
QYAPGYDKVK DISEVVTPRF LCTGGVSPYA DPNTCRGDSG GPLIVHKRSR FIQVGVISWG





721
VVDVCKNQKR QKQVPAHARD FHINLFQVLP WLKEKLQDED LGFL











SEQ ID NO: 187



BETA-AMYLOID, PARTIAL



AAB29908.1









1
DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA












SEQ ID NO: 188



BETA-AMYLOID, PARTIAL



AAB26264.2









1
GSGLTNIKTE EISEVKMDAE FRHDSGYEVH HQKLVFFAED VGSNKGAIIG LMVGGVVIAT






61
VIIITLVMLK KQYTSNHHGV VE











SEQ ID NO: 189



CD59 GLYCOPROTEIN (CD59)



NP_001120697.1









1
MGIQGGSVLF GLLLVLAVFC HSGHSLQCYN CPNPTADCKT AVNCSSDFDA CLITKAGLQV






61
YNKCWKFEHC NFNDVTTRLR ENELTYYCCK KDLCNFNEQL ENGGTSLSEK TVLLLVTPFL





121
AAAWSLHP











SEQ ID NO: 190



CHANNELRHODOPSIN-1 (CHR1) [VOLVOX CARTERI F. NAGARIENSIS]



ABZ90901.1









1
MDYPVARSLI VRYPTDLGNG TVCMPRGQCY CEGWLRSRGT SIEKTIAITL QWVVFALSVA






61
CLGWYAYQAW RATCGWEEVY VALIEMMKSI IEAFHEFDSP ATLWLSSGNG VVWMRYGEWL





121
LTCPVLLIHL SNLTGLKDDY SKRTMGLLVS DVGCIVWGAT SAMCIGWTKI LFFLISLSYG





181
MYTYFHAAKV YIEAFHTVPK GICRELVRVM AWTFFVAWGM FPVLFLLGTE GFGHISPYGS





241
AIGHSILDLI AKNMWGVLGN YLRVKIHEHI LLYGDIRKKQ KITIAGQEME VETLVAEEED





301
DTVKQSTAKY ASRDSFITMR NRMREKGLEV RASLDAGGGD SGMEAGGGGA AHAQPHMAKP





361
GTELGKTMSA SFTNGAATSL EPGRVILAVP DISMVDFFRE QFAQLPVPYE VVPALGAENT





421
VQLVQQAAML GGCDFVLMHP EFLRDRGPTG LLPQVKMMGQ RTAAFGWSQM GPMRDLIESS





481
GVGAWLEGPS FGSGISQAAL QQLVVKMQQA KRMAAMGSMM GGGMGNGMGM GMGMGMGMGM





541
GNGMGNGMGM GNGMGNGMGM GNGMGNGMGM GNGMGMGNGM GMGNGMGMGN GMGNGMGNGM





601
GMGNGMGNGM GNGMGNGMGN GMGNGMGMGN GMGMGNGMGN GMGNGMGNGM GNGMGMMTPG





661
AMGMGMGGMG NLAAAAGNAM YGGGGGGGGS TMGSGNAAMM TGLVMGGGNG VGAGPGGVVA





721
NLGSSALQPQ SQMMGGGNVV GMSSPQLQLQ QSSSMPLGGL APNRIGNNPL FGAAPSPLHS





781
QPGASPTGLS SPQLGMGAML PAGTSVGAGG GSVGPTETDM LQQLMTEINR LKDELGE











SEQ ID NO: 191



CHANNELRHODOPSIN-2 (CHR2) [VOLVOX CARTERI F. NAGARIENSIS]



ABZ90903.1









1
MDHPVARSLI GSSYTNLNNG SIVIPSDACF CMKWLKSKGS PVALKMANAL QWAAFALSVI






61
ILIYYAYATW RTTCGWEEVY VCCVELTKVV IEFFHEFDEP GMLYLANGNR VLWLRYGEWL





121
LTCPVILIHL SNLTGLKDDY NKRTMRLLVS DVGTIVWGAT AAMSTGYIKV IFFLLGCMYG





181
ANTFFHAAKV YIESYHTVPK GLCRQLVRAM AWLFFVSWGM FPVLFLLGPE GFGHLSVYGS





241
TIGHTIIDLL SKNCWGLLGH FLRLKIHEHI LLYGDIRKVQ KIRVAGEELE VETLMTEEAP





301
DTVKKSTAQY ANRESFLTMR DKLKEKGFEV RASLDNSGID AVINHNNNYN NALANAAAAV





361
GKPGMELSKL DHVAANAAGM GGIADHVATT SGAISPGRVI LAVPDISMVD YFREQFAQLP





421
VQYEVVPALG ADNAVQLVVQ AAGLGGCDFV LLHPEFLRDK SSTSLPARLR SIGQRVAAFG





481
WSPVGPVRDL IESAGLDGWL EGPSFGLGIS LPNLASLVLR MQHARKMAAM LGGMGGMLGS





541
NLMSGSGGVG LMGAGSPGGG GGAMGVGMTG MGMVGTNAMG RGAVGNSVAN ASMGGGSAGM





601
GMGMMGMVGA GVGGQQQMGA NGMGPTSFQL GSNPLYNTAP SPLSSQPGGD ASAAAAAAAA





661
AAATGAASNS MNAMQAGGSV RNSGILAGGL GSMMGPPGAP AAPTAAATAA PAVTMGAPGG





721
GGAAASEAEM LQQLMAEINR LKSELGE











SEQ ID NO: 192



COMPLEMENT FACTOR C5, ISOFORM 1



NP_001726.2









1
MGLLGILCFL IFLGKTWGQE QTYVISAPKI FRVGASENIV IQVYGYTEAF DATISIKSYP






61
DKKFSYSSGH VHLSSENKFQ NSAILTIQPK QLPGGQNPVS YVYLEVVSKH FSKSKRMPIT





121
YDNGFLFIHT DKPVYTPDQS VKVRVYSLND DLKPAKRETV LTFIDPEGSE VDMVEEIDHI





181
GIISFPDFKI PSNPRYGMWT IKAKYKEDFS TTGTAYFEVK EYVLPHFSVS IEPEYNFIGY





241
KNFKNFEITI KARYFYNKVV TEADVYITFG IREDLKDDQK EMMQTAMQNT MLINGIAQVT





301
FDSETAVKEL SYYSLEDLNN KYLYIAVTVI ESTGGFSEEA EIPGIKYVLS PYKLNLVATP





361
LFLKPGIPYP IKVQVKDSLD QLVGGVPVTL NAQTIDVNQE TSDLDPSKSV TRVDDGVASF





421
VLNLPSGVTV LEFNVKTDAP DLPEENQARE GYRAIAYSSL SQSYLYIDWT DNHKALLVGE





481
HLNIIVTPKS PYIDKITHYN YLILSKGKII HFGTREKFSD ASYQSINIPV TQNMVPSSRL





541
LVYYIVTGEQ TAELVSDSVW LNIEEKCGNQ LQVHLSPDAD AYSPGQTVSL NMATGMDSWV





601
ALAAVDSAVY GVQRGAKKPL ERVFQFLEKS DLGCGAGGGL NNANVFHLAG LTFLTNANAD





661
DSQENDEPCK EILRPRRTLQ KKIEEIAAKY KHSVVKKCCY DGACVNNDET CEQRAARISL





721
GPRCIKAFTE CCVVASQLRA NISHKDMQLG RLHMKTLLPV SKPEIRSYFP ESWLWEVHLV





781
PRRKQLQFAL PDSLTTWEIQ GVGISNTGIC VADTVKAKVF KDVFLEMNIP YSVVRGEQIQ





841
LKGTVYNYRT SGMQFCVKMS AVEGICTSES PVIDHQGTKS SKCVRQKVEG SSSHLVTFTV





901
LPLEIGLHNI NFSLETWFGK EILVKTLRVV PEGVKRESYS GVTLDPRGIY GTISRRKEFP





961
YRIPLDLVPK TEIKRILSVK GLLVGEILSA VLSQEGINIL THLPKGSAEA ELMSVVPVFY





1021
VFHYLETGNH WNIFHSDPLI EKQKLKKKLK EGMLSIMSYR NADYSYSVWK GGSASTWLTA





1081
FALRVLGQVN KYVEQNQNSI CNSLLWLVEN YQLDNGSFKE NSQYQPIKLQ GTLPVEAREN





1141
SLYLTAFTVI GIRKAFDICP LVKIDTALIK ADNFLLENTL PAQSTFTLAI SAYALSLGDK





1201
THPQFRSIVS ALKREALVKG NPPIYRFWKD NLQHKDSSVP NTGTARMVET TAYALLTSLN





1261
LKDINYVNPV IKWLSEEQRY GGGFYSTQDT INAIEGLTEY SLLVKQLRLS MDIDVSYKHK





1321
GALHNYKMTD KNFLGRPVEV LLNDDLIVST GFGSGLATVH VTTVVHKTST SEEVCSFYLK





1381
IDTQDIEASH YRGYGNSDYK RIVACASYKP SREESSSGSS HAVMDISLPT GISANEEDLK





1441
ALVEGVDQLF TDYQIKDGHV ILQLNSIPSS DFLCVRFRIF ELFEVGFLSP ATFTVYEYHR





1501
PDKQCTMFYS TSNIKIQKVC EGAACKCVEA DCGQMQEELD LTISAETRKQ TACKPEIAYA





1561
YKVSITSITV ENVFVKYKAT LLDIYKTGEA VAEKDSEITF IKKVICTNAE LVKGRQYLIM





1621
GKEALQIKYN FSFRYIYPLD SLTWIEYWPR DTTCSSCQAF LANLDEFAED IFLNGC











SEQ ID NO: 193



COMPLEMENT FACTOR C5, ISOFORM 2



NP_001304092.1









1
MPGSLGREAS GRAGPTGCGA FAFGLRCRYV ISAPKIFRVG ASENIVIQVY GYTEAFDATI






61
SIKSYPDKKF SYSSGHVHLS SENKFQNSAI LTIQPKQLPG GQNPVSYVYL EVVSKHFSKS





121
KRMPITYDNG FLFIHTDKPV YTPDQSVKVR VYSLNDDLKP AKRETVLTFI DPEGSEVDMV





181
EEIDHIGIIS FPDFKIPSNP RYGMWTIKAK YKEDFSTTGT AYFEVKEYVL PHFSVSIEPE





241
YNFIGYKNFK NFEITIKARY FYNKVVTEAD VYITFGIRED LKDDQKEMMQ TAMQNTMLIN





301
GIAQVTFDSE TAVKELSYYS LEDLNNKYLY IAVIVIESTG GFSEEAEIPG IKYVLSPYKL





361
NLVATPLFLK PGIPYPIKVQ VKDSLDQLVG GVPVTLNAQT IDVNQETSDL DPSKSVTRVD





421
DGVASFVLNL PSGVTVLEFN VKTDAPDLPE ENQAREGYRA IAYSSLSQSY LYIDWTDNHK





481
ALLVGEHLNI IVTPKSPYID KITHYNYLIL SKGKIIHFGT REKFSDASYQ SINIPVTQNM





541
VPSSRLLVYY IVTGEQTAEL VSDSVWLNIE EKCGNQLQVH LSPDADAYSP GQTVSLNMAT





601
GMDSWVALAA VDSAVYGVQR GAKKPLERVF QFLEKSDLGC GAGGGLNNAN VFHLAGLTFL





661
TNANADDSQE NDEPCKEILR PRRTLQKKIE EIAAKYKHSV VKKCCYDGAC VNNDETCEQR





721
AARISLGPRC IKAFTECCVV ASQLRANISH KDMQLGRLHM KTLLPVSKPE IRSYFPESWL





781
WEVHLVPRRK QLQFALPDSL TTWEIQGVGI SNTGICVADT VKAKVFKDVF LEMNIPYSVV





841
RGEQIQLKGT VYNYRTSGMQ FCVKMSAVEG ICTSESPVID HQGTKSSKCV RQKVEGSSSH





901
LVTFTVLPLE IGLHNINFSL ETWFGKEILV KTLRVVPEGV KRESYSGVTL DPRGIYGTIS





961
RRKEFPYRIP LDLVPKTEIK RILSVKGLLV GEILSAVLSQ EGINILTHLP KGSAEAELMS





1021
VVPVFYVFHY LETGNHWNIF HSDPLIEKQK LKKKLKEGML SIMSYRNADY SYSVWKGGSA





1081
STWLTAFALR VLGQVNKYVE QNQNSICNSL LWLVENYQLD NGSFKENSQY QPIKLQGTLP





1141
VEARENSLYL TAFTVIGIRK AFDICPLVKI DTALIKADNF LLENTLPAQS TFTLAISAYA





1201
LSLGDKTHPQ FRSIVSALKR EALVKGNPPI YRFWKDNLQH KDSSVPNTGT ARMVETTAYA





1261
LLTSLNLKDI NYVNPVIKWL SEEQRYGGGF YSTQDTINAI EGLTEYSLLV KQLRLSMDID





1321
VSYKHKGALH NYKMTDKNFL GRPVEVLLND DLIVSTGFGS GLATVHVTTV VHKTSTSEEV





1381
CSFYLKIDTQ DIEASHYRGY GNSDYKRIVA CASYKPSREE SSSGSSHAVM DISLPTGISA





1441
NEEDLKALVE GVDQLFTDYQ IKDGHVILQL NSIPSSDFLC VRFRIFELFE VGFLSPATFT





1501
VYEYHRPDKQ CTMFYSTSNI KIQKVCEGAA CKCVEADCGQ MQEELDLTIS AETRKQTACK





1561
PEIAYAYKVS ITSITVENVF VKYKATLLDI YKTGEAVAEK DSEITFIKKV TCTNAELVKG





1621
RQYLIMGKEA LQIKYNFSFR YIYPLDSLTW IEYWPRDTTC SSCQAFLANL DEFAEDIFLN





1681
GC











SEQ ID NO: 194



COMPLEMENT FACTOR C5, ISOFORM 2



NP_001304093.1









1
MGLLGILCFL IFLGKTWGQE QTYVISAPKI FRVGASENIV IQVYGYTEAF DATISIKSYP






61
DKKFSYSSGH VHLSSENKFQ NSAILTIQPK QLPGGQNPVS YVYLEVVSKH FSKSKRMPIT





121
YDNGFLFIHT DKPVYTPDQS VKVRVYSLND DLKPAKRETV LTFIDPEGSE VDMVEEIDHI





181
GIISFPDFKI PSNPRYGMWT IKAKYKEDFS TTGTAYFEVK EYVLPHFSVS IEPEYNFIGY





241
KNFKNFEITI KARYFYNKVV TEADVYITFG IREDLKDDQK EMMQTAMQNT MLINGIAQVT





301
FDSETAVKEL SYYSLEDLNN KYLYIAVTVI ESTGGFSEEA EIPGIKYVLS PYKLNLVATP





361
LFLKPGIPYP IKVQVKDSLD QLVGGVPVTL NAQTIDVNQE TSDLDPSKSV TRVDDGVASF





421
VLNLPSGVTV LEFNVKTDAP DLPEENQARE GYRAIAYSSL SQSYLYIDWT DNHKALLVGE





481
HLNIIVTPKS PYIDKITHYN YLILSKGKII HFGTREKFSD ASYQSINIPV TQNMVPSSRL





541
LVYYIVTGEQ TAELVSDSVW LNIEEKCGNQ LQVHLSPDAD AYSPGQTVSL NMATGMDSWV





601
ALAAVDSAVY GVQRGAKKPL ERVFQFLEKS DLGCGAGGGL NNANVFHLAG LTFLTNANAD





661
DSQENDEPCK EILRPRRTLQ KKIEEIAAKY KHSVVKKCCY DGACVNNDET CEQRAARISL





721
GPRCIKAFTE CCVVASQLRA NISHKDMQLG RLHMKTLLPV SKPEIRSYFP ESWLWEVHLV





781
PRRKQLQFAL PDSLTTWEIQ GVGISNTGIC VADTVKAKVF KDVFLEMNIP YSVVRGEQIQ





841
LKGTVYNYRT SGMQSLALSP RLECNGKISG HCKLRLPGSS DSPASASQVA GITGTHHHAQ





901
PT











SEQ ID NO: 195



COMPLEMENT FACTOR CSA



3PVM_A









1
MGLLGILCFL IFLGKTWGQE QTYVISAPKI FRVGASENIV IQVYGYTEAF DATISIKSYP






61
DKKFSYSSGH VHLSSENKFQ NSAILTIQPK QLPGGQNPVS YVYLEVVSKH FSKSKRMPIT





121
YDNGFLFIHT DKPVYTPDQS VKVRVYSLND DLKPAKRETV LTFIDPEGSE VDMVEEIDHI





181
GIISFPDFKI PSNPRYGMWT IKAKYKEDFS TTGTAYFEVK EYVLPHFSVS IEPEYNFIGY





241
KNFKNFEITI KARYFYNKVV TEADVYITFG IREDLKDDQK EMMQTAMQNT MLINGIAQVT





301
FDSETAVKEL SYYSLEDLNN KYLYIAVTVI ESTGGFSEEA EIPGIKYVLS PYKLNLVATP





361
LFLKPGIPYP IKVQVKDSLD QLVGGVPVTL NAQTIDVNQE TSDLDPSKSV TRVDDGVASF





421
VLNLPSGVTV LEFNVKTDAP DLPEENQARE GYRAIAYSSL SQSYLYIDWT DNHKALLVGE





481
HLNIIVTPKS PYIDKITHYN YLILSKGKII HFGTREKFSD ASYQSINIPV TQNMVPSSRL





541
LVYYIVTGEQ TAELVSDSVW LNIEEKCGNQ LQVHLSPDAD AYSPGQTVSL NMATGMDSWV





601
ALAAVDSAVY GVQRGAKKPL ERVFQFLEKS DLGCGAGGGL NNANVFHLAG LTFLTNANAD





661
DSQENDEPCK EILRPRRTLQ KKIEEIAAKY KHSVVKKCCY DGACVNNDET CEQRAARISL





721
GPRCIKAFTE CCVVASQLRA NISHKDMQLG RLHMKTLLPV SKPEIRSYFP ESWLWEVHLV





781
PRRKQLQFAL PDSLTTWEIQ GVGISNTGIC VADTVKAKVF KDVFLEMNIP YSVVRGEQIQ





841
LKGTVYNYRT SGMQFCVKMS AVEGICTSES PVIDHQGTKS SKCVRQKVEG SSSHLVTFTV





901
LPLEIGLHNI NFSLETWFGK EILVKTLRVV PEGVKRESYS GVTLDPRGIY GTISRRKEFP





961
YRIPLDLVPK TEIKRILSVK GLLVGEILSA VLSQEGINIL THLPKGSAEA ELMSVVPVFY





1021
VFHYLETGNH WNIFHSDPLI EKQKLKKKLK EGMLSIMSYR NADYSYSVWK GGSASTWLTA





1081
FALRVLGQVN KYVEQNQNSI CNSLLWLVEN YQLDNGSFKE NSQYQPIKLQ GTLPVEAREN





1141
SLYLTAFTVI GIRKAFDICP LVKIDTALIK ADNFLLENTL PAQSTFTLAI SAYALSLGDK





1201
THPQFRSIVS ALKREALVKG NPPIYRFWKD NLQHKDSSVP NTGTARMVET TAYALLTSLN





1261
LKDINYVNPV IKWLSEEQRY GGGFYSTQDT INAIEGLTEY SLLVKQLRLS MDIDVSYKHK





1321
GALHNYKMTD KNFLGRPVEV LLNDDLIVST GFGSGLATVH VTTVVHKTST SEEVCSFYLK





1381
IDTQDIEASH YRGYGNSDYK RIVACASYKP SREESSSGSS HAVMDISLPT GISANEEDLK





1441
ALVEGVDQLF TDYQIKDGHV ILQLNSIPSS DFLCVRFRIF ELFEVGFLSP ATFTVYEYHR





1501
PDKQCTMFYS TSNIKIQKVC EGAACKCVEA DCGQMQEELD LTISAETRKQ TACKPEIAYA





1561
YKVSITSITV ENVFVKYKAT LLDIYKTGEA VAEKDSEITF IKKVICTNAE LVKGRQYLIM





1621
GKEALQIKYN FSFRYIYPLD SLTWIEYWPR DTTCSSCQAF LANLDEFAED IFLNGC











SEQ ID NO: 196



COMPLEMENT FACTOR D, ISOFORM 1



NP_001919.2









1
MHSWERLAVL VLLGAAACAA PPRGRILGGR EAEAHARPYM ASVQLNGAHL CGGVLVAEQW






61
VLSAAHCLED AADGKVQVLL GAHSLSQPEP SKRLYDVLRA VPHPDSQPDT IDHDLLLLQL





121
SEKATLGPAV RPLPWQRVDR DVAPGTLCDV AGWGIVNHAG RRPDSLQHVL LPVLDRATCN





181
RRTHHDGAIT ERLMCAESNR RDSCKGDSGG PLVCGGVLEG VVTSGSRVCG NRKKPGIYTR





241
VASYAAWIDS VLA











SEQ ID NO: 197



COMPLEMENT FACTOR D, ISOFORM 2



NP_001304264.1









1
MHSWERLAVL VLLGAAACGE EAWAWAAPPR GRILGGREAE AHARPYMASV QLNGAHLCGG






61
VLVAEQWVLS AAHCLEDAAD GKVQVLLGAH SLSQPEPSKR LYDVLRAVPH PDSQPDTIDH





121
DLLLLQLSEK ATLGPAVRPL PWQRVDRDVA PGTLCDVAGW GIVNHAGRRP DSLQHVLLPV





181
LDRATCNRRT HHDGAITERL MCAESNRRDS CKGDSGGPLV CGGVLEGVVT SGSRVCGNRK





241
KPGIYTRVAS YAAWIDSVLA











SEQ ID NO: 198



DNAJ HEAT SHOCK PROTEIN FAMILY (HSP40) MEMBER C3 (DNAJC3), ALSO KNOWN AS



P58IPK


NP_006251.1









1
MVAPGSVTSR LGSVFPFLLV LVDLQYEGAE CGVNADVEKH LELGKKLLAA GQLADALSQF






61
HAAVDGDPDN YIAYYRRATV FLAMGKSKAA LPDLTKVIQL KMDFTAARLQ RGHLLLKQGK





121
LDEAEDDFKK VLKSNPSENE EKEAQSQLIK SDEMQRLRSQ ALNAFGSGDY TAAIAFLDKI





181
LEVCVWDAEL RELRAECFIK EGEPRKAISD LKAASKLKND NTEAFYKIST LYYQLGDHEL





241
SLSEVRECLK LDQDHKRCFA HYKQVKKLNK LIESAEELIR DGRYTDATSK YESVMKTEPS





301
IAEYTVRSKE RICHCFSKDE KPVEAIRVCS EVLQMEPDNV NALKDRAEAY LIEEMYDEAI





361
QDYETAQEHN ENDQQIREGL EKAQRLLKQS QKRDYYKILG VKRNAKKQEI IKAYRKLALQ





421
WHPDNFQNEE EKKKAEKKFI DIAAAKEVLS DPEMRKKFDD GEDPLDAESQ QGGGGNPFHR





481
SWNSWQGFNP FSSGGPFRFK FHFN











SEQ ID NO: 199



DNAJ HEAT SHOCK PROTEIN FAMILY (HSP40) MEMBER C3 (DNAJC3), ALSO KNOWN AS



P58IPK, ISOFORM X1


XP_011519406.1









1
MVAPGSVTSR LGSVFPFLLV LVDLQYEGAE CGVNADVEKH LELGKKLLAA GQLADALSQF






61
HAAVDGDPDN YIAYYRRATV FLAMGKSKAA LPDLTKVIQL KMDFTAARLQ RGHLLLKQGK





121
LDEAEDDFKK VVFPVPSLLG LQRSLLDDLY LLFWFFLMKK LKSNPSENEE KEAQSQLIKS





181
DEMQRLRSQA LNAFGSGDYT AAIAFLDKIL EVCVWDAELR ELRAECFIKE GEPRKAISDL





241
KAASKLKNDN TEAFYKISTL YYQLGDHELS LSEVRECLKL DQDHKRCFAH YKQVKKLNKL





301
IESAEELIRD GRYTDATSKY ESVMKTEPSI AEYTVRSKER ICHCFSKDEK PVEAIRVCSE





361
VLQMEPDNVN ALKDRAEAYL IEEMYDEAIQ DYETAQEHNE NDQQIREGLE KAQRLLKQSQ





421
KRDYYKILGV KRNAKKQEII KAYRKLALQW HPDNFQNEEE KKKAEKKFID IAAAKEVLSD





481
PEMRKKFDDG EDPLDAESQQ GGGGNPFHRS WNSWQGFNPF SSGGPFRFKF HFN











SEQ ID NO: 200



DNAJ HEAT SHOCK PROTEIN FAMILY (HSP40) MEMBER C3 (DNAJC3), ALSO KNOWN AS



P58IPK, ISOFORM X2


XP_011519407.1









1
MGKSKAALPD LTKVIQLKMD FTAARLQRGH LLLKQGKLDE AEDDFKKVVF PVPSLLGLQR






61
SLLDDLYLLF WFFLMKKLKS NPSENEEKEA QSQLIKSDEM QRLRSQALNA FGSGDYTAAI





121
AFLDKILEVC VWDAELRELR AECFIKEGEP RKAISDLKAA SKLKNDNTEA FYKISTLYYQ





181
LGDHELSLSE VRECLKLDQD HKRCFAHYKQ VKKLNKLIES AEELIRDGRY TDATSKYESV





241
MKTEPSIAEY TVRSKERICH CFSKDEKPVE AIRVCSEVLQ MEPDNVNALK DRAEAYLIEE





301
MYDEAIQDYE TAQEHNENDQ QIREGLEKAQ RLLKQSQKRD YYKILGVKRN AKKQEIIKAY





361
RKLALQWHPD NFQNEEEKKK AEKKFIDIAA AKEVLSDPEM RKKFDDGEDP LDAESQQGGG





421
GNPFHRSWNS WQGFNPFSSG GPFRFKFHFN











SEQ ID NO: 201



DNAJ HEAT SHOCK PROTEIN FAMILY (HSP40) MEMBER C3 (DNAJC3), ALSO KNOWN AS



P58IPK, ISOFORM X3


XP_016876163.1









1
MGKSKAALPD LTKVIQLKMD FTAARLQRGH LLLKQGKLDE AEDDFKKVLK SNPSENEEKE






61
AQSQLIKSDE MQRLRSQALN AFGSGDYTAA IAFLDKILEV CVWDAELREL RAECFIKEGE





121
PRKAISDLKA ASKLKNDNTE AFYKISTLYY QLGDHELSLS EVRECLKLDQ DHKRCFAHYK





181
QVKKLNKLIE SAEELIRDGR YTDATSKYES VMKTEPSIAE YTVRSKERIC HCFSKDEKPV





241
EAIRVCSEVL QMEPDNVNAL KDRAEAYLIE EMYDEAIQDY ETAQEHNEND QQIREGLEKA





301
QRLLKQSQKR DYYKILGVKR NAKKQEIIKA YRKLALQWHP DNFQNEEEKK KAEKKFIDIA





361
AAKEVLSDPE MRKKFDDGED PLDAESQQGG GGNPFHRSWN SWQGFNPFSS GGPFRFKFHF





421
N











SEQ ID NO: 202



DNAJ HEAT SHOCK PROTEIN FAMILY (HSP40) MEMBER C3 (DNAJC3), ALSO KNOWN AS



P58IPK, ISOFORM X4


XP_016876164.1









1
MCFLHFFKKV LKSNPSENEE KEAQSQLIKS DEMQRLRSQA LNAFGSGDYT AAIAFLDKIL






61
EVCVWDAELR ELRAECFIKE GEPRKAISDL KAASKLKNDN TEAFYKISTL YYQLGDHELS





121
LSEVRECLKL DQDHKRCFAH YKQVKKLNKL IESAEELIRD GRYTDATSKY ESVMKTEPSI





181
AEYTVRSKER ICHCFSKDEK PVEAIRVCSE VLQMEPDNVN ALKDRAEAYL IEEMYDEAIQ





241
DYETAQEHNE NDQQIREGLE KAQRLLKQSQ KRDYYKILGV KRNAKKQEII KAYRKLALQW





301
HPDNFQNEEE KKKAEKKFID IAAAKEVLSD PEMRKKFDDG EDPLDAESQQ GGGGNPFHRS





361
WNSWQGFNPF SSGGPFRFKF HFN











SEQ ID NO: 203



BETA-2 ADRENOCEPTOR



NP_000015.1









1
MGQPGNGSAF LLAPNRSHAP DHDVTQQRDE VWVVGMGIVM SLIVLAIVFG NVLVITAIAK






61
FERLQTVTNY FITSLACADL VMGLAVVPFG AAHILMKMWT FGNFWCEFWT SIDVLCVTAS





121
IETLCVIAVD RYFAITSPFK YQSLLTKNKA RVIILMVWIV SGLTSFLPIQ MHWYRATHQE





181
AINCYANETC CDFFTNQAYA IASSIVSFYV PLVIMVFVYS RVFQEAKRQL QKIDKSEGRF





241
HVQNLSQVEQ DGRTGHGLRR SSKFCLKEHK ALKTLGIIMG TFTLCWLPFF IVNIVHVIQD





301
NLIRKEVYIL LNWIGYVNSG FNPLIYCRSP DFRIAFQELL CLRRSSLKAY GNGYSSNGNT





361
GEQSGYHVEQ EKENKLLCED LPGTEDFVGH QGTVPSDNID SQGRNCSTND SLL











SEQ ID NO: 204



CASPASE-2 (CASP2)



AAX36439.1









61
PKRGPQAFDA FCEALRETKQ GHLEDMLLTT LSGLQHVLPP LSCDYDLSLP FPVCESCPLY






121
KKLRLSTDTV EHSLDNKDGP VCLQVKPCTP EFYQTHFQLA YRLQSRPRGL ALVLSNVHFT





181
GEKELEFRSG GDVDHSTLVT LFKLLGYDVH VLCDQTAQEM QEKLQNFAQL PAHRVTDSCI





241
VALLSHGVEG AIYGVDGKLL QLQEVFQLFD NANCPSLQNK PKMFFIQACR GGAIGSLGHL





301
LLFTAATASL AL











SEQ ID NO: 205



INSULIN RECEPTOR SUBSTRATE 1 (IRS1)



NP_005535.1









1
MASPPESDGF SDVRKVGYLR KPKSMHKRFF VLRAASEAGG PARLEYYENE KKWRHKSSAP






61
KRSIPLESCF NINKRADSKN KHLVALYTRD EHFAIAADSE AEQDSWYQAL LQLHNRAKGH





121
HDGAAALGAG GGGGSCSGSS GLGEAGEDLS YGDVPPGPAF KEVWQVILKP KGLGQTKNLI





181
GIYRLCLTSK TISFVKLNSE AAAVVLQLMN IRRCGHSENF FFIEVGRSAV TGPGEFWMQV





241
DDSVVAQNMH ETILEAMRAM SDEFRPRSKS QSSSNCSNPI SVPLRRHHLN NPPPSQVGLT





301
RRSRTESITA TSPASMVGGK PGSFRVRASS DGEGTMSRPA SVDGSPVSPS TNRTHAHRHR





361
GSARLHPPLN HSRSIPMPAS RCSPSATSPV SLSSSSTSGH GSTSDCLFPR RSSASVSGSP





421
SDGGFISSDE YGSSPCDFRS SFRSVTPDSL GHTPPARGEE ELSNYICMGG KGPSTLTAPN





481
GHYILSRGGN GHRCTPGTGL GTSPALAGDE AASAADLDNR FRKRTHSAGT SPTITHQKTP





541
SQSSVASIEE YTEMMPAYPP GGGSGGRLPG HRHSAFVPTR SYPEEGLEMH PLERRGGHHR





601
PDSSTLHTDD GYMPMSPGVA PVPSGRKGSG DYMPMSPKSV SAPQQIINPI RRHPQRVDPN





661
GYMMMSPSGG CSPDIGGGPS SSSSSSNAVP SGTSYGKLWT NGVGGHHSHV LPHPKPPVES





721
SGGKLLPCTG DYMNMSPVGD SNTSSPSDCY YGPEDPQHKP VLSYYSLPRS FKHTQRPGEP





781
EEGARHQHLR LSTSSGRLLY AATADDSSSS TSSDSLGGGY CGARLEPSLP HPHHQVLQPH





841
LPRKVDTAAQ TNSRLARPTR LSLGDPKAST LPRAREQQQQ QQPLLHPPEP KSPGEYVNIE





901
FGSDQSGYLS GPVAFHSSPS VRCPSQLQPA PREEETGTEE YMKMDLGPGR RAAWQESTGV





961
EMGRLGPAPP GAASICRPTR AVPSSRGDYM TMQMSCPRQS YVDTSPAAPV SYADMRTGIA





1021
AEEVSLPRAT MAAASSSSAA SASPTGPQGA AELAAHSSLL GGPQGPGGMS AFTRVNLSPN





1081
RNQSAKVIRA DPQGCRRRHS SETFSSTPSA TRVGNTVPFG AGAAVGGGGG SSSSSEDVKR





1141
HSSASFENVW LRPGELGGAP KEPAKLCGAA GGLENGLNYI DLDLVKDFKQ CPQECTPEPQ





1201
PPPPPPPHQP LGSGESSSTR RSSEDLSAYA SISFQKQPED RQ











SEQ ID NO: 206



HIF-1 RESPONSIVE PROTEIN RTP801 (RTP801)



Q9NX09.1









1
MPSLWDRFSS SSTSSSPSSL PRTPTPDRPP RSAWGSATRE EGFDRSTSLE SSDCESLDSS






61
NSGFGPEEDT AYLDGVSLPD FELLSDPEDE HLCANLMQLL QESLAQARLG SRRPARLLMP





121
SQLVSQVGKE LLRLAYSEPC GLRGALLDVC VEQGKSCHSV GQLALDPSLV PTFQLTLVLR





181
LDSRLWPKIQ GLFSSANSPF LPGFSQSLTL STGFRVIKKK LYSSEQLLIE EC











SEQ ID NO: 207



TRANSFORMING GROWTH FACTOR BETA 2 (TGFB2)



AAH99635.1









1
MHYCVLSAFL ILHLVTVALS LSTCSTLDMD QFMRKRIEAI RGQILSKLKL TSPPEDYPEP






61
EEVPPEVISI YNSTRDLLQE KASRRAAACE RERSDEEYYA KEVYKIDMPP FFPSENAIPP





121
TFYRPYFRIV RFDVSAMEKN ASNLVKAEFR VFRLQNPKAR VPEQRIELYQ ILKSKDLTSP





181
TQRYIDSKVV KTRAEGEWLS FDVTDAVHEW LHHKDRNLGF KISLHCPCCT FVPSNNYIIP





241
NKSEELEARF AGIDGTSTYT SGDQKTIKST RKKNSGKTPH LLLMLLPSYR LESQQTNRRK





301
KRALDAAYCF RNVQDNCCLR PLYIDFKRDL GWKWIHEPKG YNANFCAGAC PYLWSSDTQH





361
SRVLSLYNTI NPEASASPCC VSQDLEPLTI LYYIGKTPKI EQLSNMIVKS CKCS











SEQ ID NO: 208



TRANSFORMING GROWTH FACTOR BETA 2 (TGFB2), ISOFORM CRA_A



EAW93326.1









1
MHYCVLSAFL ILHLVTVALS LSTCSTLDMD QFMRKRIEAI RGQILSKLKL TSPPEDYPEP






61
EEVPPEVISI YNSTRDLLQE KASRRAAACE RERSDEEYYA KEVYKIDMPP FFPSETVCPV





121
VTTPSGSVGS LCSRQSQVLC GYLDAIPPTF YRPYFRIVRF DVSAMEKNAS NLVKAEFRVF





181
RLQNPKARVP EQRIELYQIL KSKDLTSPTQ RYIDSKVVKT RAEGEWLSFD VTDAVHEWLH





241
HKDRNLGFKI SLHCPCCTFV PSNNYIIPNK SEELEARFAG IDGTSTYTSG DQKTIKSTRK





301
KNSGKTPHLL LMLLPSYRLE SQQTNRRKKR ALDAAYCFRN VQDNCCLRPL YIDFKRDLGW





361
KWIHEPKGYN ANFCAGACPY LWSSDTQHSR VLSLYNTINP EASASPCCVS QDLEPLTILY





421
YIGKTPKIEQ LSNMIVKSCK CS











SEQ ID NO: 209



TRANSFORMING GROWTH FACTOR BETA 2 (TGFB2), ISOFORM CRA_B



EAW93327.1









1
MHYCVLSAFL ILHLVTVALS LSTCSTLDMD QFMRKRIEAI RGQILSKLKL TSPPEDYPEP






61
EEVPPEVISI YNSTRDLLQE KASRRAAACE RERSDEEYYA KEVYKIDMPP FFPSENAIPP





121
TFYRPYFRIV RFDVSAMEKN ASNLVKAEFR VFRLQNPKAR VPEQRIELYQ ILKSKDLTSP





181
TQRYIDSKVV KTRAEGEWLS FDVTDAVHEW LHHKDRNLGF KISLHCPCCT FVPSNNYIIP





241
NKSEELEARF AGIDGTSTYT SGDQKTIKST RKKNSGKTPH LLLMLLPSYR LESQQTNRRK





301
KRALDAAYCF RNVQDNCCLR PLYIDFKRDL GWKWIHEPKG YNANFCAGAC PYLWSSDTQH





361
SRVLSLYNTI NPEASASPCC VSQDLEPLTI LYYIGKTPKI EQLSNMIVKS CKCS











SEQ ID NO: 210



BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF)



AAO15434.1









1
MTILFLTMVI SYFGCMKAAP MKEANIRGQG GLAYPGVRTH GTLESVNGPK AGSRGLTSLA






61
DTFEHVIEEL LDEDQKVRPN EENNKDADLY TSRVMLSSQV PLEPPLLFLL EEYKNYLDAA





121
NMSMRVRRHS DPARRGELSV CDSISEWVTA ADKKTAVDMS GGTVTVLEKV PVSKGQLKQY





181
FYETKCNPMG YTKEGCRGID KRHWNSQCRT TQSYVRALTM DSKKRIGWRF IRIDTSCVCT





241
LTIKRGR











SEQ ID NO: 211



CILIARY NEUROTROPHIC FACTOR (CNTF)



NP_000605.1









1
MAFTEHSPLT PHRRDLCSRS IWLARKIRSD LTALTESYVK HQGLNKNINL DSADGMPVAS






61
TDQWSELTEA ERLQENLQAY RTFHVLLARL LEDQQVHFTP TEGDFHQAIH TLLLQVAAFA





121
YQIEELMILL EYKIPRNEAD GMPINVGDGG LFEKKLWGLK VLQELSQWTV RSIHDLRFIS





181
SHQTGIPARG SHYIANNKKM











SEQ ID NO: 212



PROSTAGLANDIN-ENDOPEROXIDE SYNTHASE 2 (PTGS2)



BAA05698.1









1
MLARALLLCA VLALSHTANP CCSHPCQNRG VCMSVGFDQY KCDCTRTGFY GENCSTPEFL






61
TRIKLFLKPT PNTVHYILTH FKGFWNVVNN IPFLRNAIMS YVLTSRSHLI DSPPTYNADY





121
GYKSWEAFSN LSYYTRALPP VPDDCPTPLG VKGKKQLPDS NEIVEKLLLR RKFIPDPQGS





181
NMMFAFFAQH FTHQFFKTDH KRGPAFTNGL GHGVDLNHIY GETLARQRKL RLFKDGKMKY





241
QIIDGEMYPP TVKDTQAEMI YPPQVPEHLR FAVGQEVFGL VPGLMMYATI WLREHNRVCD





301
VLKQEHPEWG DEQLFQTSRL ILIGETIKIV IEDYVQHLSG YHFKLKFDPE LLFNKQFQYQ





361
NRIAAEFNTL YHWHPLLPDT FQIHDQKYNY QQFIYNNSIL LEHGITQFVE SFTRQIAGRV





421
AGGRNVPPAV QKVSQASIDQ SRQMKYQSFN EYRKRFMLKP YESFEELTGE KEMSAELEAL





481
YGDIDAVELY PALLVEKPRP DAIFGETMVE VGAPFSLKGL MGNVICSPAY WKPSTFGGEV





541
GFQIINTASI QSLICNNVKG CPFTSFSVPD PELIKTVTIN ASSSRSGLDD INPTVLLKER





601
STEL











SEQ ID NO: 213



PROSTAGLANDIN F RECEPTOR (PTGFR)



AAQ76788.1









1
MSMNNSKQLV SPAAALLSNT TCQTENRLSV FFSVIFMTVG ILSNSLAIAI LMKAYQRFRQ






61
KSKASFLLLA SGLVITDFFG HLINGAIAVF VYASDKEWIR FDQSNVLCSI FGICMVFSGL





121
CPLLLGSVMA IERCIGVTKP IFHSTKITSK HVKMMLSGVC LFAVFIALLP ILGHRDYKIQ





181
ASRTWCFYNT EDIKDWEDRF YLLLFSFLGL LALGVSLLCN AITGITLLRV KFKSQQHRQG





241
RSHHLEMVIQ LLAIMCVSCI CWSPFLVTMA NIGINGNHSL ETCETTLFAL RMATWNQILD





301
PWVYILLRKA VLKNLYKLAS QCCGVHVISL HIWELSSIKN SLKVAAISES PVAEKSAST











SEQ ID NO: 214



PROSTAGLANDIN F RECEPTOR (PTGFR), ISOFORM CRA_A



EAX06350.1









1
MSMNNSKQLV SPAAALLSNT TCQTENRLSV FFSVIFMTVG ILSNSLAIAI LMKAYQRFRQ






61
KSKASFLLLA SGLVITDFFG HLINGAIAVF VYASDKEWIR FDQSNVLCSI FGICMVFSGL





121
CPLLLGSVMA IERCIGVTKP IFHSTKITSK HVKMMLSGVC LFAVFIALLP ILGHRDYKIQ





181
ASRTWCFYNT EDIKDWEDRF YLLLFSFLGL LALGVSLLCN AITGITLLRV KFKSQQHRQG





241
RSHHLEMVIQ LLAIMCVSCI CWSPFLVTMA NIGINGNHSL ETCETTLFAL RMATWNQILD





301
PWVYILLRKA VLKNLYKLAS QCCGVHVISL HIWELSSIKN SLKVAAISES PVAEKSAST











SEQ ID NO: 215



PROSTAGLANDIN F RECEPTOR (PTGFR), ISOFORM CRA_B



EAX06351.1









1
MSMNNSKQLV SPAAALLSNT TCQTENRLSV FFSVIFMTVG ILSNSLAIAI LMKAYQRFRQ






61
KSKASFLLLA SGLVITDFFG HLINGAIAVF VYASDKEWIR FDQSNVLCSI FGICMVFSGL





121
CPLLLGSVMA IERCIGVTKP IFHSTKITSK HVKMMLSGVC LFAVFIALLP ILGHRDYKIQ





181
ASRTWCFYNT EDIKDWEDRF YLLLFSFLGL LALGVSLLCN AITGITLLRV KFKSQQHRQG





241
RSHHLEMVIQ LLAIMCVSCI CWSPFLGYRI ILNGKEKYKV YEEQSDFLHR LQWPTLE











SEQ ID NO: 216



HYALURONIDASE



AAC70915.1









1
MTTQLGPALV LGVALCLGCG QPLPQVPERP FSVLWNVPSA HCEARFGVHL PLNALGIIAN






61
RGQHFHGQNM TIFYKNQLGL YPYFGPRGTA HNGGIPQALP LDRHLALAAY QIHHSLRPGF





121
AGPAVLDWEE WCPLWAGNWG RRRAYQAASW AWAQQVFPDL DPQEQLYKAY TGFEQAARAL





181
MEDTLRVAQA LRPHGLWGFY HYPACGNGWH SMASNYTGRC HAATLARNTQ LHWLWAASSA





241
LFPSIYLPPR LPPAHHQAFV RHRLEEAFRV ALVGHRHPLP VLAYVRLTHR RSGRFLSQDD





301
LVQSIGVSAA LGAAGVVLWG DLSLSSSEEE CWHLHDYLVD TLGPYVINVT RAAMACSHQR





361
CHGHGRCARR DPGQMEAFLH LWPDGSLGDW KSFSCHCYWG WAGPTCQEPS LGLKKQYKAR





421
APATASSFPC CHFSSPGTTL SHSCSIQFTV NPPKHTPRFP WNP











SEQ ID NO: 217



PIGMENT EPITHELIUM-DERIVED FACTOR (PEDF);



P36955.4









1
MQALVLLLCI GALLGHSSCQ NPASPPEEGS PDPDSTGALV EEEDPFFKVP VNKLAAAVSN






61
FGYDLYRVRS STSPTTNVLL SPLSVATALS ALSLGAEQRT ESIIHRALYY DLISSPDIHG





121
TYKELLDTVT APQKNLKSAS RIVFEKKLRI KSSFVAPLEK SYGTRPRVLT GNPRLDLQEI





181
NNWVQAQMKG KLARSTKEIP DEISILLLGV AHFKGQWVTK FDSRKTSLED FYLDEERTVR





241
VPMMSDPKAV LRYGLDSDLS CKIAQLPLTG SMSIIFFLPL KVTQNLTLIE ESLTSEFIHD





301
IDRELKTVQA VLTVPKLKLS YEGEVTKSLQ EMKLQSLFDS PDFSKITGKP IKLTQVEHRA





361
GFEWNEDGAG TTPSPGLQPA HLTFPLDYHL NQPFIFVLRD TDTGALLFIG KILDPRGP











SEQ ID NO: 218



PIGMENT EPITHELIUM-DERIVED FACTOR (PEDF); ISOFORM 1 PRECURSOR



NP_001316832.1









1
MQALVLLLCI GALLGHSSCQ NPASPPEEGS PDPDSTGALV EEEDPFFKVP VNKLAAAVSN






61
FGYDLYRVRS STSPTTNVLL SPLSVATALS ALSLGAEQRT ESIIHRALYY DLISSPDIHG





121
TYKELLDTVT APQKNLKSAS RIVFEKKLRI KSSFVAPLEK SYGTRPRVLT GNPRLDLQEI





181
NNWVQAQMKG KLARSTKEIP DEISILLLGV AHFKGQWVTK FDSRKTSLED FYLDEERTVR





241
VPMMSDPKAV LRYGLDSDLS CKIAQLPLTG SMSIIFFLPL KVTQNLTLIE ESLTSEFIHD





301
IDRELKTVQA VLTVPKLKLS YEGEVTKSLQ EMKLQSLFDS PDFSKITGKP IKLTQVEHRA





361
GFEWNEDGAG TTPSPGLQPA HLTFPLDYHL NQPFIFVLRD TDTGALLFIG KILDPRGP











SEQ ID NO: 219



PIGMENT EPITHELIUM-DERIVED FACTOR (PEDF); ISOFORM 2



NP_001316834.1









1
MKGKLARSTK EIPDEISILL LGVAHFKGQW VTKFDSRKTS LEDFYLDEER TVRVPMMSDP






61
KAVLRYGLDS DLSCKIAQLP LTGSMSIIFF LPLKVTQNLT LIEESLTSEF IHDIDRELKT





121
VQAVLTVPKL KLSYEGEVTK SLQEMKLQSL FDSPDFSKIT GKPIKLTQVE HRAGFEWNED





181
GAGTTPSPGL QPAHLTFPLD YHLNQPFIFV LRDTDTGALL FIGKILDPRG P











SEQ ID NO: 220



VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)



CAA44447.1









1
MNFLLSWVHW SLALLLYLHH AKWSQAAPMA EGGGQNHHEV VKFMDVYQRS YCHPIETLVD






61
IFQEYPDEIE YIFKPSCVPL MRCGGCCNDE GLECVPTEES NITMQIMRIK PHQGQHIGEM





121
SFLQHNKCEC RPKKDRARQE NPCGPCSERR KHLFVQDPQT CKCSCKNTDS RCKARQLELN





181
ERTCRCDKPR R











SEQ ID NO: 221



PLACENTAL GROWTH FACTOR (PGF)



AAH07789.1









1
MPVMRLFPCF LQLLAGLALP AVPPQQWALS AGNGSSEVEV VPFQEVWGRS YCRALERLVD






61
VVSEYPSEVE HMFSPSCVSL LRCTGCCGDE NLHCVPVETA NVTMQLLKIR SGDRPSYVEL





121
TFSQHVRCEC RPLREKMKPE RRRPKGRGKR RREKQRPTDC HLCGDAVPRR











SEQ ID NO: 222



MYOCILIN (MYOC)



BAA24532.1









1
MPAVQLLLLA CLVWDVGART AQLRKANDQS GRCQYTFSVA SPNESSCPEQ SQAMSVIHNL






61
QRDSSTQRLD LEATKARLSS LESLLHQLTL DQAARPQETQ EGLQRELGTL RRERDQLETQ





121
TRELETAYSN LLRDKSVLEE EKKRLRQENE NLARRLESSS QEVARLRRGQ CPQTRDTARA





181
VPPGSREVST WNLDTLAFQE LKSELTEVPA SRILKESPSG YLRSGEGDTG CGELVWVGEP





241
LTLRTAETIT GKYGVWMRDP KPTYPYTQET TWRIDTVGTD VRQVFEYDLI SQFMQGYPSK





301
VHILPRPLES TGAVVYSGSL YFQGAESRTV IRYELNTETV KAEKEIPGAG YHGQFPYSWG





361
GYTDIDLAVD EAGLWVIYST DEAKGAIVLS KLNPENLELE QTWETNIRKQ SVANAFIICG





421
TLYTVSSYTS ADATVNFAYD TGTGISKTLT IPFKNRYKYS SMIDYNPLEK KLFAWDNLNM





481
VTYDIKLSKM











SEQ ID NO: 223



C-C MOTIF CHEMOKINE RECEPTOR 5 (CCR5)



NP_001093638.1









1
MDYQVSSPIY DINYYTSEPC QKINVKQIAA RLLPPLYSLV FIFGFVGNML VILILINCKR






61
LKSMTDIYLL NLAISDLFFL LTVPFWAHYA AAQWDFGNTM CQLLTGLYFI GFFSGIFFII





121
LLTIDRYLAV VHAVFALKAR TVTFGVVTSV ITWVVAVFAS LPGIIFTRSQ KEGLHYTCSS





181
HFPYSQYQFW KNFQTLKIVI LGLVLPLLVM VICYSGILKT LLRCRNEKKR HRAVRLIFTI





241
MIVYFLFWAP YNIVLLLNTF QEFFGLNNCS SSNRLDQAMQ VTETLGMTHC CINPIIYAFV





301
GEKFRNYLLV FFQKHIAKRF CKCCSIFQQE APERASSVYT RSTGEQEISV GL











SEQ ID NO: 224



CD19



AAB60697.1









1
MPPPRLLFFL LFLTPMEVRP EEPLVVKVEG EGDNAVLQCL KGTSDGPTQQ LTWSRESPLK






61
PFLKLSLGLP GLGIHMRPLA SWLFIFNVSQ QMGGFYLCQP GPPSEKAWQP GWTVNVEGSG





121
ELFRWNVSDL GGLGCGLKNR SSEGPSSPSG KLMSPKLYVW AKDRPEIWEG EPPCVPPRDS





181
LNQSLSQDLT MAPGSTLWLS CGVPPDSVSR GPLSWTHVHP KGPKSLLSLE LKDDRPARDM





241
WVMETGLLLP RATAQDAGKY YCHRGNLTMS FHLEITARPV LWHWLLRTGG WKVSAVTLAY





301
LIFCLCSLVG ILHLQRALVL RRKRKRMTDP TRRFFKVTPP PGSGPQNQYG NVLSLPTPTS





361
GLGRAQRWAA GLGGTAPSYG NPSSDVQADG ALGSRSPPGV GPEEEEGEGY EEPDSEEDSE





421
FYENDSNLGQ DQLSQDGSGY ENPEDEPLGP EDEDSFSNAE SYENEDEELT QPVARTMDFL





481
SPHGSAWDPS REATSLGSQS YEDMRGILYA APQLRSIRGQ PGPNHEEDAD SYENMDNPDG





541
PDPAWGGGGR MGTWSTR











SEQ ID NO: 225



CRUMBS CELL POLARITY COMPLEX COMPONENT 2 (CRB2), PRECURSOR



NP_775960.4









1
MALARPGTPD PQALASVLLL LLWAPALSLL AGTVPSEPPS ACASDPCAPG TECQATESGG






61
YTCGPMEPRG CATQPCHHGA LCVPQGPDPT GFRCYCVPGF QGPRCELDID ECASRPCHHG





121
ATCRNLADRY ECHCPLGYAG VTCEMEVDEC ASAPCLHGGS CLDGVGSFRC VCAPGYGGTR





181
CQLDLDECQS QPCAHGGTCH DLVNGFRCDC AGTGYEGTHC EREVLECASA PCEHNASCLE





241
GLGSFRCLCW PGYSGELCEV DEDECASSPC QHGGRCLQRS DPALYGGVQA AFPGAFSFRH





301
AAGFLCHCPP GFEGADCGVE VDECASRPCL NGGHCQDLPN GFQCHCPDGY AGPTCEEDVD





361
ECLSDPCLHG GTCSDTVAGY ICRCPETWGG RDCSVQLTGC QGHTCPLAAT CIPIFESGVH





421
SYVCHCPPGT HGPFCGQNTT FSVMAGSPIQ ASVPAGGPLG LALRFRTTLP AGTLATRNDT





481
KESLELALVA ATLQATLWSY STTVLVLRLP DLALNDGHWH QVEVVLHLAT LELRLWHEGC





541
PARLCVASGP VALASTASAT PLPAGISSAQ LGDATFAGCL QDVRVDGHLL LPEDLGENVL





601
LGCERREQCR PLPCVHGGSC VDLWTHFRCD CARPHRGPTC ADEIPAATFG LGGAPSSASF





661
LLQELPGPNL TVSFLLRTRE SAGLLLQFAN DSAAGLTVFL SEGRIRAEVP GSPAVVLPGR





721
WDDGLRHLVM LSFGPDQLQD LGQHVHVGGR LLAADSQPWG GPFRGCLQDL RLDGCHLPFF





781
PLPLDNSSQP SELGGRQSWN LTAGCVSEDM CSPDPCFNGG TCLVTWNDFH CTCPANFTGP





841
TCAQQLWCPG QPCLPPATCE EVPDGFVCVA EATFREGPPA AFSGHNASSG RLLGGLSLAF





901
RTRDSEAWLL RAAAGALEGV WLAVRNGSLA GGVRGGHGLP GAVLPIPGPR VADGAWHRVR





961
LAMERPAATT SRWLLWLDGA ATPVALRGLA SDLGFLQGPG AVRILLAENF TGCLGRVALG





1021
GLPLPLARPR PGAAPGAREH FASWPGTPAP ILGCRGAPVC APSPCLHDGA CRDLFDAFAC





1081
ACGPGWEGPR CEAHVDPCHS APCARGRCHT HPDGRFECRC PPGFGGPRCR LPVPSKECSL





1141
NVTCLDGSPC EGGSPAANCS CLEGLAGQRC QVPTLPCEAN PCLNGGTCRA AGGVSECICN





1201
ARFSGQFCEV AKGLPLPLPF PLLEVAVPAA CACLLLLLLG LLSGILAARK RRQSEGTYSP





1261
SQQEVAGARL EMDSVLKVPP EERLI











SEQ ID NO: 226



CRUMBS CELL POLARITY COMPLEX COMPONENT 2 (CRB2), ISOFORM X1



XP_011516858.1









1
MALARPGTPD PQALASVLLL LLWAPALSLL AGTVPSEPPS ACASDPCAPG TECQATESGG






61
YTCGPMEPRG CATQPCHHGA LCVPQGPDPT GFRCYCVPGF QGPRCELDID ECASRPCHHG





121
ATCRNLADRY ECHCPLGYAG VTCEMEVDEC ASAPCLHGGS CLDGVGSFRC VCAPGYGGTR





181
CQLDLDECQS QPCAHGGTCH DLVNGFRCDC AGTGYEGTHC EREVLECASA PCEHNASCLE





241
GLGSFRCLCW PGYSGELCEV DEDECASSPC QHGGRCLQRS DPALYGGVQA AFPGAFSFRH





301
AAGFLCHCPP GFEGADCGVE VDECASRPCL NGGHCQDLPN GFQCHCPDGY AGPTCEEDVD





361
ECLSDPCLHG GTCSDTVAGY ICRCPETWGG RDCSVQLTGC QGHTCPLAAT CIPIFESGVH





421
SYVCHCPPGT HGPFCGQNTT FSVMAGSPIQ ASVPAGGPLG LALRFRTTLP AGTLATRNDT





481
KESLELALVA ATLQATLWSY STTVLVLRLP DLALNDGHWH QVEVVLHLAT LELRLWHEGC





541
PARLCVASGP VALASTASAT PLPAGISSAQ LGDATFAGCL QDVRVDGHLL LPEDLGENVL





601
LGCERREQCR PLPCVHGGSC VDLWTHFRCD CARPHRGPTC ADEIPAATFG LGGAPSSASF





661
LLQELPGPNL TVSFLLRTRE SAGLLLQFAN DSAAGLTVFL SEGRIRAEVP GSPAVVLPGR





721
WDDGLRHLVM LSFGPDQLQD LGQHVHVGGR LLAADSQPWG GPFRGCLQDL RLDGCHLPFF





781
PLPLDNSSQP SELGGRQSWN LTAGCVSEDM CSPDPCFNGG TCLVTWNDFH CTCPANFTGP





841
TCAQQLWCPG QPCLPPATCV AEATFREGPP AAFSGHNASS GRLLGGLSLA FRTRDSEAWL





901
LRAAAGALEG VWLAVRNGSL AGGVRGGHGL PGAVLPIPGP RVADGAWHRV RLAMERPAAT





961
TSRWLLWLDG AATPVALRGL ASDLGFLQGP GAVRILLAEN FTGCLGRVAL GGLPLPLARP





1021
RPGAAPGARE HFASWPGTPA PILGCRGAPV CAPSPCLHDG ACRDLFDAFA CACGPGWEGP





1081
RCEAHVDPCH SAPCARGRCH THPDGRFECR CPPGFGGPRC RLPVPSKECS LNVTCLDGSP





1141
CEGGSPAANC SCLEGLAGQR CQVPTLPCEA NPCLNGGTCR AAGGVSECIC NARFSGQFCE





1201
VAKGLPLPLP FPLLEVAVPA ACACLLLLLL GLLSGILAAR KRRQSEGTYS PSQQEVAGAR





1261
LEMDSVLKVP PEERLI











SEQ ID NO: 227



CRUMBS CELL POLARITY COMPLEX COMPONENT 2 (CRB2), ISOFORM X2



XP_011516860.1









1
MEPRGCATQP CHHGALCVPQ GPDPTGFRCY CVPGFQGPRC ELDIDECASR PCHHGATCRN






61
LADRYECHCP LGYAGVTCEM EVDECASAPC LHGGSCLDGV GSFRCVCAPG YGGTRCQLDL





121
DECQSQPCAH GGTCHDLVNG FRCDCAGTGY EGTHCEREVL ECASAPCEHN ASCLEGLGSF





181
RCLCWPGYSG ELCEVDEDEC ASSPCQHGGR CLQRSDPALY GGVQAAFPGA FSFRHAAGFL





241
CHCPPGFEGA DCGVEVDECA SRPCLNGGHC QDLPNGFQCH CPDGYAGPTC EEDVDECLSD





301
PCLHGGTCSD TVAGYICRCP ETWGGRDCSV QLTGCQGHTC PLAATCIPIF ESGVHSYVCH





361
CPPGTHGPFC GQNTTFSVMA GSPIQASVPA GGPLGLALRF RTTLPAGTLA TRNDTKESLE





421
LALVAATLQA TLWSYSTTVL VLRLPDLALN DGHWHQVEVV LHLATLELRL WHEGCPARLC





481
VASGPVALAS TASATPLPAG ISSAQLGDAT FAGCLQDVRV DGHLLLPEDL GENVLLGCER





541
REQCRPLPCV HGGSCVDLWT HFRCDCARPH RGPTCADEIP AATFGLGGAP SSASFLLQEL





601
PGPNLTVSFL LRTRESAGLL LQFANDSAAG LTVFLSEGRI RAEVPGSPAV VLPGRWDDGL





661
RHLVMLSFGP DQLQDLGQHV HVGGRLLAAD SQPWGGPFRG CLQDLRLDGC HLPFFPLPLD





721
NSSQPSELGG RQSWNLTAGC VSEDMCSPDP CFNGGTCLVT WNDFHCTCPA NFTGPTCAQQ





781
LWCPGQPCLP PATCEEVPDG FVCVAEATFR EGPPAAFSGH NASSGRLLGG LSLAFRTRDS





841
EAWLLRAAAG ALEGVWLAVR NGSLAGGVRG GHGLPGAVLP IPGPRVADGA WHRVRLAMER





901
PAATTSRWLL WLDGAATPVA LRGLASDLGF LQGPGAVRIL LAENFTGCLG RVALGGLPLP





961
LARPRPGAAP GAREHFASWP GTPAPILGCR GAPVCAPSPC LHDGACRDLF DAFACACGPG





1021
WEGPRCEAHV DPCHSAPCAR GRCHTHPDGR FECRCPPGFG GPRCRLPVPS KECSLNVTCL





1081
DGSPCEGGSP AANCSCLEGL AGQRCQVPTL PCEANPCLNG GTCRAAGGVS ECICNARFSG





1141
QFCEVAKGLP LPLPFPLLEV AVPAACACLL LLLLGLLSGI LAARKRRQSE GTYSPSQQEV





1201
AGARLEMDSV LKVPPEERLI











SEQ ID NO: 228



HISTONE DEACETYLASE 4 (HDAC4)



NP_006028.2









1
MSSQSHPDGL SGRDQPVELL NPARVNHMPS TVDVATALPL QVAPSAVPMD LRLDHQFSLP






61
VAEPALREQQ LQQELLALKQ KQQIQRQILI AEFQRQHEQL SRQHEAQLHE HIKQQQEMLA





121
MKHQQELLEH QRKLERHRQE QELEKQHREQ KLQQLKNKEK GKESAVASTE VKMKLQEFVL





181
NKKKALAHRN LNHCISSDPR YWYGKTQHSS LDQSSPPQSG VSTSYNHPVL GMYDAKDDFP





241
LRKTASEPNL KLRSRLKQKV AERRSSPLLR RKDGPVVTAL KKRPLDVTDS ACSSAPGSGP





301
SSPNNSSGSV SAENGIAPAV PSIPAETSLA HRLVAREGSA APLPLYTSPS LPNITLGLPA





361
TGPSAGTAGQ QDAERLTLPA LQQRLSLFPG THLTPYLSTS PLERDGGAAH SPLLQHMVLL





421
EQPPAQAPLV TGLGALPLHA QSLVGADRVS PSIHKLRQHR PLGRTQSAPL PQNAQALQHL





481
VIQQQHQQFL EKHKQQFQQQ QLQMNKIIPK PSEPARQPES HPEETEEELR EHQALLDEPY





541
LDRLPGQKEA HAQAGVQVKQ EPIESDEEEA EPPREVEPGQ RQPSEQELLF RQQALLLEQQ





601
RIHQLRNYQA SMEAAGIPVS FGGHRPLSRA QSSPASATFP VSVQEPPTKP RFTTGLVYDT





661
LMLKHQCTCG SSSSHPEHAG RIQSIWSRLQ ETGLRGKCEC IRGRKATLEE LQTVHSEAHT





721
LLYGTNPLNR QKLDSKKLLG SLASVFVRLP CGGVGVDSDT IWNEVHSAGA ARLAVGCVVE





781
LVFKVATGEL KNGFAVVRPP GHHAEESTPM GFCYFNSVAV AAKLLQQRLS VSKILIVDWD





841
VHHGNGTQQA FYSDPSVLYM SLHRYDDGNF FPGSGAPDEV GTGPGVGFNV NMAFTGGLDP





901
PMGDAEYLAA FRTVVMPIAS EFAPDVVLVS SGFDAVEGHP TPLGGYNLSA RCFGYLTKQL





961
MGLAGGRIVL ALEGGHDLTA ICDASEACVS ALLGNELDPL PEKVLQQRPN ANAVRSMEKV





1021
MEIHSKYWRC LQRTTSTAGR SLIEAQTCEN EEAETVTAMA SLSVGVKPAE KRPDEEPMEE





1081
EPPL











SEQ ID NO: 229



HISTONE DEACETYLASE 4 (HDAC4) ISOFORM X2



XP_006712940.1









1
MNIDLCAFEI QKTSSPGYEV WFRKQYLAVD GDGLSGRDQP VELLNPARVN HMPSTVDVAT






61
ALPLQVAPSA VPMDLRLDHQ FSLPVAEPAL REQQLQQELL ALKQKQQIQR QILIAEFQRQ





121
HEQLSRQHEA QLHEHIKQQQ EMLAMKHQQE LLEHQRKLER HRQEQELEKQ HREQKLQQLK





181
NKEKGKESAV ASTEVKMKLQ EFVLNKKKAL AHRNLNHCIS SDPRYWYGKT QHSSLDQSSP





241
PQSGVSTSYN HPVLGMYDAK DDFPLRKTAS EPNLKLRSRL KQKVAERRSS PLLRRKDGPV





301
VTALKKRPLD VTDSACSSAP GSGPSSPNNS SGSVSAENGI APAVPSIPAE TSLAHRLVAR





361
EGSAAPLPLY TSPSLPNITL GLPATGPSAG TAGQQDAERL TLPALQQRLS LFPGTHLTPY





421
LSTSPLERDG GAAHSPLLQH MVLLEQPPAQ APLVTGLGAL PLHAQSLVGA DRVSPSIHKL





481
RQHRPLGRTQ SAPLPQNAQA LQHLVIQQQH QQFLEKHKQQ FQQQQLQMNK IIPKPSEPAR





541
QPESHPEETE EELREHQALL DEPYLDRLPG QKEAHAQAGV QVKQEPIESD EEEAEPPREV





601
EPGQRQPSEQ ELLFRQQALL LEQQRIHQLR NYQASMEAAG IPVSFGGHRP LSRAQSSPAS





661
ATFPVSVQEP PTKPRFTTGL VYDTLMLKHQ CTCGSSSSHP EHAGRIQSIW SRLQETGLRG





721
KCECIRGRKA TLEELQTVHS EAHTLLYGTN PLNRQKLDSK KLLGSLASVF VRLPCGGVGV





781
DSDTIWNEVH SAGAARLAVG CVVELVFKVA TGELKNGFAV VRPPGHHAEE STPMGFCYFN





841
SVAVAAKLLQ QRLSVSKILI VDWDVHHGNG TQQAFYSDPS VLYMSLHRYD DGNFFPGSGA





901
PDEVGTGPGV GFNVNMAFTG GLDPPMGDAE YLAAFRTVVM PIASEFAPDV VLVSSGFDAV





961
EGHPTPLGGY NLSARCFGYL TKQLMGLAGG RIVLALEGGH DLTAICDASE ACVSALLGNE





1021
LDPLPEKVLQ QRPNANAVRS MEKVMEIHSK YWRCLQRTTS TAGRSLIEAQ TCENEEAETV





1081
TAMASLSVGV KPAEKRPDEE PMEEEPPL











SEQ ID NO: 230



HISTONE DEACETYLASE 4 (HDAC4) ISOFORM X3



XP_011510520.1









1
MNIDLCAFEI QKTSSPGYEV WFRKQYLAVD GDGLSGRDQP VELLNPARVN HMPSTVDVAT






61
ALPLQVAPSA VPMDLRLDHQ FSLPVAEPAL REQQLQQELL ALKQKQQIQR QILIAEFQRQ





121
HEQLSRQHEA QLHEHIKQQQ EMLAMKHQQE LLEHQRKLER HRQEQELEKQ HREQKLQQLK





181
NKEKGKESAV ASTEVKMKLQ EFVLNKKKAL AHRNLNHCIS SDPRYWYGKT QHSSLDQSSP





241
PQSGVSTSYN HPVLGMYDAK DDFPLRKTAS EPNLKLRSRL KQKVAERRSS PLLRRKDGPV





301
VTALKKRPLD VTDSACSSAP GSGPSSPNNS SGSVSAENGI APAVPSIPAE TSLAHRLVAR





361
EGSAAPLPLY TSPSLPNITL GLPATGPSAG TAGQQDAERL TLPALQQRLS LFPGTHLTPY





421
LSTSPLERDG GAAHSPLLQH MVLLEQPPAQ APLVTDWYLS GLGALPLHAQ SLVGADRVSP





481
SIHKLRQHRP LGRTQSAPLP QNAQALQHLV IQQQHQQFLE KHKQQFQQQQ LQMNKIIPKP





541
SEPARQPESH PEETEEELRE HQALLDEPYL DRLPGQKEAH AQAGVQVKQE PIESDEEEAE





601
PPREVEPGQR QPSEQELLFR QQALLLEQQR IHQLRNYQAS MEAAGIPVSF GGHRPLSRAQ





661
SSPASATFPV SVQEPPTKPR FTTGLVYDTL MLKHQCTCGS SSSHPEHAGR IQSIWSRLQE





721
TGLRGKCECI RGRKATLEEL QTVHSEAHTL LYGTNPLNRQ KLDSSLASVF VRLPCGGVGV





781
DSDTIWNEVH SAGAARLAVG CVVELVFKVA TGELKNGFAV VRPPGHHAEE STPMGFCYFN





841
SVAVAAKLLQ QRLSVSKILI VDWDVHHGNG TQQAFYSDPS VLYMSLHRYD DGNFFPGSGA





901
PDEVGTGPGV GFNVNMAFTG GLDPPMGDAE YLAAFRTVVM PIASEFAPDV VLVSSGFDAV





961
EGHPTPLGGY NLSARCFGYL TKQLMGLAGG RIVLALEGGH DLTAICDASE ACVSALLGNE





1021
LDPLPEKVLQ QRPNANAVRS MEKVMEIHSK YWRCLQRTTS TAGRSLIEAQ TCENEEAETV





1081
TAMASLSVGV KPAEKRPDEE PMEEEPPL











SEQ ID NO: 231



HISTONE DEACETYLASE 4 (HDAC4) ISOFORM X4



XP_011510521.1









1
MNIDLCAFEI QKTSSPGYEV WFRKQYLAVD GDGLSGRDQP VELLNPARVN HMPSTVDVAT






61
ALPLQVAPSA VPMDLRLDHQ FSLPVAEPAL REQQLQQELL ALKQKQQIQR QILIAEFQRQ





121
HEQLSRQHEA QLHEHIKQQQ EMLAMKHQQE LLEHQRKLER HRQEQELEKQ HREQKLQQLK





181
NKEKGKESAV ASTEVKMKLQ EFVLNKKKAL AHRNLNHCIS SDPRYWYGKT QHSSLDQSSP





241
PQSGVSTSYN HPVLGMYDAK DDFPLRKTAS EPNLKLRSRL KQKVAERRSS PLLRRKDGPV





301
VTALKKRPLD VTDSACSSAP GSGPSSPNNS SGSVSAENGI APAVPSIPAE TSLAHRLVAR





361
EGSAAPLPLY TSPSLPNITL GLPATGPSAG TAGQQDAERL TLPALQQRLS LFPGTHLTPY





421
LSTSPLERDG GAAHSPLLQH MVLLEQPPAQ APLVTGLGAL PLHAQSLVGA DRVSPSIHKL





481
RQHRPLGRTQ SAPLPQNAQA LQHLVIQQQH QQFLEKHKQQ FQQQQLQMNK IIPKPSEPAR





541
QPESHPEETE EELREHQALL DEPYLDRLPG QKEAHAQAGV QVKQEPIESD EEEAEPPREV





601
EPGQRQPSEQ ELLFRQQALL LEQQRIHQLR NYQASMEAAG IPVSFGGHRP LSRAQSSPAS





661
ATFPVSVQEP PTKPRFTTGL VYDTLMLKHQ CTCGSSSSHP EHAGRIQSIW SRLQETGLRG





721
KCECIRGRKA TLEELQTVHS EAHTLLYGTN PLNRQKLDSS LASVFVRLPC GGVGVDSDTI





781
WNEVHSAGAA RLAVGCVVEL VFKVATGELK NGFAVVRPPG HHAEESTPMG FCYFNSVAVA





841
AKLLQQRLSV SKILIVDWDV HHGNGTQQAF YSDPSVLYMS LHRYDDGNFF PGSGAPDEVG





901
TGPGVGFNVN MAFTGGLDPP MGDAEYLAAF RTVVMPIASE FAPDVVLVSS GFDAVEGHPT





961
PLGGYNLSAR CFGYLTKQLM GLAGGRIVLA LEGGHDLTAI CDASEACVSA LLGNELDPLP





1021
EKVLQQRPNA NAVRSMEKVM EIHSKYWRCL QRTTSTAGRS LIEAQTCENE EAETVTAMAS





1081
LSVGVKPAEK RPDEEPMEEE PPL











SEQ ID NO: 232



HISTONE DEACETYLASE 4 (HDAC4) ISOFORM X5



XP_011510522.1









1
MRKLGPREDG LSGRDQPVEL LNPARVNHMP STVDVATALP LQVAPSAVPM DLRLDHQFSL






61
PVAEPALREQ QLQQELLALK QKQQIQRQIL IAEFQRQHEQ LSRQHEAQLH EHIKQQQEML





121
AMKHQQELLE HQRKLERHRQ EQELEKQHRE QKLQQLKNKE KGKESAVAST EVKMKLQEFV





181
LNKKKALAHR NLNHCISSDP RYWYGKTQHS SLDQSSPPQS GVSTSYNHPV LGMYDAKDDF





241
PLRKTASEPN LKLRSRLKQK VAERRSSPLL RRKDGPVVTA LKKRPLDVTD SACSSAPGSG





301
PSSPNNSSGS VSAENGIAPA VPSIPAETSL AHRLVAREGS AAPLPLYTSP SLPNITLGLP





361
ATGPSAGTAG QQDAERLTLP ALQQRLSLFP GTHLTPYLST SPLERDGGAA HSPLLQHMVL





421
LEQPPAQAPL VTDWYLSGLG ALPLHAQSLV GADRVSPSIH KLRQHRPLGR TQSAPLPQNA





481
QALQHLVIQQ QHQQFLEKHK QQFQQQQLQM NKIIPKPSEP ARQPESHPEE TEEELREHQA





541
LLDEPYLDRL PGQKEAHAQA GVQVKQEPIE SDEEEAEPPR EVEPGQRQPS EQELLFRQQA





601
LLLEQQRIHQ LRNYQASMEA AGIPVSFGGH RPLSRAQSSP ASATFPVSVQ EPPTKPRFTT





661
GLVYDTLMLK HQCTCGSSSS HPEHAGRIQS IWSRLQETGL RGKCECIRGR KATLEELQTV





721
HSEAHTLLYG TNPLNRQKLD SKKLLGSLAS VFVRLPCGGV GVDSDTIWNE VHSAGAARLA





781
VGCVVELVFK VATGELKNGF AVVRPPGHHA EESTPMGFCY FNSVAVAAKL LQQRLSVSKI





841
LIVDWDVHHG NGTQQAFYSD PSVLYMSLHR YDDGNFFPGS GAPDEVGTGP GVGFNVNMAF





901
TGGLDPPMGD AEYLAAFRTV VMPIASEFAP DVVLVSSGFD AVEGHPTPLG GYNLSARCFG





961
YLTKQLMGLA GGRIVLALEG GHDLTAICDA SEACVSALLG NELDPLPEKV LQQRPNANAV





1021
RSMEKVMEIH SKYWRCLQRT TSTAGRSLIE AQTCENEEAE TVTAMASLSV GVKPAEKRPD





1081
EEPMEEEPPL











SEQ ID NO: 233



HISTONE DEACETYLASE 4 (HDAC4) ISOFORM X6



XP_011510523.1









1
MSSQSHPDGL SGRDQPVELL NPARVNHMPS TVDVATALPL QVAPSAVPMD LRLDHQFSLP






61
VAEPALREQQ LQQELLALKQ KQQIQRQILI AEFQRQHEQL SRQHEAQLHE HIKQQQEMLA





121
MKHQQELLEH QRKLERHRQE QELEKQHREQ KLQQLKNKEK GKESAVASTE VKMKLQEFVL





181
NKKKALAHRN LNHCISSDPR YWYGKTQHSS LDQSSPPQSG VSTSYNHPVL GMYDAKDDFP





241
LRKTASEPNL KLRSRLKQKV AERRSSPLLR RKDGPVVTAL KKRPLDVTDS ACSSAPGSGP





301
SSPNNSSGSV SAENGIAPAV PSIPAETSLA HRLVAREGSA APLPLYTSPS LPNITLGLPA





361
TGPSAGTAGQ QDAERLTLPA LQQRLSLFPG THLTPYLSTS PLERDGGAAH SPLLQHMVLL





421
EQPPAQAPLV TDWYLSGLGA LPLHAQSLVG ADRVSPSIHK LRQHRPLGRT QSAPLPQNAQ





481
ALQHLVIQQQ HQQFLEKHKQ QFQQQQLQMN KIIPKPSEPA RQPESHPEET EEELREHQAL





541
LDEPYLDRLP GQKEAHAQAG VQVKQEPIES DEEEAEPPRE VEPGQRQPSE QELLFRQQAL





601
LLEQQRIHQL RNYQASMEAA GIPVSFGGHR PLSRAQSSPA SATFPVSVQE PPTKPRFTTG





661
LVYDTLMLKH QCTCGSSSSH PEHAGRIQSI WSRLQETGLR GKCECIRGRK ATLEELQTVH





721
SEAHTLLYGT NPLNRQKLDS KKLLGSLASV FVRLPCGGVG VDSDTIWNEV HSAGAARLAV





781
GCVVELVFKV ATGELKNGFA VVRPPGHHAE ESTPMGFCYF NSVAVAAKLL QQRLSVSKIL





841
IVDWDVHHGN GTQQAFYSDP SVLYMSLHRY DDGNFFPGSG APDEVGTGPG VGFNVNMAFT





901
GGLDPPMGDA EYLAAFRTVV MPIASEFAPD VVLVSSGFDA VEGHPTPLGG YNLSARCFGY





961
LTKQLMGLAG GRIVLALEGG HDLTAICDAS EACVSALLGN ELDPLPEKVL QQRPNANAVR





1021
SMEKVMEIHS KYWRCLQRTT STAGRSLIEA QTCENEEAET VTAMASLSVG VKPAEKRPDE





1081
EPMEEEPPL











SEQ ID NO: 234



HISTONE DEACETYLASE 4 (HDAC4) ISOFORM X7



XP_011510526.1









1
MFDGLSGRDQ PVELLNPARV NHMPSTVDVA TALPLQVAPS AVPMDLRLDH QFSLPVAEPA






61
LREQQLQQEL LALKQKQQIQ RQILIAEFQR QHEQLSRQHE AQLHEHIKQQ QEMLAMKHQQ





121
ELLEHQRKLE RHRQEQELEK QHREQKLQQL KNKEKGKESA VASTEVKMKL QEFVLNKKKA





181
LAHRNLNHCI SSDPRYWYGK TQHSSLDQSS PPQSGVSTSY NHPVLGMYDA KDDFPLRKTA





241
SEPNLKLRSR LKQKVAERRS SPLLRRKDGP VVTALKKRPL DVTDSACSSA PGSGPSSPNN





301
SSGSVSAENG IAPAVPSIPA ETSLAHRLVA REGSAAPLPL YTSPSLPNIT LGLPATGPSA





361
GTAGQQDAER LTLPALQQRL SLFPGTHLTP YLSTSPLERD GGAAHSPLLQ HMVLLEQPPA





421
QAPLVTDWYL SGLGALPLHA QSLVGADRVS PSIHKLRQHR PLGRTQSAPL PQNAQALQHL





481
VIQQQHQQFL EKHKQQFQQQ QLQMNKIIPK PSEPARQPES HPEETEEELR EHQALLDEPY





541
LDRLPGQKEA HAQAGVQVKQ EPIESDEEEA EPPREVEPGQ RQPSEQELLF RQQALLLEQQ





601
RIHQLRNYQA SMEAAGIPVS FGGHRPLSRA QSSPASATFP VSVQEPPTKP RFTTGLVYDT





661
LMLKHQCTCG SSSSHPEHAG RIQSIWSRLQ ETGLRGKCEC IRGRKATLEE LQTVHSEAHT





721
LLYGTNPLNR QKLDSKKLLG SLASVFVRLP CGGVGVDSDT IWNEVHSAGA ARLAVGCVVE





781
LVFKVATGEL KNGFAVVRPP GHHAEESTPM GFCYFNSVAV AAKLLQQRLS VSKILIVDWD





841
VHHGNGTQQA FYSDPSVLYM SLHRYDDGNF FPGSGAPDEV GTGPGVGFNV NMAFTGGLDP





901
PMGDAEYLAA FRTVVMPIAS EFAPDVVLVS SGFDAVEGHP TPLGGYNLSA RCFGYLTKQL





961
MGLAGGRIVL ALEGGHDLTA ICDASEACVS ALLGNELDPL PEKVLQQRPN ANAVRSMEKV





1021
MEIHSKYWRC LQRTTSTAGR SLIEAQTCEN EEAETVTAMA SLSVGVKPAE KRPDEEPMEE





1081
EPPL











SEQ ID NO: 235



HISTONE DEACETYLASE 4 (HDAC4) ISOFORM X8



XP_011510527.1









1
MFDGLSGRDQ PVELLNPARV NHMPSTVDVA TALPLQVAPS AVPMDLRLDH QFSLPVAEPA






61
LREQQLQQEL LALKQKQQIQ RQILIAEFQR QHEQLSRQHE AQLHEHIKQQ QEMLAMKHQQ





121
ELLEHQRKLE RHRQEQELEK QHREQKLQQL KNKEKGKESA VASTEVKMKL QEFVLNKKKA





181
LAHRNLNHCI SSDPRYWYGK TQHSSLDQSS PPQSGVSTSY NHPVLGMYDA KDDFPLRKTA





241
SEPNLKLRSR LKQKVAERRS SPLLRRKDGP VVTALKKRPL DVTDSACSSA PGSGPSSPNN





301
SSGSVSAENG IAPAVPSIPA ETSLAHRLVA REGSAAPLPL YTSPSLPNIT LGLPATGPSA





361
GTAGQQDAER LTLPALQQRL SLFPGTHLTP YLSTSPLERD GGAAHSPLLQ HMVLLEQPPA





421
QAPLVTGLGA LPLHAQSLVG ADRVSPSIHK LRQHRPLGRT QSAPLPQNAQ ALQHLVIQQQ





481
HQQFLEKHKQ QFQQQQLQMN KIIPKPSEPA RQPESHPEET EEELREHQAL LDEPYLDRLP





541
GQKEAHAQAG VQVKQEPIES DEEEAEPPRE VEPGQRQPSE QELLFRQQAL LLEQQRIHQL





601
RNYQASMEAA GIPVSFGGHR PLSRAQSSPA SATFPVSVQE PPTKPRFTTG LVYDTLMLKH





661
QCTCGSSSSH PEHAGRIQSI WSRLQETGLR GKCECIRGRK ATLEELQTVH SEAHTLLYGT





721
NPLNRQKLDS KKLLGSLASV FVRLPCGGVG VDSDTIWNEV HSAGAARLAV GCVVELVFKV





781
ATGELKNGFA VVRPPGHHAE ESTPMGFCYF NSVAVAAKLL QQRLSVSKIL IVDWDVHHGN





841
GTQQAFYSDP SVLYMSLHRY DDGNFFPGSG APDEVGTGPG VGFNVNMAFT GGLDPPMGDA





901
EYLAAFRTVV MPIASEFAPD VVLVSSGFDA VEGHPTPLGG YNLSARCFGY LTKQLMGLAG





961
GRIVLALEGG HDLTAICDAS EACVSALLGN ELDPLPEKVL QQRPNANAVR SMEKVMEIHS





1021
KYWRCLQRTT STAGRSLIEA QTCENEEAET VTAMASLSVG VKPAEKRPDE EPMEEEPPL











SEQ ID NO: 236



HISTONE DEACETYLASE 4 (HDAC4) ISOFORM X9



XP_016860883.1









1
MNIDLCAFEI QKTSSPGYEV WFRKQYLAVD GDGLSGRDQP VELLNPARVN HMPSTVDVAT






61
ALPLQVAPSA VPMDLRLDHQ FSLPVAEPAL REQQLQQELL ALKQKQQIQR QILIAEFQRQ





121
HEQLSRQHEA QLHEHIKQQQ EMLAMKHQQE LLEHQRKLER HRQEQELEKQ HREQKLQQLK





181
NKEKGKESAV ASTEVKMKLQ EFVLNKKKAL AHRNLNHCIS SDPRYWYGKT QHSSLDQSSP





241
PQSGVSTSYN HPVLGMYDAK DDFPLRKTDS ACSSAPGSGP SSPNNSSGSV SAENGIAPAV





301
PSIPAETSLA HRLVAREGSA APLPLYTSPS LPNITLGLPA TGPSAGTAGQ QDAERLTLPA





361
LQQRLSLFPG THLTPYLSTS PLERDGGAAH SPLLQHMVLL EQPPAQAPLV TDWYLSGLGA





421
LPLHAQSLVG ADRVSPSIHK LRQHRPLGRT QSAPLPQNAQ ALQHLVIQQQ HQQFLEKHKQ





481
QFQQQQLQMN KIIPKPSEPA RQPESHPEET EEELREHQAL LDEPYLDRLP GQKEAHAQAG





541
VQVKQEPIES DEEEAEPPRE VEPGQRQPSE QELLFRQQAL LLEQQRIHQL RNYQASMEAA





601
GIPVSFGGHR PLSRAQSSPA SATFPVSVQE PPTKPRFTTG LVYDTLMLKH QCTCGSSSSH





661
PEHAGRIQSI WSRLQETGLR GKCECIRGRK ATLEELQTVH SEAHTLLYGT NPLNRQKLDS





721
KKLLGSLASV FVRLPCGGVG VDSDTIWNEV HSAGAARLAV GCVVELVFKV ATGELKNGFA





781
VVRPPGHHAE ESTPMGFCYF NSVAVAAKLL QQRLSVSKIL IVDWDVHHGN GTQQAFYSDP





841
SVLYMSLHRY DDGNFFPGSG APDEVGTGPG VGFNVNMAFT GGLDPPMGDA EYLAAFRTVV





901
MPIASEFAPD VVLVSSGFDA VEGHPTPLGG YNLSARCFGY LTKQLMGLAG GRIVLALEGG





961
HDLTAICDAS EACVSALLGN ELDPLPEKVL QQRPNANAVR SMEKVMEIHS KYWRCLQRTT





1021
STAGRSLIEA QTCENEEAET VTAMASLSVG VKPAEKRPDE EPMEEEPPL











SEQ ID NO: 237



HISTONE DEACETYLASE 4 (HDAC4) ISOFORM X10



XP_011510528.1









1
MSSQSHPVDV ATALPLQVAP SAVPMDLRLD HQFSLPVAEP ALREQQLQQE LLALKQKQQI






61
QRQILIAEFQ RQHEQLSRQH EAQLHEHIKQ QQEMLAMKHQ QELLEHQRKL ERHRQEQELE





121
KQHREQKLQQ LKNKEKGKES AVASTEVKMK LQEFVLNKKK ALAHRNLNHC ISSDPRYWYG





181
KTQHSSLDQS SPPQSGVSTS YNHPVLGMYD AKDDFPLRKT ASEPNLKLRS RLKQKVAERR





241
SSPLLRRKDG PVVTALKKRP LDVTDSACSS APGSGPSSPN NSSGSVSAEN GIAPAVPSIP





301
AETSLAHRLV AREGSAAPLP LYTSPSLPNI TLGLPATGPS AGTAGQQDAE RLTLPALQQR





361
LSLFPGTHLT PYLSTSPLER DGGAAHSPLL QHMVLLEQPP AQAPLVTDWY LSGLGALPLH





421
AQSLVGADRV SPSIHKLRQH RPLGRTQSAP LPQNAQALQH LVIQQQHQQF LEKHKQQFQQ





481
QQLQMNKIIP KPSEPARQPE SHPEETEEEL REHQALLDEP YLDRLPGQKE AHAQAGVQVK





541
QEPIESDEEE AEPPREVEPG QRQPSEQELL FRQQALLLEQ QRIHQLRNYQ ASMEAAGIPV





601
SFGGHRPLSR AQSSPASATF PVSVQEPPTK PRFTTGLVYD TLMLKHQCTC GSSSSHPEHA





661
GRIQSIWSRL QETGLRGKCE CIRGRKATLE ELQTVHSEAH TLLYGTNPLN RQKLDSKKLL





721
GSLASVFVRL PCGGVGVDSD TIWNEVHSAG AARLAVGCVV ELVFKVATGE LKNGFAVVRP





781
PGHHAEESTP MGFCYFNSVA VAAKLLQQRL SVSKILIVDW DVHHGNGTQQ AFYSDPSVLY





841
MSLHRYDDGN FFPGSGAPDE VGTGPGVGFN VNMAFTGGLD PPMGDAEYLA AFRTVVMPIA





901
SEFAPDVVLV SSGFDAVEGH PTPLGGYNLS ARCFGYLTKQ LMGLAGGRIV LALEGGHDLT





961
AICDASEACV SALLGNELDP LPEKVLQQRP NANAVRSMEK VMEIHSKYWR CLQRTTSTAG





1021
RSLIEAQTCE NEEAETVTAM ASLSVGVKPA EKRPDEEPME EEPPL











SEQ ID NO: 238



HISTONE DEACETYLASE 4 (HDAC4) ISOFORM X11



XP_006712943.1









1
MPSTVDVATA LPLQVAPSAV PMDLRLDHQF SLPVAEPALR EQQLQQELLA LKQKQQIQRQ






61
ILIAEFQRQH EQLSRQHEAQ LHEHIKQQQE MLAMKHQQEL LEHQRKLERH RQEQELEKQH





121
REQKLQQLKN KEKGKESAVA STEVKMKLQE FVLNKKKALA HRNLNHCISS DPRYWYGKTQ





181
HSSLDQSSPP QSGVSTSYNH PVLGMYDAKD DFPLRKTASE PNLKLRSRLK QKVAERRSSP





241
LLRRKDGPVV TALKKRPLDV TDSACSSAPG SGPSSPNNSS GSVSAENGIA PAVPSIPAET





301
SLAHRLVARE GSAAPLPLYT SPSLPNITLG LPATGPSAGT AGQQDAERLT LPALQQRLSL





361
FPGTHLTPYL STSPLERDGG AAHSPLLQHM VLLEQPPAQA PLVTDWYLSG LGALPLHAQS





421
LVGADRVSPS IHKLRQHRPL GRTQSAPLPQ NAQALQHLVI QQQHQQFLEK HKQQFQQQQL





481
QMNKIIPKPS EPARQPESHP EETEEELREH QALLDEPYLD RLPGQKEAHA QAGVQVKQEP





541
IESDEEEAEP PREVEPGQRQ PSEQELLFRQ QALLLEQQRI HQLRNYQASM EAAGIPVSFG





601
GHRPLSRAQS SPASATFPVS VQEPPTKPRF TTGLVYDTLM LKHQCTCGSS SSHPEHAGRI





661
QSIWSRLQET GLRGKCECIR GRKATLEELQ TVHSEAHTLL YGTNPLNRQK LDSKKLLGSL





721
ASVFVRLPCG GVGVDSDTIW NEVHSAGAAR LAVGCVVELV FKVATGELKN GFAVVRPPGH





781
HAEESTPMGF CYFNSVAVAA KLLQQRLSVS KILIVDWDVH HGNGTQQAFY SDPSVLYMSL





841
HRYDDGNFFP GSGAPDEVGT GPGVGFNVNM AFTGGLDPPM GDAEYLAAFR TVVMPIASEF





901
APDVVLVSSG FDAVEGHPTP LGGYNLSARC FGYLTKQLMG LAGGRIVLAL EGGHDLTAIC





961
DASEACVSAL LGNELDPLPE KVLQQRPNAN AVRSMEKVME IHSKYWRCLQ RTTSTAGRSL





1021
IEAQTCENEE AETVTAMASL SVGVKPAEKR PDEEPMEEEP PL











SEQ ID NO: 239



RHODOPSIN (RHO)



NP_000530.1









1
MNGTEGPNFY VPFSNATGVV RSPFEYPQYY LAEPWQFSML AAYMFLLIVL GFPINFLTLY






61
VTVQHKKLRT PLNYILLNLA VADLFMVLGG FTSTLYTSLH GYFVFGPTGC NLEGFFATLG





121
GEIALWSLVV LAIERYVVVC KPMSNFRFGE NHAIMGVAFT WVMALACAAP PLAGWSRYIP





181
EGLQCSCGID YYTLKPEVNN ESFVIYMFVV HFTIPMIIIF FCYGQLVFTV KEAAAQQQES





241
ATTQKAEKEV TRMVIIMVIA FLICWVPYAS VAFYIFTHQG SNFGPIFMTI PAFFAKSAAI





301
YNPVIYIMMN KQFRNCMLTT ICCGKNPLGD DEASATVSKT ETSQVAPA











SEQ ID NO: 240



NERVE GROWTH FACTOR (NGF)



CAA37703.1









1
MSILFYVIFL AYLRGIQGNN MDQRSLPEDS LNSLIIKLIQ ADILKNKLSK QMVDVKENYQ






61
STLPKAEAPR EPERGGPAKS AFQPVIAMDT ELLRQQRRYN SPRVLLSDST PLEPPPLYLM





121
EDYVGSPVVA NRTSRRKRYA EHKSHRGEYS VCDSESLWVT DKSSAIDIRG HQVTVLGEIK





181
TGNSPVKQYF YETRCKEARP VKNGCRGIDD KHWNSQCKTS QTYVRALTSE NNKLVGWRWI





241
RIDTSCVCAL SRKIGRT











SEQ ID NO: 241



NUCLEAR FACTOR, ERYTHROID 2 LIKE 2 (NRF2)



AAB32188.1









1
MDLIDILWRQ DIDLGVSREV FDFSQRRKEY ELEKQKKLEK ERQEQLQKEQ EKAFFTQLQL






61
DEETGEFLPI QPAQHTQSET SGSANYSQVA HIPKSDALYF DDCMQLLAQT FPFVDDNEVS





121
SATFQSLVPD IPGHIESPVF IATNQAQSPE TSVAQVAPVD LDGMQQDIEQ VWEELLSIPE





181
LQCLNIENDK LVETTMVPSP EAKLTEVDNY HFYSSIPSME KEVGNCSPHF LNAFEDSFSS





241
ILSTEDPNQL TVNSLNSDAT VNTDFGDEFY SAFIAEPSIS NSMPSPATLS HSLSELLNGP





301
IDVSDLSLCK AFNQNHPEST AEFNDSDSGI SLNTSPSVAS PEHSVESSSY GDTLLGLSDS





361
EVEELDSAPG SVKQNGPKTP VHSSGDMVQP LSPSQGQSTH VHDAQCENTP EKELPVSPGH





421
RKTPFTKDKH SSRLEAHLTR DELRAKALHI PFPVEKIINL PVVDFNEMMS KEQFNEAQLA





481
LIRDIRRRGK NKVAAQNCRK RKLENIVELE QDLDHLKDEK EKLLKEKGEN DKSLHLLKKQ





541
LSTLYLEVFS MLRDEDGKPY SPSEYSLQQT RDGNVFLVPK SKKPDVKKN











SEQ ID NO: 242



GLUTATHIONE S-TRANSFERASE PI 1 (GSTP1)



AAH10915.1









1
MPPYTVVYFP VRGRCAALRM LLADQGQSWK EEVVTVETWQ EGSLKASCLY GQLPKFQDGD






61
LTLYQSNTIL RHLGRTLGLY GKDQQEAALV DMVNDGVEDL RCKYVSLIYT NYEAGKDDYV





121
KALPGQLKPF ETLLSQNQGG KTFIVGDQIS FADYNLLDLL LIHEVLAPGC LDAFPLLSAY





181
VGRLSARPKL KAFLASPEYV NLPINGNGKQ











SEQ ID NO: 243



ROD-DERIVED CONE VIABILITY FACTOR (RDCVF)



NP_612463.1









1
MASLFSGRIL IRNNSDQDEL DTEAEVSRRL ENRLVLLFFG AGACPQCQAF VPILKDFFVR






61
LTDEFYVLRA AQLALVYVSQ DSTEEQQDLF LKDMPKKWLF LPFEDDLRRD LGRQFSVERL





121
PAVVVLKPDG DVLTRDGADE IQRLGTACFA NWQEAAEVLD RNFQLPEDLE DQEPRSLTEC





181
LRRHKYRVEK AARGGRDPGG GGGEEGGAGG LF











SEQ ID NO: 244



RETINALDEHYDE BINDING PROTEIN 1 (RLBP1)



EAX02038.1









1
MSEGVGTFRM VPEEEQELRA QLEQLTTKDH GPVFGPCSQL PRHTLQKAKD ELNEREETRE






61
EAVRELQEMV QAQAASGEEL AVAVAERVQE KDSGFFLRFI RARKFNVGRA YELLRGYVNF





121
RLQYPELFDS LSPEAVRCTI EAGYPGVLSS RDKYGRVVML FNIENWQSQE ITFDEILQAY





181
CFILEKLLEN EETQINGFCI IENFKGFTMQ QAASLRTSDL RKMVDMLQDS FPARFKAIHF





241
IHQPWYFITT YNVVKPFLKS KLLERVFVHG DDLSGFYQEI DENILPSDFG GTLPKYDGKA





301
VAEQLFGPQA QAENTAF











SEQ ID NO: 245



DOUBLE HOMEOBOX 4 (DUX4)



AUA60624.1









1
MALPTPSDST LPAEARGRGR RRRLVWTPSQ SEALRACFER NPYPGIATRE RLAQAIGIPE






61
PRVQIWFQNE RSRQLRQHRR ESRPWPGRRG PPEGRRKRTA VTGSQTALLL RAFEKDRFPG





121
IAAREELARE TGLPESRIQI WFQNRRARHP GQGGRAPAQA GGLCSAAPGG GHPAPSWVAF





181
AHTGAWGTGL PAPHVPCAPG ALPQGAFVSQ AARAAPALQP SQAAPAEGIS QPAPARGDFA





241
YAAPAPPDGA LSHPQAPRWP PHPGKSREDR DPQRDGLPGP CAVAQPGPAQ AGPQGQGVLA





301
PPTSQGSPWW GWGRGPQVAG TAWEPQAGAA PPPQPAPPDA SASARQGQMQ GIPAPSQALQ





361
EPAPWSALPC GLLLDELLAS PEFLQQAQPL LETEAPGELE ASEEAASLEA PLSEEEYRAL





421
LEEL











SEQ ID NO: 246



NLR FAMILY PYRIN DOMAIN CONTAINING 3 (NLRP3)



AAI43360.1









1
MKMASTRCKL ARYLEDLEDV DLKKFKMHLE DYPPQKGCIP LPRGQTEKAD HVDLATLMID






61
FNGEEKAWAM AVWIFAAINR RDLYEKAKRD EPKWGSDNAR VSNPTVICQE DSIEEEWMGL





121
LEYLSRISIC KMKKDYRKKY RKYVRSRFQC IEDRNARLGE SVSLNKRYTR LRLIKEHRSQ





181
QEREQELLAI GKTKTCESPV SPIKMELLFD PDDEHSEPVH TVVFQGAAGI GKTILARKMM





241
LDWASGTLYQ DRFDYLFYIH CREVSLVTQR SLGDLIMSCC PDPNPPIHKI VRKPSRILFL





301
MDGFDELQGA FDEHIGPLCT DWQKAERGDI LLSSLIRKKL LPEASLLITT RPVALEKLQH





361
LLDHPRHVEI LGFSEAKRKE YFFKYFSDEA QARAAFSLIQ ENEVLFTMCF IPLVCWIVCT





421
GLKQQMESGK SLAQTSKTTT AVYVFFLSSL LQPRGGSQEH GLCAHLWGLC SLAADGIWNQ





481
KILFEESDLR NHGLQKADVS AFLRMNLFQK EVDCEKFYSF IHMTFQEFFA AMYYLLEEEK





541
EGRTNVPGSR LKLPSRDVTV LLENYGKFEK GYLIFVVRFL FGLVNQERTS YLEKKLSCKI





601
SQQIRLELLK WIEVKAKAKK LQIQPSQLEL FYCLYEMQEE DFVQRAMDYF PKIEINLSTR





661
MDHMVSSFCI ENCHRVESLS LGFLHNMPKE EEEEEKEGRH LDMVQCVLPS SSHAACSHGL





721
VNSHLTSSFC RGLFSVLSTS QSLTELDLSD NSLGDPGMRV LCETLQHPGC NIRRLCNQKL





781
VELDLSDNAL GDFGIRLLCV GLKHLLCNLK KLWLVSCCLT SACCQDLASV LSTSHSLTRL





841
YVGENALGDS GVAILCEKAK NPQCNLQKLG LVNSGLTSVC CSALSSVLST NQNLTHLYLR





901
GNTLGDKGIK LLCEGLLHPD CKLQVLELDN CNLTSHCCWD LSTLLTSSQS LRKLSLGNND





961
LGDLGVMMFC EVLKQQSCLL QNLGLSEMYF NYETKSALET LQEEKPELTV VFEPSW











SEQ ID NO: 247



SPLEEN ASSOCIATED TYROSINE KINASE (SYK), ISOFORM SYK(S)



NP_001167639.1









1
MASSGMADSA NHLPFFFGNI TREEAEDYLV QGGMSDGLYL LRQSRNYLGG FALSVAHGRK






61
AHHYTIEREL NGTYAIAGGR THASPADLCH YHSQESDGLV CLLKKPFNRP QGVQPKTGPF





121
EDLKENLIRE YVKQTWNLQG QALEQAIISQ KPQLEKLIAT TAHEKMPWFH GKISREESEQ





181
IVLIGSKTNG KFLIRARDNN GSYALCLLHE GKVLHYRIDK DKTGKLSIPE GKKFDTLWQL





241
VEHYSYKADG LLRVLTVPCQ KIGTQGNVNF GGRPQLPGSH PASSPAQGNR QESTVSFNPY





301
EPELAPWAAD KGPQREALPM DTEVYESPYA DPEEIRPKEV YLDRKLLTLE DKELGSGNFG





361
TVKKGYYQMK KVVKTVAVKI LKNEANDPAL KDELLAEANV MQQLDNPYIV RMIGICEAES





421
WMLVMEMAEL GPLNKYLQQN RHVKDKNIIE LVHQVSMGMK YLEESNFVHR DLAARNVLLV





481
TQHYAKISDF GLSKALRADE NYYKAQTHGK WPVKWYAPEC INYYKFSSKS DVWSFGVLMW





541
EAFSYGQKPY RGMKGSEVTA MLEKGERMGC PAGCPREMYD LMNLCWTYDV ENRPGFAAVE





601
LRLRNYYYDV VN











SEQ ID NO: 248



SPLEEN ASSOCIATED TYROSINE KINASE (SYK), ISOFORM SYK(L)



NP_003168.2









1
MASSGMADSA NHLPFFFGNI TREEAEDYLV QGGMSDGLYL LRQSRNYLGG FALSVAHGRK






61
AHHYTIEREL NGTYAIAGGR THASPADLCH YHSQESDGLV CLLKKPFNRP QGVQPKTGPF





121
EDLKENLIRE YVKQTWNLQG QALEQAIISQ KPQLEKLIAT TAHEKMPWFH GKISREESEQ





181
IVLIGSKTNG KFLIRARDNN GSYALCLLHE GKVLHYRIDK DKTGKLSIPE GKKFDTLWQL





241
VEHYSYKADG LLRVLTVPCQ KIGTQGNVNF GGRPQLPGSH PATWSAGGII SRIKSYSFPK





301
PGHRKSSPAQ GNRQESTVSF NPYEPELAPW AADKGPQREA LPMDTEVYES PYADPEEIRP





361
KEVYLDRKLL TLEDKELGSG NFGTVKKGYY QMKKVVKTVA VKILKNEAND PALKDELLAE





421
ANVMQQLDNP YIVRMIGICE AESWMLVMEM AELGPLNKYL QQNRHVKDKN IIELVHQVSM





481
GMKYLEESNF VHRDLAARNV LLVTQHYAKI SDFGLSKALR ADENYYKAQT HGKWPVKWYA





541
PECINYYKFS SKSDVWSFGV LMWEAFSYGQ KPYRGMKGSE VTAMLEKGER MGCPAGCPRE





601
MYDLMNLCWT YDVENRPGFA AVELRLRNYY YDVVN











SEQ ID NO: 249



ADRENOCORTICOTROPIC HORMONE (ACTH), PREPROPROTEIN



NP_000930.1









1
MPRSCCSRSG ALLLALLLQA SMEVRGWCLE SSQCQDLTTE SNLLECIRAC KPDLSAETPM






61
FPGNGDEQPL TENPRKYVMG HFRWDRFGRR NSSSSGSSGA GQKREDVSAG EDCGPLPEGG





121
PEPRSDGAKP GPREGKRSYS MEHFRWGKPV GKKRRPVKVY PNGAEDESAE AFPLEFKREL





181
TGQRLREGDG PDGPADDGAG AQADLEHSLL VAAEKKDEGP YRMEHFRWGS PPKDKRYGGF





241
MTSEKSQTPL VTLFKNAIIK NAYKKGE











SEQ ID NO: 250



CASPASE 1 (CASP1), ISOFORM ALPHA PRECURSOR



NP_001244047.1









1
MADKVLKEKR KLFIRSMGEG TINGLLDELL QTRVLNKEEM EKVKRENATV MDKTRALIDS






61
VIPKGAQACQ ICITYICEED SYLAGTLGLS ADQTSGNYLN MQDSQGVLSS FPAPQAVQDN





121
PAMPTSSGSE GNVKLCSLEE AQRIWKQKSA EIYPIMDKSS RTRLALIICN EEFDSIPRRT





181
GAEVDITGMT MLLQNLGYSV DVKKNLTASD MTTELEAFAH RPEHKTSDST FLVFMSHGIR





241
EGICGKKHSE QVPDILQLNA IFNMLNTKNC PSLKDKPKVI IIQACRGDSP GVVWFKDSVG





301
VSGNLSLPTT EEFEDDAIKK AHIEKDFIAF CSSTPDNVSW RHPTMGSVFI GRLIEHMQEY





361
ACSCDVEEIF RKVRFSFEQP DGRAQMPTTE RVTLTRCFYL FPGH











SEQ ID NO: 251



CASPASE 1 (CASP1), ISOFORM BETA PRECURSOR



NP_001244048.1









1
MADKVLKEKR KLFIRSMGEG TINGLLDELL QTRVLNKEEM EKVKRENATV MDKTRALIDS






61
VIPKGAQACQ ICITYICEED SYLAGTLGLS AAPQAVQDNP AMPTSSGSEG NVKLCSLEEA





121
QRIWKQKSAE IYPIMDKSSR TRLALIICNE EFDSIPRRTG AEVDITGMTM LLQNLGYSVD





181
VKKNLTASDM TTELEAFAHR PEHKTSDSTF LVFMSHGIRE GICGKKHSEQ VPDILQLNAI





241
FNMLNTKNCP SLKDKPKVII IQACRGDSPG VVWFKDSVGV SGNLSLPTTE EFEDDAIKKA





301
HIEKDFIAFC SSTPDNVSWR HPTMGSVFIG RLIEHMQEYA CSCDVEEIFR KVRFSFEQPD





361
GRAQMPTTER VTLTRCFYLF PGH











SEQ ID NO: 252



CD59



CAG46523.1









1
MGIQGGSVLF GLLLVLAVFC HSGHSLQCYN CPNPTADCKT AVNCSSDFDA CLITKAGLQV






61
YNKCWKFEHC NFNDVTTRLR ENELTYYCCK KDLCNFNEQL ENGGTSLSEK TVLLLVTPFL





121
AAAWSLHP











SEQ ID NO: 253



NOTCH REGULATED ANKYRIN REPEAT PROTEIN (NRARP)



NP_001004354.1









1
MSQAELSTCS APQTQRIFQE AVRKGNTQEL QSLLQNMTNC EFNVNSFGPE GQTALHQSVI






61
DGNLELVKLL VKFGADIRLA NRDGWSALHI AAFGGHQDIV LYLITKAKYA ASGR











SEQ ID NO: 254



ALPHA-2-ANTIPLASMIN (A2AP), ISOFORM A PRECURSOR



NP_000925.2









1
MALLWGLLVL SWSCLQGPCS VFSPVSAMEP LGRQLTSGPN QEQVSPLTLL KLGNQEPGGQ






61
TALKSPPGVC SRDPTPEQTH RLARAMMAFT ADLFSLVAQT STCPNLILSP LSVALALSHL





121
ALGAQNHTLQ RLQQVLHAGS GPCLPHLLSR LCQDLGPGAF RLAARMYLQK GFPIKEDFLE





181
QSEQLFGAKP VSLTGKQEDD LANINQWVKE ATEGKIQEFL SGLPEDTVLL LLNAIHFQGF





241
WRNKFDPSLT QRDSFHLDEQ FTVPVEMMQA RTYPLRWFLL EQPEIQVAHF PFKNNMSFVV





301
LVPTHFEWNV SQVLANLSWD TLHPPLVWER PTKVRLPKLY LKHQMDLVAT LSQLGLQELF





361
QAPDLRGISE QSLVVSGVQH QSTLELSEVG VEAAAATSIA MSRMSLSSFS VNRPFLFFIF





421
EDTTGLPLFV GSVRNPNPSA PRELKEQQDS PGNKDFLQSL KGFPRGDKLF GPDLKLVPPM





481
EEDYPQFGSP K











SEQ ID NO: 255



ALPHA-2-ANTIPLASMIN (A2AP), ISOFORM B PRECURSOR



NP_001159393.1









1
MALLWGLLVL SWSCLQGPCS VFSPVSAMEP LGRQLTSGPN QEQVSPLTLL KLGNQVQPGA






61
QNHTLQRLQQ VLHAGSGPCL PHLLSRLCQD LGPGAFRLAA RMYLQKGFPI KEDFLEQSEQ





121
LFGAKPVSLT GKQEDDLANI NQWVKEATEG KIQEFLSGLP EDTVLLLLNA IHFQGFWRNK





181
FDPSLTQRDS FHLDEQFTVP VEMMQARTYP LRWFLLEQPE IQVAHFPFKN NMSFVVLVPT





241
HFEWNVSQVL ANLSWDTLHP PLVWERPTKV RLPKLYLKHQ MDLVATLSQL GLQELFQAPD





301
LRGISEQSLV VSGVQHQSTL ELSEVGVEAA AATSIAMSRM SLSSFSVNRP FLFFIFEDTT





361
GLPLFVGSVR NPNPSAPREL KEQQDSPGNK DFLQSLKGFP RGDKLFGPDL KLVPPMEEDY





421
PQFGSPK











SEQ ID NO: 256



PLASMINOGEN (PLG)



AAA60113.1









1
MEHKEVVLLL LLFLKSGQGE PLDDYVNTQG ASLFSVTKKQ LGAGSIEECA AKCEEDEEFT






61
CRAFQYHSKE QQCVIMAENR KSSIIIRMRD VVLFEKKVYL SECKTGNGKN YRGTMSKTKN





121
GITCQKWSST SPHRPRFSPA THPSEGLEEN YCRNPDNDPQ GPWCYTTDPE KRYDYCDILE





181
CEEECMHCSG ENYDGKISKT MSGLECQAWD SQSPHAHGYI PSKFPNKNLK KNYCRNPDRE





241
LRPWCFTTDP NKRWELCDIP RCTTPPPSSG PTYQCLKGTG ENYRGNVAVT VSGHTCQHWS





301
AQTPHTHNRT PENFPCKNLD ENYCRNPDGK RAPWCHTTNS QVRWEYCKIP SCDSSPVSTE





361
QLAPTAPPEL TPVVQDCYHG DGQSYRGTSS TTTTGKKCQS WSSMTPHRHQ KTPENYPNAG





421
LTMNYCRNPD ADKGPWCFTT DPSVRWEYCN LKKCSGTEAS VVAPPPVVLL PNVETPSEED





481
CMFGNGKGYR GKRATTVTGT PCQDWAAQEP HRHSIFTPET NPRAGLEKNY CRNPDGDVGG





541
PWCYTTNPRK LYDYCDVPQC AAPSFDCGKP QVEPKKCPGR VVGGCVAHPH SWPWQVSLRT





601
RFGMHFCGGT LISPEWVLTA AHCLEKSPRP SSYKVILGAH QEVNLEPHVQ EIEVSRLFLE





661
PTRKDIALLK LSSPAVITDK VIPACLPSPN YVVADRTECF ITGWGETQGT FGAGLLKEAQ





721
LPVIENKVCN RYEFLNGRVQ STELCAGHLA GGTDSCQGDS GGPLVCFEKD KYILQGVTSW





781
GLGCARPNKP GVYVRVSRFV TWIEGVMRNN











SEQ ID NO: 257



GROWTH HORMONE



AAA98618.1









1
MATGSRTSLL LAFGLLCLPW LQEGSAFPTI PLSRLFDNAM LRAHRLHQLA FDTYQEFEEA






61
YIPKEQKYSF LQNPQTSLCF SESIPTPSNR EETQQKSNLE LLRISLLLIQ SWLEPVQFLR





121
SVFANSLVYG ASDSNVYDLL KDLEEGIQTL MGRLEDGSPR TGQIFKQTYS KFDTNSHNDD





181
ALLKNYGLLY CFRKDMDKVE TFLRIVQCRS VEGSCGF











SEQ ID NO: 258



INSULIN LIKE GROWTH FACTOR 1 (IGF1)



CAG46659.1









1
MGKISSLPTQ LFKCCFCDFL KVKMHTMSSS HLFYLALCLL TFTSSATAGP ETLCGAELVD






61
ALQFVCGDRG FYFNKPTGYG SSSRRAPQTG IVDECCFRSC DLRRLEMYCA PLKPAKSARS





121
VRAQRHTDMP KTQKEVHLKN ASRGSAGNKN YRM











SEQ ID NO: 259



INTERLEUKIN 1 BETA (IL1B)



AAA74137.1









1
MAEVPELASE MMAYYSGNED DLFFEADGPK QMKCSFQDLD LCPLDGGIQL RISDHHYSKG






61
FRQAASVVVA MDKLRKMLVP CPQTFQENDL STFFPFIFEE EPIFFDTWDN EAYVHDAPVR





121
SLNCTLRDSQ QKSLVMSGPY ELKALHLQGQ DMEQQVVFSM SFVQGEESND KIPVALGLKE





181
KNLYLSCVLK DDKPTLQLES VDPKNYPKKK MEKRFVFNKI EINNKLEFES AQFPNWYIST





241
SQAENMPVFL GGTKGGQDIT DFTMQFVSS











SEQ ID NO: 260



ANGIOTENSIN I CONVERTING ENZYME 2 (ACE2)



ACT66268.1









1
MSSSSWLLLS LVAVTAAQST IEEQAKTFLD KFNHEAEDLF YQSSLASWNY NTNITEENVQ






61
NMNNAGDKWS AFLKEQSTLA QMYPLQEIQN LTVKLQLQAL QQNGSSVLSE DKSKRLNTIL





121
NTMSTIYSTG KVCNPDNPQE CLLLEPGLNE IMANSLDYNE RLWAWESWRS EVGKQLRPLY





181
EEYVVLKNEM ARANHYEDYG DYWRGDYEVN GVDGYDYSRG QLIEDVEHTF EEIKPLYEHL





241
HAYVRAKLMN AYPSYISPIG CLPAHLLGDM WGRFWTNLYS LTVPFGQKPN IDVTDAMVDQ





301
AWDAQRIFKE AEKFFVSVGL PNMTQGFWEN SMLTDPGNVQ KAVCHPTAWD LGKGDFRILM





361
CTKVTMDDFL TAHHEMGHIQ YDMAYAAQPF LLRNGANEGF HEAVGEIMSL SAATPKHLKS





421
IGLLSPDFQE DNETEINFLL KQALTIVGTL PFTYMLEKWR WMVFKGEIPK DQWMKKWWEM





481
KREIVGVVEP VPHDETYCDP ASLFHVSNDY SFIRYYTRTL YQFQFQEALC QAAKHEGPLH





541
KCDISNSTEA GQKLFNMLRL GKSEPWTLAL ENVVGAKNMN VRPLLNYFEP LFTWLKDQNK





601
NSFVGWSTDW SPYADQSIKV RISLKSALGD KAYEWNDNEM YLFRSSVAYA MRQYFLKVKN





661
QMILFGEEDV RVANLKPRIS FNFFVTAPKN VSDIIPRTEV EKAIRMSRSR INDAFRLNDN





721
SLEFLGIQPT LGPPNQPPVS IWLIVFGVVM GVIVVGIVIL IFTGIRDRKK KNKARSGENP





781
YASIDISKGE NNPGFQNTDD VQTSF











SEQ ID NO: 261



INTEGRIN ALPHA SUBUNIT PRECURSOR



AAA51620.1









1
MTRTRAALLL FTALATSLGF NLDTEELTAF RVDSAGFGDS VVQYANSWVV VGAPQKITAA






61
NQTGGLYQCG YSTGACEPIG LQVPPEAVNM SLGLSLASTT SPSQLLACGP TVHHECGRNM





121
YLTGLCFLLG PTQLTQRLPV SRQECPRQEQ DIVFLIDGSG SISSRNFATM MNFVRAVISQ





181
FQRPSTQFSL MQFSNKFQTH LTFEEFRRTS NPLSLLASVH QLQGFTYTAT AIQNVVHRLF





241
HASYGARRDA TKILIVITDG KKEGDTLDYK DVIPMADAAG IIRYAIGVGL AFQNRNSWKE





301
LNDIASKPSQ EHIFKVEDFD ALKDIQTQLR EKIFPIEGTE TTSSSSFELE MAQEGFSAVF





361
TPDGPVLGAV GSFTWSGGAF LYPPNMSPTF INMSQENVDM RDSYLGYSTE LALWKGVQSL





421
VLGAPRYQHT GKAVIFTQVS RQWRMKAEVT GTQIGSYFGP SLCSVDVDSD GSTDLVLIGP





481
PHYYEQTRGA QVSVCPLPRG WRRWWCDAVL YGEQGHPWGR FGAALTVLGD VNGDKLTDVV





541
IGAPGEEENR GAVYLFHGVL GPSISPSHSQ RIAGSQLSSR LQYFGQALSG GQDLTQDGLV





601
DLAVGARGQV LLLRTRPVLW VGVSMQFIPA EIPRSAFECR EQVVSEQTLV QSNICLYIDK





661
RSKNLLGSRD LQSSVTLDLA LDPGRLSPRA TFQETKNRSL SRVRVLGLKA HCENFNLLLP





721
SCVEDSVTPI TLRLNFTLVG KPLLAFRNLR PMLAADAQRY FTASLPFEKN CGADHICQDN





781
LGISFSFPGL KSLLVGSNLE LNAEVMVWND GEDSYGTTIT FSHPAGLSYR YVAEGQKQGQ





841
LRSLHLTCDS APVGSQGTWS TSCRINHLIF RGGAQITFLA TFDVSPKAVL GDRLLLTANV





901
SSENNTPRTS KTTFQLELPV KYAVYTVVSS HEQFTKYLNF SESEEKESHV AMHRYQVNNL





961
GQRDLPVSIN FWVPVELNQE AVWMDVEVSL PQNPSLRCSS EKIAGPASDF LAHIQKNPVL





1021
DCSIAGCLRF RCDVPSFSVQ EELDFTLKGN LSFGWVRQIL QKKVSVVSVA EITFDTSVYS





1081
QLPGQEAFMR AQTTTVLEKY KVHNPTPLIV GSSIGGLLLL ALITAVLYKV GFFKRQYKEM





1141
MEEANGQIAP ENGTQTPSPP SEK











SEQ ID NO: 262



INTEGRIN ALPHA SUBUNIT PRECURSOR



P05556.2









1
MNLQPIFWIG LISSVCCVFA QTDENRCLKA NAKSCGECIQ AGPNCGWCTN STFLQEGMPT






61
SARCDDLEAL KKKGCPPDDI ENPRGSKDIK KNKNVTNRSK GTAEKLKPED ITQIQPQQLV





121
LRLRSGEPQT FTLKFKRAED YPIDLYYLMD LSYSMKDDLE NVKSLGTDLM NEMRRITSDF





181
RIGFGSFVEK TVMPYISTTP AKLRNPCTSE QNCTSPFSYK NVLSLTNKGE VFNELVGKQR





241
ISGNLDSPEG GFDAIMQVAV CGSLIGWRNV TRLLVFSTDA GFHFAGDGKL GGIVLPNDGQ





301
CHLENNMYTM SHYYDYPSIA HLVQKLSENN IQTIFAVTEE FQPVYKELKN LIPKSAVGTL





361
SANSSNVIQL IIDAYNSLSS EVILENGKLS EGVTISYKSY CKNGVNGTGE NGRKCSNISI





421
GDEVQFEISI TSNKCPKKDS DSFKIRPLGF TEEVEVILQY ICECECQSEG IPESPKCHEG





481
NGTFECGACR CNEGRVGRHC ECSTDEVNSE DMDAYCRKEN SSEICSNNGE CVCGQCVCRK





541
RDNTNEIYSG KFCECDNFNC DRSNGLICGG NGVCKCRVCE CNPNYTGSAC DCSLDTSTCE





601
ASNGQICNGR GICECGVCKC TDPKFQGQTC EMCQTCLGVC AEHKECVQCR AFNKGEKKDT





661
CTQECSYFNI TKVESRDKLP QPVQPDPVSH CKEKDVDDCW FYFTYSVNGN NEVMVHVVEN





721
PECPTGPDII PIVAGVVAGI VLIGLALLLI WKLLMIIHDR REFAKFEKEK MNAKWDTGEN





781
PIYKSAVTTV VNPKYEGK











SEQ ID NO: 263



CD40



AAH64518.1









1
MVRLPLQCVL WGCLLTAVHP EPPTACREKQ YLINSQCCSL CQPGQKLVSD CTEFTETECL






61
PCGESEFLDT WNRETHFHQH KYCDPNLGLR VQQKGTSETD TICTCEEGWH CTSEACESCV





121
LHRSCSPGFG VKQIDICQPH FPKDRGLNLL M











SEQ ID NO: 264



INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR (IGF1R)



AAI43722.1









1
MKSGSGGGSP TSLWGLLFLS AALSLWPTSG EICGPGIDIR NDYQQLKRLE NCTVIEGYLH






61
ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVIF





121
EMTNLKDIGL YNLRNITRGA IRIEKNADLC YLSTVDWSLI LDAVSNNYIV GNKPPKECGD





181
LCPGTMEEKP MCEKTTINNE YNYRCWTTNR CQKMCPSTCG KRACTENNEC CHPECLGSCS





241
APDNDTACVA CRHYYYAGVC VPACPPNTYR FEGWRCVDRD FCANILSAES SDSEGFVIHD





301
GECMQECPSG FIRNGSQSMY CIPCEGPCPK VCEEEKKTKT IDSVTSAQML QGCTIFKGNL





361
LINIRRGNNI ASELENFMGL IEVVTGYVKI RHSHALVSLS FLKNLRLILG EEQLEGNYSF





421
YVLDNQNLQQ LWDWDHRNLT IKAGKMYFAF NPKLCVSEIY RMEEVTGTKG RQSKGDINTR





481
NNGERASCES DVLHFTSTTT SKNRIIITWH RYRPPDYRDL ISFTVYYKEA PFKNVTEYDG





541
QDACGSNSWN MVDVDLPPNK DVEPGILLHG LKPWTQYAVY VKAVTLTMVE NDHIRGAKSE





601
ILYIRTNASV PSIPLDVLSA SNSSSQLIVK WNPPSLPNGN LSYYIVRWQR QPQDGYLYRH





661
NYCSKDKIPI RKYADGTIDI EEVTENPKTE VCGGEKGPCC ACPKTEAEKQ AEKEEAEYRK





721
VFENFLHNSI FVPRPERKRR DVMQVANTTM SSRSRNTTAA DTYNITDPEE LETEYPFFES





781
RVDNKERTVI SNLRPFTLYR IDIHSCNHEA EKLGCSASNF VFARTMPAEG ADDIPGPVTW





841
EPRPENSIFL KWPEPENPNG LILMYEIKYG SQVEDQRECV SRQEYRKYGG AKLNRLNPGN





901
YTARIQATSL SGNGSWTDPV FFYVQAKRYE NFIHLIIALP VAVLLIVGGL VIMLYVFHRK





961
RNNSRLGNGV LYASVNPEYF SAADVYVPDE WEVAREKITM SRELGQGSFG MVYEGVAKGV





1021
VKDEPETRVA IKTVNEAASM RERIEFLNEA SVMKEFNCHH VVRLLGVVSQ GQPTLVIMEL





1081
MTRGDLKSYL RSLRPEMENN PVLAPPSLSK MIQMAGEIAD GMAYLNANKF VHRDLAARNC





1141
MVAEDFTVKI GDFGMTRDIY ETDYYRKGGK GLLPVRWMSP ESLKDGVFTT YSDVWSFGVV





1201
LWEIATLAEQ PYQGLSNEQV LRFVMEGGLL DKPDNCPDML FELMRMCWQY NPKMRPSFLE





1261
IISSIKEEME PGFREVSFYY SEENKLPEPE ELDLEPENME SVPLDPSASS SSLPLPDRHS





1321
GHKAENGPGP GVLVLRASFD ERQPYAHMNG GRKNERALPL PQSSTC











SEQ ID NO: 265



INSULIN-LIKE GROWTH FACTOR 2 RECEPTOR (IGF2R)



AAK56918.1









1
MGAAAGRSPH LGPAPARRPQ RSLLLLQLLL LVAAPGSTQA QAAPFPELCS YTWEAVDTKN






61
NVLYKINICG SVDIVQCGPS SAVCMHDLKT RTYHSVGDSV LRSATRSLLE FNTTVSCDQQ





121
GTNHRVQSSI AFLCGKTLGT PEFVTATECV HYFEWRTTAA CKKDIFKANK EVPCYVFDEE





181
LRKHDLNPLI KLSGAYLVDD SDPDTSLFIN VCRDIDTLRD PGSQLRACPP GTAACLVRGH





241
QAFDVGQPRD GLKLVRKDRL VLSYVREEAG KLDFCDGHSP AVTITFVCPS ERREGTIPKL





301
TAKSNCRYEI EWITEYACHR DYLESKTCSL SGEQQDVSID LTPLAQSGGS SYISDGKEYL





361
FYLNVCGETE IQFCNKKQAA VCQVKKSDTS QVKAAGRYHN QTLRYSDGDL TLIYFGGDEC





421
SSGFQRMSVI NFECNKTAGN DGKGTPVFTG EVDCTYFFTW DTEYACVKEK EDLLCGATDG





481
KKRYDLSALV RHAEPEQNWE AVDGSQTETE KKHFFINICH RVLQEGKARG CPEDAAVCAV





541
DKNGSKNLGK FISSPMKEKG NIQLSYSDGD DCGHGKKIKT NITLVCKPGD LESAPVLRTS





601
GEGGCFYEFE WHTAAACVLS KTEGENCTVF DSQAGFSFDL SPLTKKNGAY KVETKKYDFY





661
INVCGPVSVS PCQPDSGACQ VAKSDEKTWN LGLSNAKLSY YDGMIQLNYR GGTPYNNERH





721
TPRATLITFL CDRDAGVGFP EYQEEDNSTY NFRWYTSYAC PEEPLECVVT DPSTLEQYDL





781
SSLAKSEGGL GGNWYAMDNS GEHVTWRKYY INVCRPLNPV PGCNRYASAC QMKYEKDQGS





841
FTEVVSISNL GMAKTGPVVE DSGSLLLEYV NGSACTTSDG RQTTYTTRIH LVCSRGRLNS





901
HPIFSLNWEC VVSFLWNTEA ACPIQTTTDT DQACSIRDPN SGFVFNLNPL NSSQGYNVSG





961
IGKIFMFNVC GTMPVCGTIL GKPASGCEAE TQTEELKNWK PARPVGIEKS LQLSTEGFIT





1021
LTYKGPLSAK GTADAFIVRF VCNDDVYSGP LKFLHQDIDS GQGIRNTYFE FETALACVPS





1081
PVDCQVTDLA GNEYDLTGLS TVRKPWTAVD TSVDGRKRTF YLSVCNPLPY IPGCQGSAVG





1141
SCLVSEGNSW NLGVVQMSPQ AAANGSLSIM YVNGDKCGNQ RFSTRITFEC AQISGSPAFQ





1201
LQDGCEYVFI WRTVEACPVV RVEGDNCEVK DPRHGNLYDL KPLGLNDTIV SAGEYTYYFR





1261
VCGKLSSDVC PTSDKSKVVS SCQEKREPQG FHKVAGLLTQ KLTYENGLLK MNFTGGDTCH





1321
KVYQRSTAIF FYCDRGTQRP VFLKETSDCS YLFEWRTQYA CPPFDLTECS FKDGAGNSFD





1381
LSSLSRYSDN WEAITGTGDP EHYLINVCKS LAPQAGTEPC PPEAAACLLG GSKPVNLGRV





1441
RDGPQWRDGI IVLKYVDGDL CPDGIRKKST TIRFTCSESQ VNSRPMFISA VEDCEYTFAW





1501
PTATACPMKS NEHDDCQVTN PSTGHLFDLS SLSGRAGFTA AYSEKGLVYM SICGENENCP





1561
PGVGACFGQT RISVGKANKR LRYVDQVLQL VYKDGSPCPS KSGLSYKSVI SFVCRPEARP





1621
TNRPMLISLD KQTCTLFFSW HTPLACEQAT ECSVRNGSSI VDLSPLIHRT GGYEAYDESE





1681
DDASDTNPDF YINICQPLNP MHGVPCPAGA AVCKVPIDGP PIDIGRVAGP PILNPIANEI





1741
YLNFESSTPC LADKHFNYTS LIAFHCKRGV SMGTPKLLRT SECDFVFEWE TPVVCPDEVR





1801
MDGCTLTDEQ LLYSFNLSSL STSTFKVTRD SRTYSVGVCT FAVGPEQGGC KDGGVCLLSG





1861
TKGASFGRLQ SMKLDYRHQD EAVVLSYVNG DRCPPETDDG VPCVFPFIFN GKSYEECIIE





1921
SRAKLWCSTT ADYDRDHEWG FCRHSNSYRT SSIIFKCDED EDIGRPQVFS EVRGCDVTFE





1981
WKTKVVCPPK KLECKFVQKH KTYDLRLLSS LTGSWSLVHN GVSYYINLCQ KIYKGPLGCS





2041
ERASICRRTT TGDVQVLGLV HTQKLGVIGD KVVVTYSKGY PCGGNKTASS VIELTCTKTV





2101
GRPAFKRFDI DSCTYYFSWD SRAACAVKPQ EVQMVNGTIT NPINGKSFSL GDIYFKLFRA





2161
SGDMRTNGDN YLYEIQLSSI TSSRNPACSG ANICQVKPND QHFSRKVGTS DKTKYYLQDG





2221
DLDVVFASSS KCGKDKTKSV SSTIFFHCDP LVEDGIPEFS HETADCQYLF SWYTSAVCPL





2281
GVGFDSENPG DDGQMHKGLS ERSQAVGAVL SLLLVALTCC LLALLLYKKE RRETVISKLT





2341
TCCRRSSNVS YKYSKVNKEE ETDENETEWL MEEIQLPPPR QGKEGQENGH ITTKSVKALS





2401
SLHGDDQDSE DEVLTIPEVK VHSGRGAGAE SSHPVRNAQS NALQEREDDR VGLVRGEKAR





2461
KGKSSSAQQK TVSSTKLVSF HDDSDEDLLH I











SEQ ID NO: 266



RT P801



AAL38424.1









1
MPSLWDRFSS SSTSSSPSSL PRTPTPDRPP RSAWGSATRE EGFDRSTSLE SSDCESLDSS






61
NSGFGPEEDT AYLDGVSLPD FELLSDPEDE HLCANLMQLL QESLAQARLG SRRPARLLMP





121
SQLVSQVGKE LLRLAYSEPC GLRGALLDVC VEQGKSCHSV GQLALDPSLV PTFQLTLVLR





181
LDSRLWPKIQ GLFSSANSPF LPGFSQSLTL STGFRVIKKK LYSSEQLLIE EC











SEQ ID NO: 267



METALLOPROTEINASE 2 (MMP2)



BAA12023









1
MILLTFSTGR RLDFVHHSGV FFLQTLLWIL CATVCGTEQY FNVEVWLQKY GYLPPTDPRM






61
SVLRSAETMQ SALAAMQQFY GINMTGKVDR NTIDWMKKPR CGVPDQTRGS SKFHIRRKRY





121
ALTGQKWQHK HITYSIKNVT PKVGDPETRK AIRRAFDVWQ NVTPLTFEEV PYSELENGKR





181
DVDITIIFAS GFHGDSSPFD GEGGFLAHAY FPGPGIGGDT HFDSDEPWTL GNPNHDGNDL





241
FLVAVHELGH ALGLEHSNDP TAIMAPFYQY METDNFKLPN DDLQGIQKIY GPPDKIPPPT





301
RPLPTVPPHR SIPPADPRKN DRPKPPRPPT GRPSYPGAKP NICDGNFNTL AILRREMFVF





361
KDQWFWRVRN NRVMDGYPMQ ITYFWRGLPP SIDAVYENSD GNFVFFKVKG DTLSVIQDGW





421
LYKYHWKWIL EQRQSVPVLS RQTEKHKTYE ELSSITY











SEQ ID NO: 268



G-PROTEIN COUPLED RECEPTOR 143 (GPR143)



NP_000264









1
MASPRLGTFC CPTRDAATQL VLSFQPRAFH ALCLGSGGLR LALGLLQLLP GRRPAGPGSP






61
ATSPPASVRI LRAAAACDLL GCLGMVIRST VWLGFPNFVD SVSDMNHTEI WPAAFCVGSA





121
MWIQLLYSAC FWWLFCYAVD AYLVIRRSAG LSTILLYHIM AWGLATLLCV EGAAMLYYPS





181
VSRCERGLDH AIPHYVTMYL PLLLVLVANP ILFQKTVTAV ASLLKGRQGI YTENERRMGA





241
VIKIRFFKIM LVLIICWLSN IINESLLFYL EMQTDINGGS LKPVRTAAKT TWFIMGILNP





301
AQGFLLSLAF YGWTGCSLGF QSPRKEIQWE SLTTSAAEGA HPSPLMPHEN PASGKVSQVG





361
GQTSDEALSM LSEGSDASTI EIHTASESCN KNEGDPALPT HGDL











SEQ ID NO: 269



G-PROTEIN COUPLED RECEPTOR 143 (GPR143)



EAW98773.1









1
MTQAGRRGPG TPEPRPRTQP MASPRLGTFC CPTRDAATQL VLSFQPRAFH ALCLGSGGLR






61
LALGLLQLLP GRRPAGPGSP ATSPPASVRI LRAAAACDLL GCLGMVIRST VWLGFPNFVD





121
SVSDMNHTEI WPAAFCVGSA MWIQLLYSAC FWWLFCYAVD AYLVIRRSAG LSTILLYHIM





181
AWGLATLLCV EGAAMLYYPS VSRCERGLDH AIPHYVTMYL PLLLVLVANP ILFQKTVTAV





241
ASLLKGRQGI YTENERRMGA VIKIRFFKIM LVLIICWLSN IINESLLFYL EMQTDINGGS





301
LKPVRTAAKT TWFIMGILNP AQGFLLSLAF YGWTGCSLGF QSPRKEIQWE SLTTSAAEGA





361
HPSPLMPHEN PASGKVSQVG GQTSDEALSM LSEGSDASTI EIHTASESCN KNEGDPALPT





421
HGDL











SEQ ID NO: 270



TYROSINASE (TYR)



AAB60319.1









1
MLLAVLYCLL WSFQTSAGHF PRACVSSKNL MEKECCPPWS GDRSPCGQLS GRGSCQNILL






61
SNAPLGPQFP FTGVDDRESW PSVFYNRTCQ CSGNFMGFNC GNCKFGFWGP NCTERRLLVR





121
RNIFDLSAPE KDKFFAYLTL AKHTISSDYV IPIGTYGQMK NGSTPMFNDI NIYDLFVWMH





181
YYVSMDALLG GSEIWRDIDF AHEAPAFLPW HRLFLLRWEQ EIQKLTGDEN FTIPYWDWRD





241
AEKCDICTDE YMGGQHPTNP NLLSPASFFS SWQIVCSRLE EYNSHQSLCN GTPEGPLRRN





301
PGNHDKSRTP RLPSSADVEF CLSLTQYESG SMDKAANFSF RNTLEGFASP LTGIADASQS





361
SMHNALHIYM NGTMSQVQGS ANDPIFLLHH AFVDSIFEQW LQRHRPLQEV YPEANAPIGH





421
NRESYMVPFI PLYRNGDFFI SSKDLGYDYS YLQDSDPDSF QDYIKSYLEQ ASRIWSWLLG





481
AAMVGAVLTA LLAGLVSLLC RHKRKQLPEE KQPLLMEKED YHSLYQSHL











SEQ ID NO: 271



CASPASE 2 (CASP2)



CAG46548.1









1
MHPHHQETLK KNRVVLAKQL LLSELLEHLL EKDIITLEMR ELIQAKVGSF SQNVELLNLL






61
PKRGPQAFDA FCEALRETKQ GHLEDMLLTT LSGLQHVLPP LSCDYDLSLP FPVCESCPLY





121
KKLRLSTDTV EHSLDNKDGP VCLQVKPCTP EFYQTHFQLA YRLQSRPRGL ALVLSNVHFT





181
GEKELEFRSG GDVDHSTLVT LFKLLGYDVH VLCDQTAQEM QEKLQNFAQL PAHRVTDSCI





241
VALLSHGVEG AIYGVDGKLL QLQEVFQLFD NANCPSLQNK PKMFFIQACR GGAIGSLGHL





301
LLFTAATASL AL











SEQ ID NO: 272



LEUCINE RICH REPEAT AND IG DOMAIN CONTAINING PROTEIN 1 (LINGO1)



AAH68558.1









1
MLAGGVRSMP SPLLACWQPI LLLVLGSVLS GSATGCPPRY ECSAQDRAVL CHRKRFVAVP






61
EGIPTETRLL DLGKNRIKTL NQDEFASFPH LEELELNENI VSAVEPGAFN NLFNLRTLGL





121
RSNRLKLIPL GVFTGLSNLT KLDISENKIV ILLDYMFQDL YNLRSLEVGD NDLVYISHRA





181
FSGLNSLEQL TLEKCNLTSI PTEALSHLHG LIVLRLRHLN INAIRDYSFK RLYRLKVLEI





241
SHWPYLDTMT PNCLYGLNLT SLSITHCNLT AVPYLAVRHL VYLRFLNLSY NRISTIEGSM





301
LHELLRLQEI QLVGGQLAVV EPYAFRGLNY LRVLNVSGNQ LTTLEESVFH SVGNLETLIL





361
DSNPLACDCR LLWVFRRRWR LNFNRQQPTC ATPEFVQGKE FKDFPDVLLP NYFTCRRARI





421
RDRKAQQVFV DEGHTVQFVC RADGDPPPAI LWLSPRKHLV SAKSNGRLTV FPDGTLEVRY





481
AQVQDNGTYL CIAANAGGND SMPAHLHVRS YSPDWPHQPN KTFAFISNQP GEGEANSTRA





541
TVPFPFDIKT LIIATTMGFI SFLGVVLFCL VLLFLWSRGK GNTKHNIEIE YVPRKSDAGI





601
SSADAPRKFN MKMI











SEQ ID NO: 273



PALMITOYL-PROTEIN THIOESTERASE 1 (PPT1)



AAH08426.1









1
MASPGCLWLL AVALLPWTCA SRALQHLDPP APLPLVIWHG MGDSCCNPLS MGAIKKMVEK






61
KIPGIYVLSL EIGKTLMEDV ENSFFLNVNS QVTTVCQALA KDPKLQQGYN AMGFSQGGQF





121
LRAVAQRCPS PPMINLISVG GQHQGVFGLP RCPGESSHIC DFIRKTLNAG AYSKVVQERL





181
VQAEYWHDPI KEDVYRNHSI FLADINQERG INESYKKNLM ALKKFVMVKF LNDSIVDPVD





241
SEWFGFYRSG QAKETIPLQE TSLYTQDRLG LKEMDNAGQL VFLATEGDHL QLSEEWFYAH





301
IIPFLG











SEQ ID NO: 274



TRIPEPTIDYL-PEPTIDASE 1 (TPP1)



NP_000382.3









1
MGLQACLLGL FALILSGKCS YSPEPDQRRT LPPGWVSLGR ADPEEELSLT FALRQQNVER






61
LSELVQAVSD PSSPQYGKYL TLENVADLVR PSPLTLHTVQ KWLLAAGAQK CHSVITQDFL





121
TCWLSIRQAE LLLPGAEFHH YVGGPTETHV VRSPHPYQLP QALAPHVDFV GGLHRFPPTS





181
SLRQRPEPQV TGTVGLHLGV TPSVIRKRYN LTSQDVGSGT SNNSQACAQF LEQYFHDSDL





241
AQFMRLFGGN FAHQASVARV VGQQGRGRAG IEASLDVQYL MSAGANISTW VYSSPGRHEG





301
QEPFLQWLML LSNESALPHV HTVSYGDDED SLSSAYIQRV NTELMKAAAR GLTLLFASGD





361
SGAGCWSVSG RHQFRPTFPA SSPYVTTVGG TSFQEPFLIT NEIVDYISGG GFSNVFPRPS





421
YQEEAVTKFL SSSPHLPPSS YFNASGRAYP DVAALSDGYW VVSNRVPIPW VSGTSASTPV





481
FGGILSLINE HRILSGRPPL GFLNPRLYQQ HGAGLFDVTR GCHESCLDEE VEGQGFCSGP





541
GWDPVTGWGT PNFPALLKTL LNP











SEQ ID NO: 275



BATTENIN (CLN3)



AAI11069.1









1
MLSAAHDILS HKRTSGNQSH AVLLADILPT LVIKLLAPLG LHLLPYSPRV LVSGICAAGS






61
FVLVAFSHSV GTSLCGVVFA SISSGLGEVT FLSLTAFYPR AVISWWSSGT GGAGLLGALS





121
YLGLTQAGLS PQQTLLSMLG IPALLLASYF LLLTSPEAQD PGGEEEAESA ARQPLIRTEA





181
PESKPGSSSS LSLRERWTVF KGLLWYIVPL VVVYFAEYFI NQGLFELLFF WNTSLSHAQQ





241
YRWYQMLYQA GVFASRSSLR CCRIRFTWAL ALLQCLNLVF LLADVWFGFL PSIYLVFLII





301
LYEGLLGGAA YVNTFHNIAL ETSDEHREFA MAATCISDTL GISLSGLLAL PLHDFLCQLS











SEQ ID NO: 276



CLN6 TRANSMEMBRANE ER PROTEIN (CLN6)



NP_060352.1









1
MEATRRRQHL GATGGPGAQL GASFLQARHG SVSADEAART APFHLDLWFY FTLQNWVLDF






61
GRPIAMLVFP LEWFPLNKPS VGDYFHMAYN VITPFLLLKL IERSPRTLPR SITYVSIIIF





121
IMGASIHLVG DSVNHRLLFS GYQHHLSVRE NPIIKNLKPE TLIDSFELLY YYDEYLGHCM





181
WYIPFFLILF MYFSGCFTAS KAESLIPGPA LLLVAPSGLY YWYLVTEGQI FILFIFTFFA





241
MLALVLHQKR KRLFLDSNGL FLFSSFALTL LLVALWVAWL WNDPVLRKKY PGVIYVPEPW





301
AFYTLHVSSR H











SEQ ID NO: 277



MAJOR FACILITATOR SUPERFAMILY DOMAIN CONTAINING 8 (MFSD8)



AAH29503.1









1
MAGLRNESEQ EPLLGDTPGS REWDILETEE HYKSRWRSIR ILYLTMFLSS VGFSVVMMSI






61
WPYLQKIDPT ADTSFLGWVI ASYSLGQMVA SPIFGLWSNY RPRKEPLIVS ILISVAANCL





121
YAYLHIPASH NKYYMLVARG LLGIGAGNVA VVRSYTAGAT SLQERTSSMA NISMCQALGF





181
ILGPVFQTCF TFLGEKGVTW DVIKLQINMY TTPVLLSAFL GILNIILILA ILREHRVDDS





241
GRQCKSINFE EASTDEAQVP QGNIDQVAVV AINVLFFVTL FIFALFETII TPLTMDMYAW





301
TQEQAVLYNG IILAALGVEA VVIFLGVKLL SKKIGERAIL LGGLIVVWVG FFILLPWGNQ





361
FPKIQWEDLH NNSIPNTIFG EIIIGLWKSP MEDDNERPTG CSIEQAWCLY TPVIHLAQFL





421
TSAVLIGLGY PVCNLMSYTL YSKILGPKPQ GVYMGWLTAS GSGARILGPM FISQVYAHWG





481
PRWAFSLVCG IIVLTITLLG VVYKRLIALS VRYGRIQE











SEQ ID NO: 278



MYOSIN VIIA (MYO7A)



AAB03679.1









1
MVILQQGDHV WMDLRLGQEF DVPIGAVVKL CDSGQVQVVD DEDNEHWISP QNATHIKPMH






61
PTSVHGVEDM IRLGDLNEAG ILRNLLIRYR DHLIYTYTGS ILVAVNPYQL LSIYSPEHIR





121
QYTNKKIGEM PPHIFAIADN CYFNMKRNSR DQCCIISGES GAGKTESTKL ILQFLAAISG





181
QHSWIEQQVL EATPILEAFG NAKTIRNDNS SRFGKYIDIH FNKRGAIEGA KIEQYLLEKS





241
RVCRQALDER NYHVFYCMLE GMSEDQKKKL GLGQASDYNY LAMGNCITCE GRVDSQEYAN





301
IRSAMKVLMF TDTENWEISK LLAAILHLGN LQYEARTFEN LDACEVLFSP SLATAASLLE





361
VNPPDLMSCL TSRTLITRGE TVSTPLSREQ ALDVRDAFVK GIYGRLFVWI VDKINAAIYK





421
PPSQDVKNSR RSIGLLDIFG FENFAVNSFE QLCINFANEH LQQFFVRHVF KLEQEEYDLE





481
SIDWLHIEFT DNQDALDMIA NKPMNIISLI DEESKFPKGT DTTMLHKLNS QHKLNANYIP





541
PKNNHETQFG INHFAGIVYY ETQGFLEKNR DTLHGDIIQL VHSSRNKFIK QIFQADVAMG





601
AETRKRSPTL SSQFKRSLEL LMRTLGACQP FFVRCIKPNE FKKPMLFDRH LCVRQLRYSG





661
MMETIRIRRA GYPIRYSFVE FVERYRVLLP GVKPAYKQGD LRGTCQRMAE AVLGTHDDWQ





721
IGKTKIFLKD HHDMLLEVER DKAITDRVIL LQKVIRGFKD RSNFLKLKNA ATLIQRHWRG





781
HNCRKNYGLM RLGFLRLQAL HRSRKLHQQY RLARQRIIQF QARCRAYLVR KAFRHRLWAV





841
LTVQAYARGM IARRLHQRLR AEYLWRLEAE KMRLAEEEKL RKEMSAKKAK EEAERKHQER





901
LAQLAREDAE RELKEKEAAR RKKELLEQME RARHEPVNHS DMVDKMFGFL GTSGGLPGQE





961
GQAPSGFEDL ERGRREMVEE DLDAALPLPD EDEEDLSEYK FAKFAATYFQ GTTTHSYTRR





1021
PLKQPLLYHD DEGDQLAALA VWITILRFMG DLPEPKYHTA MSDGSEKIPV MTKIYETLGK





1081
KTYKRELQAL QGEGEAQLPE GQKKSSVRHK LVHLTLKKKS KLTEEVTKRL HDGESTVQGN





1141
SMLEDRPTSN LEKLHFIIGN GILRPALRDE IYCQISKQLT HNPSKSSYAR GWILVSLCVG





1201
CFAPSEKFVK YLRNFIHGGP PGYAPYCEER LRRTFVNGTR TQPPSWLELQ ATKSKKPIML





1261
PVTFMDGTTK TLLTDSATTA KELCNALADK ISLKDRFGFS LYIALFDKVS SLGSGSDHVM





1321
DAISQCEQYA KEQGAQERNA PWRLFFRKEV FTPWHSPSED NVATNLIYQQ VVRGVKFGEY





1381
RCEKEDDLAE LASQQYFVDY GSEMILERLL NLVPTYIPDR EITPLKTLEK WAQLAIAAHK





1441
KGIYAQRRTD AQKVKEDVVS YARFKWPLLF SRFYEAYKFS GPSLPKNDVI VAVNWTGVYF





1501
VDEQEQVLLE LSFPEIMAVS SSRECRVWLS LGCSDLGCAA PHSGWAGLTP AGPCSPCWSC





1561
RGAKTTAPSF TLATIKGDEY TFTSSNAEDI RDLVVTFLEG LRKRSKYVVA LQDNPNPAGE





1621
ESGFLSFAKG DLIILDHDTG EQVMNSGWAN GINERTKQRG DFPTDCVYVM PTVIMPPREI





1681
VALVTMTPDQ RQDVVRLLQL RTAEPEVRAK PYTLEEFSYD YFRPPPKHTL SRVMVSKARG





1741
KDRLWSHTRE PLKQALLKKL LGSEELSQEA CLAFIAVLKY MGDYPSKRTR SVNELTDQIF





1801
EGPLKAEPLK DEAYVQILKQ LTDNHIRYSE ERGWELLWLC TGLFPPSNIL LPHVQRFLQS





1861
RKHCPLAIDC LQRLQKALRN GSRKYPPHLV EVEAIQHKTT QIFHKVYFPD DTDEAFEVES





1921
STKAKDFCQN IATRLLLKSS EGFSLFVKIA DKVISVPEND FFFDFVRHLT DWIKKARPIK





1981
DGIVPSLTYQ VFFMKKLWTT TVPGKDPMAD SIFHYYQELP KYLRGYHKCT REEVLQLGAL





2041
IYRVKFEEDK SYFPSIPKLL RELVPQDLIR QVSPDDWKRS IVAYFNKHAG KSKEEAKLAF





2101
LKLIFKWPTF GSAFFEVKQT TEPNFPEILL IAINKYGVSL IDPKTKDILT THPFTKISNW





2161
SSGNTYFHIT IGNLVRGSKL LCETSLGYKM DDLLTSYISQ MLTAMSKQRG SRSGK











SEQ ID NO: 279



MYOSIN VIIA (MYO7A), ISOFORM CRA_A



EAW75018.1









1
MVILQQGDHV WMDLRLGQEF DVPIGAVVKL CDSGQVQVVD DEDNEHWISP QNATHIKPMH






61
PTSVHGVEDM IRLGDLNEAG ILRNLLIRYR DHLIYTYTGS ILVAVNPYQL LSIYSPEHIR





121
QYTNKKIGEM PPHIFAIADN CYFNMKRNSR DQCCIISGES GAGKTESTKL ILQFLAAISG





181
QHSWIEQQVL EATPILEAFG NAKTIRNDNS SRFGKYIDIH FNKRGAIEGA KIEQYLLEKS





241
RVCRQALDER NYHVFYCMLE GMSEDQKKKL GLGQASDYNY LAMGNCITCE GRVDSQEYAN





301
IRSAMKVLMF TDTENWEISK LLAAILHLGN LQYEARTFEN LDACEVLFSP SLATAASLLE





361
VNPPDLMSCL TSRTLITRGE TVSTPLSREQ ALDVRDAFVK GIYGRLFVWI VDKINAAIYK





421
PPSQDVKNSR RSIGLLDIFG FENFAVNSFE QLCINFANEH LQQFFVRHVF KLEQEEYDLE





481
SIDWLHIEFT DNQDALDMIA NKPMNIISLI DEESKFPKGT DTTMLHKLNS QHKLNANYIP





541
PKNNHETQFG INHFAGIVYY ETQGFLEKNR DTLHGDIIQL VHSSRNKFIK QIFQADVAMG





601
AETRKRSPTL SSQFKRSLEL LMRTLGACQP FFVRCIKPNE FKKPMLFDRH LCVRQLRYSG





661
MMETIRIRRA GYPIRYSFVE FVERYRVLLP GVKPAYKQGD LRGTCQRMAE AVLGTHDDWQ





721
IGKTKIFLKD HHDMLLEVER DKAITDRVIL LQKVIRGFKD RSNFLKLKNA ATLIQRHWRG





781
HNCRKNYGLM RLGFLRLQAL HRSRKLHQQY RLARQRIIQF QARCRAYLVR KAFRHRLWAV





841
LTVQAYARGM IARRLHQRLR AEYLWRLEAE KMRLAEEEKL RKEMSAKKAK EEAERKHQER





901
LAQLAREDAE RELKEKEAAR RKKELLEQME RARHEPVNHS DMVDKMFGFL GTSGGLPGQE





961
GQAPSGFEDL ERGRREMVEE DLDAALPLPD EDEEDLSEYK FAKFAATYFQ GTTTHSYTRR





1021
PLKQPLLYHD DEGDQLAALA VWITILRFMG DLPEPKYHTA MSDGSEKIPV MTKIYETLGK





1081
KTYKRELQAL QGEGEAQLPE GQKKSSVRHK LVHLTLKKKS KLTEEVTKRL HDGESTVQGN





1141
SMLEDRPTSN LEKLHFIIGN GILRPALRSV PGGGDTRA











SEQ ID NO: 280



MYOSIN VIIA (MYO7A), ISOFORM CRA_B



EAW75019.1









1
MVILQQGDHV WMDLRLGQEF DVPIGAVVKL CDSGQVQVVD DEDNEHWISP QNATHIKPMH






61
PTSVHGVEDM IRLGDLNEAG ILRNLLIRYR DHLIYTYTGS ILVAVNPYQL LSIYSPEHIR





121
QYTNKKIGEM PPHIFAIADN CYFNMKRNSR DQCCIISGES GAGKTESTKL ILQFLAAISG





181
QHSWIEQQVL EATPILEAFG NAKTIRNDNS SRFGKYIDIH FNKRGAIEGA KIEQYLLEKS





241
RVCRQALDER NYHVFYCMLE GMSEDQKKKL GLGQASDYNY LAMGNCITCE GRVDSQEYAN





301
IRSAMKVLMF TDTENWEISK LLAAILHLGN LQYEARTFEN LDACEVLFSP SLATAASLLE





361
VNPPDLMSCL TSRTLITRGE TVSTPLSREQ ALDVRDAFVK GIYGRLFVWI VDKINAAIYK





421
PPSQDVKNSR RSIGLLDIFG FENFAVNSFE QLCINFANEH LQQFFVRHVF KLEQEEYDLE





481
SIDWLHIEFT DNQDALDMIA NKPMNIISLI DEESKFPKGT DTTMLHKLNS QHKLNANYIP





541
PKNNHETQFG INHFAGIVYY ETQGFLEKNR DTLHGDIIQL VHSSRNKFIK QIFQADVAMG





601
AETRKRSPTL SSQFKRSLEL LMRTLGACQP FFVRCIKPNE FKKPMLFDRH LCVRQLRYSG





661
MMETIRIRRA GYPIRYSFVE FVERYRVLLP GVKPAYKQGD LRGTCQRMAE AVLGTHDDWQ





721
IGKTKIFLKD HHDMLLEVER DKAITDRVIL LQKVIRGFKD RSNFLKLKNA ATLIQRHWRG





781
HNCRKNYGLM RLGFLRLQAL HRSRKLHQQY RLARQRIIQF QARCRAYLVR KAFRHRLWAV





841
LTVQAYARGM IARRLHQRLR AEYLWRLEAE KMRLAEEEKL RKEMSAKKAK EEAERKHQER





901
LAQLAREDAE RELKEKEAAR RKKELLEQME RARHEPVNHS DMVDKMFGFL GTSGGLPGQE





961
GQAPSGFEDL ERGRREMVEE DLDAALPLPD EDEEDLSEYK FAKFAATYFQ GTTTHSYTRR





1021
PLKQPLLYHD DEGDQLAALA VWITILRFMG DLPEPKYHTA MSDGSEKIPV MTKIYETLGK





1081
KTYKRELQAL QGEGEAQLPE GQKKSSVRHK LVHLTLKKKS KLTEEVTKRL HDGESTVQGN





1141
SMLEDRPTSN LEKLHFIIGN GILRPALRDE IYCQISKQLT HNPSKSSYAR GWILVSLCVG





1201
CFAPSEKFVK YLRNFIHGGP PGYAPYCEER LRRTFVNGTR TQPPSWLELQ ATKSKKPIML





1261
PVTFMDGTTK TLLTDSATTA KELCNALADK ISLKDRFGFS LYIALFDKVS SLGSGSDHVM





1321
DAISQCEQYA KEQGAQERNA PWRLFFRKEV FTPWHSPSED NVATNLIYQQ VVRGVKFGEY





1381
RCEKEDDLAE LASQQYFVDY GSEMILERLL NLVPTYIPDR EITPLKTLEK WAQLAIAAHK





1441
KGIYAQRRTD AQKVKEDVVS YARFKWPLLF SRFYEAYKFS GPSLPKNDVI VAVNWTGVYF





1501
VDEQEQVLLE LSFPEIMAVS SSRECRVWLS LGCSDLGCAA PHSGWAGLTP AGPCSPCWSC





1561
RGAKTTAPSF TLATIKGDEY TFTSSNAEDI RDLVVTFLEG LRKRSKYVVA LQDNPNPAGE





1621
ESGFLSFAKG DLIILDHDTG EQVMNSGWAN GINERTKQRG DFPTDCVYVM PTVIMPPREI





1681
VALVTMTPDQ RQDVVRLLQL RTAEPEVRAK PYTLEEFSYD YFRPPPKHTL SRVMVSKARG





1741
KDRLWSHTRE PLKQALLKKL LGSEELSQEA CLAFIAVLKY MGDYPSKRTR SVNELTDQIF





1801
EGPLKAEPLK DEAYVQILKQ LTDNHIRYSE ERGWELLWLC TGLFPPSNIL LPHVQRFLQS





1861
RKHCPLAIDC LQRLQKALRN GSRKYPPHLV EVEAIQHKTT QIFHKVYFPD DTDEAFEVES





1921
STKAKDFCQN IATRLLLKSS EGFSLFVKIA DKVISVPEND FFFDFVRHLT DWIKKARPIK





1981
DGIVPSLTYQ VFFMKKLWTT TVPGKDPMAD SIFHYYQELP KYLRGYHKCT REEVLQLGAL





2041
IYRVKFEEDK SYFPSIPKLL RELVPQDLIR QVSPDDWKRS IVAYFNKHAG KSKEEAKLAF





2101
LKLIFKWPTF GSAFFEVKQT TEPNFPEILL IAINKYGVSL IDPKTKDILT THPFTKISNW





2161
SSGNTYFHIT IGNLVRGSKL LCETSLGYKM DDLLTSYISQ MLTAMSKQRG SRSGK











SEQ ID NO: 281



MYOSIN VIIA (MYO7A), ISOFORM CRA_C



EAW75020.1









1
MVILQQGDHV WMDLRLGQEF DVPIGAVVKL CDSGQVQVVD DEDNEHWISP QNATHIKPMH






61
PTSVHGVEDM IRLGDLNEAG ILRNLLIRYR DHLIYTYTGS ILVAVNPYQL LSIYSPEHIR





121
QYTNKKIGEM PPHIFAIADN CYFNMKRNSR DQCCIISGES GAGKTESTKL ILQFLAAISG





181
QHSWIEQQVL EATPILEAFG NAKTIRNDNS SRFGKYIDIH FNKRGAIEGA KIEQYLLEKS





241
RVCRQALDER NYHVFYCMLE GMSEDQKKKL GLGQASDYNY LAMGNCITCE GRVDSQEYAN





301
IRSAMKVLMF TDTENWEISK LLAAILHLGN LQYEARTFEN LDACEVLFSP SLATAASLLE





361
VNPPDLMSCL TSRTLITRGE TVSTPLSREQ ALDVRDAFVK GIYGRLFVWI VDKINAAIYK





421
PPSQDVKNSR RSIGLLDIFG FENFAVNSFE QLCINFANEH LQQFFVRHVF KLEQEEYDLE





481
SIDWLHIEFT DNQDALDMIA NKPMNIISLI DEESKFPKGT DTTMLHKLNS QHKLNANYIP





541
PKNNHETQFG INHFAGIVYY ETQGFLEKNR DTLHGDIIQL VHSSRNKFIK QIFQADVAMG





601
AETRKRSPTL SSQFKRSLEL LMRTLGACQP FFVRCIKPNE FKKPMLFDRH LCVRQLRYSG





661
MMETIRIRRA GYPIRYSFVE FVERYRVLLP GVKPAYKQGD LRGTCQRMAE AVLGTHDDWQ





721
IGKTKIFLKD HHDMLLEVER DKAITDRVIL LQKVIRGFKD RSNFLKLKNA ATLIQRHWRG





781
HNCRKNYGLM RLGFLRLQAL HRSRKLHQQY RLARQRIIQF QARCRAYLVR KAFRHRLWAV





841
LTVQAYARGM IARRLHQRLR AEYLWRLEAE KMRLAEEEKL RKEMSAKKAK EEAERKHQER





901
LAQLAREDAE RELKEKEAAR RKKELLEQME RARHEPVNHS DMVDKMFGFL GTSGGLPGQE





961
GQAPSGFEDL ERGRREMVEE DLDAALPLPD EDEEDLSEYK FAKFAATYFQ GTTTHSYTRR





1021
PLKQPLLYHD DEGDQLAALA VWITILRFMG DLPEPKYHTA MSDGSEKIPV MTKIYETLGK





1081
KTYKRELQAL QGEGEAQLPE GQKKSSVRHK LVHLTLKKKS KLTEEVTKRL HDGESTVQGN





1141
SMLEDRPTSN LEKLHFIIGN GILRPALRDE IYCQISKQLT HNPSKSSYAR GWILVSLCVG





1201
CFAPSEKFVK YLRNFIHGGP PGYAPYCEER LRRTFVNGTR TQPPSWLELQ ATKSKKPIML





1261
PVTFMDGTTK TLLTDSATTA KELCNALADK ISLKDRFGFS LYIALFDKVS SLGSGSDHVM





1321
DAISQCEQYA KEQGAQERNA PWRLFFRKEV FTPWHSPSED NVATNLIYQQ VVRGVKFGEY





1381
RCEKEDDLAE LASQQYFVDY GSEMILERLL NLVPTYIPDR EITPLKTLEK WAQLAIAAHK





1441
KGIYAQRRTD AQKVKEDVVS YARFKWPLLF SRFYEAYKFS GPSLPKNDVI VAVNWTGVYF





1501
VDEQEQVLLE LSFPEIMAVS SSRECRVWLS LGCSDLGCAA PHSGWAGLTP AGPCSPCWSC





1561
RGAKTTAPSF TLATIKGDEY TFTSSNAEDI RDLVVTFLEG LRKRSKYVVA LQDNPNPAGE





1621
ESGFLSFAKG DLIILDHDTG EQVMNSGWAN GINERTKQRG DFPTDCVYVM PTVIMPPREI





1681
VALVTMTPDQ RQDVVRLLQL RTAEPEVRAK PYTLEEFSYD YFRPPPKHTL SRVMVSKARG





1741
KDRLWSHTRE PLKQALLKKL LGSEELSQEA CLAFIDIPVL KYMGDYPSKR TRSVNELTDQ





1801
IFEGPLKAEP LKDEAYVQIL KQLTDNHIRY SEERGWELLW LCTGLFPPSN ILLPHVQRFL





1861
QSRKHCPLAI DCLQRLQKAL RNGSRKYPPH LVEVEAIQHK TTQIFHKVYF PDDTDEAFEV





1921
ESSTKAKDFC QNIATRLLLK SSEGFSLFVK IADKVISVPE NDFFFDFVRH LTDWIKKARP





1981
IKDGIVPSLT YQVFFMKKLW TTTVPGKDPM ADSIFHYYQE LPKYLRGYHK CTREEVLQLG





2041
ALIYRVKFEE DKSYFPSIPK LLRELVPQDL IRQVSPDDWK RSIVAYFNKH AGKSKEEAKL





2101
AFLKLIFKWP TFGSAFFEVK QTTEPNFPEI LLIAINKYGV SLIDPKTKDI LITHPFTKIS





2161
NWSSGNTYFH ITIGNLVRGS KLLCETSLGY KMDDLLTSYI SQMLTAMSKQ RGSRSGK











SEQ ID NO: 282



MYOSIN VIIA (MYO7A), ISOFORM CRA_D



EAW75021.1









1
MVILQQGDHV WMDLRLGQEF DVPIGAVVKL CDSGQVQVVD DEDNEHWISP QNATHIKPMH






61
PTSVHGVEDM IRLGDLNEAG ILRNLLIRYR DHLIYTYTGS ILVAVNPYQL LSIYSPEHIR





121
QYTNKKIGEM PPHIFAIADN CYFNMKRNSR DQCCIISGES GAGKTESTKL ILQFLAAISG





181
QHSWIEQQVL EATPILEAFG NAKTIRNDNS SRFGKYIDIH FNKRGAIEGA KIEQYLLEKS





241
RVCRQALDER NYHVFYCMLE GMSEDQKKKL GLGQASDYNY LAMGNCITCE GRVDSQEYAN





301
IRSAMKVLMF TDTENWEISK LLAAILHLGN LQYEARTFEN LDACEVLFSP SLATAASLLE





361
VNPPDLMSCL TSRTLITRGE TVSTPLSREQ ALDVRDAFVK GIYGRLFVWI VDKINAAIYK





421
PPSQDVKNSR RSIGLLDIFG FENFAVNSFE QLCINFANEH LQQFFVRHVF KLEQEEYDLE





481
SIDWLHIEFT DNQDALDMIA NKPMNIISLI DEESKFPKGT DTTMLHKLNS QHKLNANYIP





541
PKNNHETQFG INHFAGIVYY ETQGFLEKNR DTLHGDIIQL VHSSRNKFIK QIFQADVAMG





601
AETRKRSPTL SSQFKRSLEL LMRTLGACQP FFVRCIKPNE FKKPMLFDRH LCVRQLRYSG





661
MMETIRIRRA GYPIRYSFVE FVERYRVLLP GVKPAYKQGD LRGTCQRMAE AVLGTHDDWQ





721
IGKTKIFLKD HHDMLLEVER DKAITDRVIL LQKVIRGFKD RCVFPPAPPL LSPHTGVRVV





781
FGSPLLCPHE H











SEQ ID NO: 283



MYOSIN VIIA (MYO7A), ISOFORM CRA_E



EAW75022.1









1
MVILQQGDHV WMDLRLGQEF DVPIGAVVKL CDSGQVQVVD DEDNEHWISP QNATHIKPMH






61
PTSVHGVEDM IRLGDLNEAG ILRNLLIRYR DHLIYTYTGS ILVAVNPYQL LSIYSPEHIR





121
QYTNKKIGEM PPHIFAIADN CYFNMKRNSR DQCCIISGES GAGKTESTKL ILQFLAAISG





181
QHSWIEQQVL EATPILEAFG NAKTIRNDNS SRFGKYIDIH FNKRGAIEGA KIEQYLLEKS





241
RVCRQALDER NYHVFYCMLE GMSEDQKKKL GLGQASDYNY LAMGNCITCE GRVDSQEYAN





301
IRSAMKVLMF TDTENWEISK LLAAILHLGN LQYEARTFEN LDACEVLFSP SLATAASLLE





361
VNPPDLMSCL TSRTLITRGE TVSTPLSREQ ALDVRDAFVK GIYGRLFVWI VDKINAAIYK





421
PPSQDVKNSR RSIGLLDIFG FENFAVNSFE QLCINFANEH LQQFFVRHVF KLEQEEYDLE





481
SIDWLHIEFT DNQDALDMIA NKPMNIISLI DEESKFPKGT DTTMLHKLNS QHKLNANYIP





541
PKNNHETQFG INHFAGIVYY ETQGFLEKNR DTLHGDIIQL VHSSRNKFIK QIFQADVAMG





601
AETRKRSPTL SSQFKRSLEL LMRTLGACQP FFVRCIKPNE FKKPMLFDRH LCVRQLRYSG





661
MMETIRIRRA GYPIRYSFVE FVERYRVLLP GVKPAYKQGD LRGTCQRMAE AVLGTHDDWQ





721
IGKTKIFLKD HHDMLLEVER DKAITDRVIL LQKVIRGFKD RSNFLKLKNA ATLIQRHWRG





781
HNCRKNYGLM RLGFLRLQAL HRSRKLHQQY RLARQRIIQF QARCRAYLVR KAFRHRLWAV





841
LTVQAYARGM IARRLHQRLR AEYLWRLEAE KMRLAEEEKL RKEMSAKKAK EEAERKHQER





901
LAQLAREDAE RELKEKEAAR RKKELLEQME RARHEPVNHS DMVDKMFGFL GTSGGLPGQE





961
GQAPSGFEDL ERGRREMVEE DLDAALPLPD EDEEDLSEYK FAKFAATYFQ GTTTHSYTRR





1021
PLKQPLLYHD DEGDQLAALA VWITILRFMG DLPEPKYHTA MSDGSEKIPV MTKIYETLGK





1081
KTYKRELQAL QGEGEAQLPE GQKKSSVRHK LVHLTLKKKS KLTEEVTKRL HDGESTVQGN





1141
SMLEDRPTSN LEKLHFIIGN GILRPALRDE IYCQISKQLT HNPSKSSYAR GWILVSLCVG





1201
CFAPSEKFVK YLRNFIHGGP PGYAPYCEER LRRTFVNGTR TQPPSWLELQ ATKSKKPIML





1261
PVTFMDGTTK TLLTDSATTA KELCNALADK ISLKDRFGFS LYIALFDKVS SLGSGSDHVM





1321
DAISQCEQYA KEQGAQERNA PWRLFFRKEV FTPWHSPSED NVATNLIYQQ VVRGVKFGEY





1381
RCEKEDDLAE LASQQYFVDY GSEMILERLL NLVPTYIPDR EITPLKTLEK WAQLAIAAHK





1441
KGIYAQRRTD AQKVKEDVVS YARFKWPLLF SRFYEAYKFS GPSLPKNDVI VAVNWTGVYF





1501
VDEQEQVLLE LSFPEIMAVS SSRGAKTTAP SFTLATIKGD EYTFTSSNAE DIRDLVVTFL





1561
EGLRKRSKYV VALQDNPNPA GEESGFLSFA KGDLIILDHD TGEQVMNSGW ANGINERTKQ





1621
RGDFPTDCVY VMPTVTMPPR EIVALVTMTP DQRQDVVRLL QLRTAEPEVR AKPYTLEEFS





1681
YDYFRPPPKH TLSRVMVSKA RGKDRLWSHT REPLKQALLK KLLGSEELSQ EACLAFIDIP





1741
VLKYMGDYPS KRTRSVNELT DQIFEGPLKA EPLKDEAYVQ ILKQLTDNHI RYSEERGWEL





1801
LWLCTGLFPP SNILLPHVQR FLQSRKHCPL AIDCLQRLQK ALRNGSRKYP PHLVEVEAIQ





1861
HKTIQIFHKV YFPDDTDEAF EVESSTKAKD FCQNIATRLL LKSSEGFSLF VKIADKVISV





1921
PENDFFFDFV RHLTDWIKKA RPIKDGIVPS LTYQVFFMKK LWTTTVPGKD PMADSIFHYY





1981
QELPKYLRGY HKCTREEVLQ LGALIYRVKF EEDKSYFPSI PKLLRELVPQ DLIRQVSPDD





2041
WKRSIVAYFN KHAGKSKEEA KLAFLKLIFK WPTFGSAFFE QTTEPNFPEI LLIAINKYGV





2101
SLIDPKTKDI LITHPFTKIS NWSSGNTYFH ITIGNLVRGS KLLCETSLGY KMDDLLTSYI





2161
SQMLTAMSKQ RGSRSGK











SEQ ID NO: 284



MYOSIN VITA (MYO7A), ISOFORM CRA_F



EAW75023.1









1
MLEGMSEDQK KKLGLGQASD YNYLAMGNCI TCEGRVDSQE YANIRSAMKV LMFTDTENWE






61
ISKLLAAILH LGNLQYEART FENLDACEVL FSPSLATAAS LLEVNPPDLM SCLTSRTLIT





121
RGETVSTPLS REQALDVRDA FVKGIYGRLF VWIVDKINAA IYKPPSQDVK NSRRSIGLLD





181
IFGFENFAVN SFEQLCINFA NEHLQQFFVR HVFKLEQEEY DLESIDWLHI EFTDNQDALD





241
MIANKPMNII SLIDEESKFP KGTDTTMLHK LNSQHKLNAN YIPPKNNHET QFGINHFAGI





301
VYYETQGFLE KNRDTLHGDI IQLVHSSRNK FIKQIFQADV AMGAETRKRS PTLSSQFKRS





361
LELLMRTLGA CQPFFVRCIK PNEFKKPMLF DRHLCVRQLR YSGMMETIRI RRAGYPIRYS





421
FVEFVERYRV LLPGVKPAYK QGDLRGTCQR MAEAVLGTHD DWQIGKTKIF LKDHHDMLLE





481
VERDKAITDR VILLQKVIRG FKDRSNFLKL KNAATLIQRH WRGHNCRKNY GLMRLGFLRL





541
QALHRSRKLH QQYRLARQRI IQFQARCRAY LVRKAFRHRL WAVLTVQAYA RGMIARRLHQ





601
RLRAEYLWRL EAEKMRLAEE EKLRKEMSAK KAKEEAERKH QERLAQLARE DAERELKEKE





661
AARRKKELLE QMERARHEPV NHSDMVDKMF GFLGTSGGLP GQEGQAPSGF EDLERGRREM





721
VEEDLDAALP LPDEDEEDLS EYKFAKFAAT YFQGTTTHSY TRRPLKQPLL YHDDEGDQLA





781
ALAVWITILR FMGDLPEPKY HTAMSDGSEK IPVMTKIYET LGKKTYKREL QALQGEGEAQ





841
LPEGQKKSSV RHKLVHLTLK KKSKLTEEVT KRLHDGESTV QGNSMLEDRP TSNLEKLHFI





901
IGNGILRPAL RDEIYCQISK QLTHNPSKSS YARGWILVSL CVGCFAPSEK FVKYLRNFIH





961
GGPPGYAPYC EERLRRTFVN GTRTQPPSWL ELQATKSKKP IMLPVTFMDG TTKTLLTDSA





1021
TTAKELCNAL ADKISLKDRF GFSLYIALFD KVSSLGSGSD HVMDAISQCE QYAKEQGAQE





1081
RNAPWRLFFR KEVFTPWHSP SEDNVATNLI YQQVVRGVKF GEYRCEKEDD LAELASQQYF





1141
VDYGSEMILE RLLNLVPTYI PDREITPLKT LEKWAQLAIA AHKKGIYAQR RTDAQKVKED





1201
VVSYARFKWP LLFSRFYEAY KFSGPSLPKN DVIVAVNWTG VYFVDEQEQV LLELSFPEIM





1261
AVSSSRECRV WLSLGCSDLG CAAPHSGWAG LTPAGPCSPC WSCRGAKTTA PSFTLATIKG





1321
DEYTFTSSNA EDIRDLVVTF LEGLRKRSKY VVALQDNPNP AGEESGFLSF AKGDLIILDH





1381
DTGEQVMNSG WANGINERTK QRGDFPTDCV YVMPTVTMPP REIVALVTMT PDQRQDVVRL





1441
LQLRTAEPEV RAKPYTLEEF SYDYFRPPPK HTLSRVMVSK ARGKDRLWSH TREPLKQALL





1501
KKLLGSEELS QEACLAFIAV LKYMGDYPSK RTRSVNELTD QIFEGPLKAE PLKDEAYVQI





1561
LKQLTDNHIR YSEERGWELL WLCTGLFPPS NILLPHVQRF LQSRKHCPLA IDCLQRLQKA





1621
LRNGSRKYPP HLVEVEAIQH KTTQIFHKVY FPDDTDEAFE VESSTKAKDF CQNIATRLLL





1681
KSSEGFSLFV KIADKVISVP ENDFFFDFVR HLTDWIKKAR PIKDGIVPSL TYQVFFMKKL





1741
WTTTVPGKDP MADSIFHYYQ ELPKYLRGYH KCTREEVLQL GALIYRVKFE EDKSYFPSIP





1801
KLLRELVPQD LIRQVSPDDW KRSIVAYFNK HAGKSKEEAK LAFLKLIFKW PTFGSAFFEV





1861
KQTTEPNFPE ILLIAINKYG VSLIDPKTKD ILTTHPFTKI SNWSSGNTYF HITIGNLVRG





1921
SKLLCETSLG YKMDDLLTSY ISQMLTAMSK QRGSRSGK











SEQ ID NO: 285



CADHERIN RELATED 23 (CDH23)



AAG27034.2









1
MGRHVATSCH VAWLLVLISG CWGQVNRLPF FTNHFFDTYL LISEDTPVGS SVTQLLAQDM






61
DNDPLVFGVS GEEASRFFAV EPDTGVVWLR QPLDRETKSE FTVEFSVSDH QGVITRKVNI





121
QVGDVNDNAP TFHNQPYSVR IPENTPVGTP IFIVNATDPD LGAGGSVLYS FQPPSQFFAI





181
DSARGIVTVI RELDYETTQA YQLTVNATDQ DKTRPLSTLA NLAIIITDVQ DMDPIFINLP





241
YSTNIYEHSP PGTTVRIITA IDQDKGRPRG IGYTIVSGNT NSIFALDYIS GVLTLNGLLD





301
RENPLYSHGF ILTVKGTELN DDRTPSDATV TTTFNILVID INDNAPEFNS SEYSVAITEL





361
AQVGFALPLF IQVVDKDENL GLNSMFEVYL VGNNSHHFII SPTSVQGKAD IRIRVAIPLD





421
YETVDRYDFD LFANESVPDH VGYAKVKITL INENDNRPIF SQPLYNISLY ENVTVGTSVL





481
TVLATDNDAG TFGEVSYFFS DDPDRFSLDK DTGLIMLIAR LDYELIQRFT LTIIARDGGG





541
EETTGRVRIN VLDVNDNVPT FQKDAYVGAL RENEPSVTQL VRLRATDEDS PPNNQITYSI





601
VSASAFGSYF DISLYEGYGV ISVSRPLDYE QISNGLIYLT VMAMDAGNPP LNSTVPVTIE





661
VFDENDNPPT FSKPAYFVSV VENIMAGATV LFLNATDLDR SREYGQESII YSLEGSTQFR





721
INARSGEITT TSLLDRETKS EYILIVRAVD GGVGHNQKTG IATVNITLLD INDNHPTWKD





781
APYYINLVEM TPPDSDVTTV VAVDPDLGEN GTLVYSIQPP NKFYSLNSTT GKIRTTHAML





841
DRENPDPHEA ELMRKIVVSV TDCGRPPLKA TSSATVFVNL LDLNDNDPTF QNLPFVAEVL





901
EGIPAGVSIY QVVAIDLDEG LNGLVSYRMP VGMPRMDFLI NSSSGVVVTT TELDRERIAE





961
YQLRVVASDA GTPTKSSTST LTIHVLDVND ETPTFFPAVY NVSVSEDVPR EFRVVWLNCT





1021
DNDVGLNAEL SYFITGGNVD GKFSVGYRDA VVRTVVGLDR ETTAAYMLIL EAIDNGPVGK





1081
RHTGTATVFV TVLDVNDNRP IFLQSSYEAS VPEDIPEGHS ILQLKATDAD EGEFGRVWYR





1141
ILHGNHGNNF RIHVSNGLLM RGPRPLDRER NSSHVLIVEA YNHDLGPMRS SVRVIVYVED





1201
INDEAPVFTQ QQYSRLGLRE TAGIGTSVIV VQATDRDSGD GGLVNYRILS GAEGKFEIDE





1261
STGLIITVNY LDYETKTSYM MNVSATDQAP PFNQGFCSVY ITLLNELDEA VQFSNASYEA





1321
AILENLALGT EIVRVQAYSI DNLNQITYRF DAYTSTQAKA LFKIDAITGV ITVQGLVDRE





1381
KGDFYTLTVV ADDGGPKVDS TVKVYITVLD ENDNSPRFDF TSDSAVSIPE DCPVGQRVAT





1441
VKAWDPDAGS NGQVVFSLAS GNIAGAFEIV TTNDSIGEVF VARPLDREEL DHYILQVVAS





1501
DRGTPPRKKD HILQVTILDI NDNPPVIESP FGYNVSVNEN VGGGTAVVQV RATDRDIGIN





1561
SVLSYYITEG NKDMTFRMDR ISGEIATRPA PPDRERQSFY HLVATVEDEG TPTLSATTHV





1621
YVTIVDENDN APMFQQPHYE VLLDEGPDTL NTSLITIQAL DLDEGPNGTV TYAIVAGNIV





1681
NTFRIDRHMG VITAAKELDY EISHGRYTLI VTATDQCPIL SHRLTSTTTV LVNVNDINDN





1741
VPTFPRDYEG PFEVTEGQPG PRVWTFLAHD RDSGPNGQVE YSIMDGDPLG EFVISPVEGV





1801
LRVRKDVELD RETIAFYNLT ICARDRGMPP LSSTMLVGIR VLDINDNDPV LLNLPMNITI





1861
SENSPVSSFV AHVLASDADS GCNARLTFNI TAGNRERAFF INATTGIVTV NRPLDRERIP





1921
EYKLTISVKD NPENPRIARR DYDLLLIFLS DENDNHPLFT KSTYQAEVME NSPAGTPLTV





1981
LNGPILALDA DQDIYAVVTY QLLGAQSGLF DINSSTGVVT VRSGVIIDRE AFSPPILELL





2041
LLAEDIGLLN STAHLLITIL DDNDNRPTFS PATLTVHLLE NCPPGFSVLQ VTATDEDSGL





2101
NGELVYRIEA GAQDRFLIHL VTGVIRVGNA TIDREEQESY RLTVVATDRG TVPLSGTAIV





2161
TILIDDINDS RPEFLNPIQT VSVLESAEPG TVIANITAID HDLNPKLEYH IVGIVAKDDT





2221
DRLVPNQEDA FAVNINTGSV MVKSPMNREL VATYEVTLSV IDNASDLPER SVSVPNAKLT





2281
VNVLDVNDNT PQFKPFGITY YMERILEGAT PGTTLIAVAA VDPDKGLNGL VTYTLLDLVP





2341
PGYVQLEDSS AGKVIANRTV DYEEVHWLNF TVRASDNGSP PRAAEIPVYL EIVDINDNNP





2401
IFDQPSYQEA VFEDVPVGTI ILTVTATDAD SGNFALIEYS LGDGESKFAI NPTTGDIYVL





2461
SSLDREKKDH YILTALAKDN PGDVASNRRE NSVQVVIQVL DVNDCRPQFS KPQFSTSVYE





2521
NEPAGTSVIT MMATDQDEGP NGELTYSLEG PGVEAFHVDM DSGLVTTQRP LQSYEKFSLT





2581
VVATDGGEPP LWGTTMLLVE VIDVNDNRPV FVRPPNGTIL HIREEIPLRS NVYEVYATDK





2641
DEGLNGAVRY SFLKTAGNRD WEFFIIDPIS GLIQTAQRLD RESQAVYSLI LVASDLGQPV





2701
PYETMQPLQV ALEDIDDNEP LFVRPPKGSP QYQLLTVPEH SPRGTLVGNV TGAVDADEGP





2761
NAIVYYFIAA GNEEKNFHLQ PDGCLLVLRD LDREREAIFS FIVKASSNRS WTPPRGPSPT





2821
LDLVADLTLQ EVRVVLEDIN DQPPRFTKAE YTAGVATDAK VGSELIQVLA LDADIGNNSL





2881
VFYSILAIHY FRALANDSED VGQVFTMGSM DGILRTFDLF MAYSPGYFVV DIVARDLAGH





2941
NDTAIIGIYI LRDDQRVKIV INEIPDRVRG FEEEFIHLLS NITGAIVNTD NVQFHVDKKG





3001
RVNFAQTELL IHVVNRDTNR ILDVDRVIQM IDENKEQLRN LFRNYNVLDV QPAISVRLPD





3061
DMSALQMAII VLAILLFLAA MLFVLMNWYY RTVHKRKLKA IVAGSAGNRG FIDIMDMPNT





3121
NKYSFDGANP VWLDPFCRNL ELAAQAEHED DLPENLSEIA DLWNSPTRTH GTFGREPAAV





3181
KPDDDRYLRA AIQEYDNIAK LGQIIREGPI KGSLLKVVLE DYLRLKKLFA QRMVQKASSC





3241
HSSISELIQT ELDEEPGDHS PGQGSLRFRH KPPVELKGPD GIHVVHGSTG TLLATDLNSL





3301
PEEDQKGLGR SLETLTAAEA TAFERNARTE SAKSTPLHKL RDVIMETPLE ITEL











SEQ ID NO: 286



PROTOCADHERIN RELATED 15 (PCDH15)



AAK31581.1









1
MFRQFYLWTC LASGIILGSL FEICLGQYDD DCKLARGGPP ATIVAIDEES RNGTILVDNM






61
LIKGTAGGPD PTIELSLKDN VDYWVLMDPV KQMLFLNSTG RVLDRDPPMN IHSIVVQVQC





121
INKKVGTIIY HEVRIVVRDR NDNSPTFKHE SYYATVNELT PVGTTIFTGF SGDNGATDID





181
DGPNGQIEYV IQYNPDDPTS NDTFEIPLML TGNIVLRKRL NYEDKTRYFV IIQANDRAQN





241
LNERRTTTTT LTVDVLDGDD SGPMFLPCVL VPNTRDCRPL TYQAAIPELR TPEELNPIIV





301
TPPIQAIDQD RNIQPPSDRP GILYSILVGT PEDYPRFFHM HPRTAELSLL EPVNRDFHQK





361
FDLVIKAEQD NGHPLPAFAG LHIEILDENN QSPYFTMPSY QGYILESAPV GATISDSLNL





421
TSPLRIVALD KDIEDTKDPE LHLFLNDYTS VFTVTQTGIT RYLTLLLPVD REEQQTYTFS





481
ITAFDGVQES EPVIVNIQVM DANDNTPTFP EISYDVYVYT DMRPGDSVIQ LTAVDADEGS





541
NGEITYEILV GAQGDFIINK TTGLITIAPG VEMIVGRTYA LTVQAADNAP PAERRNSICT





601
VYIEVLPPNN QSPPRFPQLM YSLEISEAMR VGAVLLNLQA TDREGDSITY AIENGDPQRV





661
FNLSETTGIL TLGKALDRES TDRYILIITA SDGRPDGTST ATVNIVVTDV NDNAPVFDPY





721
LPRNLSVVEE EANAFVGQVK ATDPDAGING QVHYSLGNFN NLFRITSNGS IYTAVKLNRE





781
VRDYYELVVV ATDGAVHPRH STLTLAIKVL DIDDNSPVFT NSTYTVLVEE NLPAGTTILQ





841
IEAKDVDLGA NVSYRIRSPE VKHFFALHPF TGELSLLRSL DYEAFPDQEA SITFLVEAFD





901
IYGTMPPGIA TVTVIVKDMN DYPPVFSKQI YKGMVAPDAV KGTPITTVYA EDADPPGLPA





961
SRVRYRVDDV QFPYPASIFE VEEDSGRVIT RVNLNEEPTT IFKLVVVAFD DGEPVMSSSA





1021
TVKILVLHPG EIPRFTQEEY RPPPVSELAT KGTMVGVISA AAINQSIVYS IVSGNEEDTF





1081
GINNITGVIY VNGPLDYETR TSYVLRVQAD SLEVVLANLR VPSKSNTAKV YIEIQDENNH





1141
PPVFQKKFYI GGVSEDARMF TSVLRVKATD KDTGNYSVMA YRLIIPPIKE GKEGFVVETY





1201
TGLIKTAMLF HNMRRSYFKF QVIATDDYGK GLSGKADVLV SVVNQLDMQV IVSNVPPTLV





1261
EKKIEDLTEI LDRYVREQIP GAKVVVESIG ARRHGDAFSL EDYTKCDLTV YAIDPQTNRA





1321
IDRNELFKFL DGKLLDINKD FQPYYGEGGR ILEIRTPEAV TSIKKRGESL GYTEGALLAL





1381
AFIIILCCIP AILVVLVSYR QFKVRQAECT KTARIQAALP AAKPAVPAPA PVAAPPPPPP





1441
PPPGAHLYEE LGDSSILFLL YHFQQSRGNN SVSEDRKHQQ VVMPFSSNTI EAHKSAHVDG





1501
SLKSNKLKSA RKFTFLSDED DLSAHNPLYK ENISQVSTNS DISQRTDFVD PFSPKIQAKS





1561
KSLRGPREKI QRLWSQSVSL PRRLMRKVPN RPEIIDLQQW QGTRQKAENE NTGICTNKRG





1621
SSNPLLTTEE ANLTEKEEIR QGETLMIEGT EQLKSLSSDS SFCFPRPHFS FSTLPTVSRT





1681
VELKSEPNVI SSPAECSLEL SPSRPCVLHS SLSRRETPIC MLPIETERNI FENFAHPPNI





1741
SPSACPLPPP PPISPPSPPP APAPLAPPPD ISPFSLFCPP PSPPSIPLPL PPPTFFPLSV





1801
STSGPPTPPL LPPFPTPLPP PPPSIPCPPP PSASFLSTEC VCITGVKCTT NLMPAEKIKS





1861
SMTQLSTTTV CKTDPQREPK GILRHVKNLA ELEKSVANMY SQIEKNYLRT NVSELQTMCP





1921
SEVTNMEITS EQNKGSLNNI VEGTEKQSHS QSTSL











SEQ ID NO: 287



PROTOCADHERIN RELATED 15 (PCDH15), ISOFORM CRA A



EAW54151.1









1
MFRQFYLWTC LASGIILGSL FEICLGQYDD DCKLARGGPP ATIVAIDEES RNGTILVDNM






61
LIKGTAGGPD PTIELSLKDN VDYWVLMDPV KQMLFLNSTG RVLDRDPPMN IHSIVVQVQC





121
INKKVGTIIY HEVRIVVRDR NDNSPTFKHE SYYATVNELT PVGTTIFTGF SGDNGATDID





181
DGPNGQIEYV IQYNPDDPTS NDTFEIPLML TGNIVLRKRL NYEDKTRYFV IIQANDRAQN





241
LNERRTTTTT LTVDVLDGDD LGPMFLPCVL VPNTRDCRPL TYQAAIPELR TPEELNPIIV





301
TPPIQAIDQD RNIQPPSDRP GILYSILVGT PEDYPRFFHM HPRTAELSLL EPVNRDFHQK





361
FDLVIKAEQD NGHPLPAFAG LHIEILDENN QSPYFTMPSY QGYILESAPV GATISDSLNL





421
TSPLRIVALD KDIEDTKDPE LHLFLNDYTS VFTVTQTGIT RYLTLLQPVD REEQQTYTFS





481
ITAFDGVQES EPVIVNIQVM DANDNTPTFP EISYDVYVYT DMRPGDSVIQ LTAVDADEGS





541
NGEITYEILV GAQGDFIINK TTGLITIAPG VEMIVGRTYA LTVQAADNAP PAERRNSICT





601
VYIEVLPPNN QSPPRFPQLM YSLEISEAMR VGAVLLNLQA TDREGDSITY AIENGDPQRV





661
FNLSETTGIL TLGKALDRES TDRYILIITA SDGRPDGTST ATVNIVVTDV NDNAPVFDPY





721
LPRNLSVVEE EANAFVGQVK ATDPDAGING QVHYSLGNFN NLFRITSNGS IYTAVKLNRE





781
VRDYYELVVV ATDGAVHPRH STLTLAIKVL DIDDNSPVFT NSTYTVLVEE NLPAGTTILQ





841
IEAKDVDLGA NVSYRIRSPE VKHFFALHPF TGELSLLRSL DYEAFPDQEA SITFLVEAFD





901
IYGTMPPGIA TVTVIVKDMN DYPPVFSKRI YKGMVAPDAV KGTPITTVYA EDADPPGLPA





961
SRVRYRVDDV QFPYPASIFE VEEDSGRVIT RVNLNEEPTT IFKLVVVAFD DGEPVMSSSA





1021
TVKILVLHPG EIPRFTQEEY RPPPVSELAT KGTMVGVISA AAINQSIVYS IVSGNEEDTF





1081
GINNITGVIY VNGPLDYETR TSYVLRVQAD SLEVVLANLR VPSKSNTAKV YIEIQDENNH





1141
PPVFQKKFYI GGVSEDARMF TSVLRVKATD KDTGNYSVMA YRLIIPPIKE GKEGFVVETY





1201
TGLIKTAMLF HNMRRSYFKF QVIATDDYGK GLSGKADVLV SVVNQLDMQV IVSNVPPTLV





1261
EKKIEDLTEI LDRYVQEQIP GAKVVVESIG ARRHGDAFSL EDYTKCDLTV YAIDPQTNRA





1321
IDRNELFKFL DGKLLDINKD FQPYYGEGGR ILEIRTPEAV TSIKKRGESL GYTEGALLAL





1381
AFIIILCCIP AILVVLVSYR Q











SEQ ID NO: 288



PROTOCADHERIN RELATED 15 (PCDH15), ISOFORM X1



XP_016872062.1









1
MFRQFYLWTC LASGIILGSL FEICLGQYDD DWQYEDCKLA RGGPPATIVA IDEESRNGTI






61
LVDNMLIKGT AGGPDPTIEL SLKDNVDYWV LMDPVKQMLF LNSTGRVLDR DPPMNIHSIV





121
VQVQCINKKV GTIIYHEVRI VVRDRNDNSP TFKHESYYAT VNELTPVGTT IFTGFSGDNG





181
ATDIDDGPNG QIEYVIQYNP DDPTSNDTFE IPLMLTGNIV LRKRLNYEDK TRYFVIIQAN





241
DRAQNLNERR TTTTTLTVDV LDGDDLGPMF LPCVLVPNTR DCRPLTYQAA IPELRTPEEL





301
NPIIVTPPIQ AIDQDRNIQP PSDRPGILYS ILVGTPEDYP RFFHMHPRTA ELSLLEPVNR





361
DFHQKFDLVI KAEQDNGHPL PAFAGLHIEI LDENNQSPYF TMPSYQGYIL ESAPVGATIS





421
DSLNLTSPLR IVALDKDIED TKDPELHLFL NDYTSVFTVT QTGITRYLTL LQPVDREEQQ





481
TYTFSITAFD GVQESEPVIV NIQVMDANDN TPTFPEISYD VYVYTDMRPG DSVIQLTAVD





541
ADEGSNGEIT YEILVGAQGD FIINKTTGLI TIAPGVEMIV GRTYALTVQA ADNAPPAERR





601
NSICTVYIEV LPPNNQSPPR FPQLMYSLEI SEAMRVGAVL LNLQATDREG DSITYAIENG





661
DPQRVFNLSE TTGILTLGKA LDRESTDRYI LIITASDGRP DGTSTATVNI VVTDVNDNAP





721
VFDPYLPRNL SVVEEEANAF VGQVKATDPD AGINGQVHYS LGNFNNLFRI TSNGSIYTAV





781
KLNREVRDYY ELVVVATDGA VHPRHSTLTL AIKVLDIDDN SPVFTNSTYT VLVEENLPAG





841
TTILQIEAKD VDLGANVSYR IRSPEVKHFF ALHPFTGELS LLRSLDYEAF PDQEASITFL





901
VEAFDIYGTM PPGIATVTVI VKDMNDYPPV FSKRIYKGMV APDAVKGTPI TTVYAEDADP





961
PGLPASRVRY RVDDVQFPYP ASIFEVEEDS GRVITRVNLN EEPTTIFKLV VVAFDDGEPV





1021
MSSSATVKIL VLHPGEIPRF TQEEYRPPPV SELATKGTMV GVISAAAINQ SIVYSIVSGN





1081
EEDTFGINNI TGVIYVNGPL DYETRTSYVL RVQADSLEVV LANLRVPSKS NTAKVYIEIQ





1141
DENNHPPVFQ KKFYIGGVSE DARMFTSVLR VKATDKDTGN YSVMAYRLII PPIKEGKEGF





1201
VVETYTGLIK TAMLFHNMRR SYFKFQVIAT DDYGKGLSGK ADVLVSVVNQ LDMQVIVSNV





1261
PPTLVEKKIE DLTEILDRYV QEQIPGAKVV VESIGARRHG DAFSLEDYTK CDLTVYAIDP





1321
QTNRAIDRNE LFKFLDGKLL DINKDFQPYY GEGGRILEIR TPEAVTSIKK RGESLGYTEG





1381
ALLALAFIII LCCIPAILVV LVSYRQFKVR QAECTKTARI QAALPAAKPA VPAPAPVAAP





1441
PPPPPPPPGA HLYEELGDSS MHKYEMPQYG SRRRLLPPAG QEEYGEVVGE AEEEYEEEEE





1501
EPKKIKKPKV EIREPSEEEE VVVTIEKPPA AEPTYTTWKR ARIFPMIFKK VRGLADKRGI





1561
VDLEGEEWQR RLEEEDKDYL KLTLDQEEAT ESTVESEEES SSDYTEYSEE ESEFSESETT





1621
EEESESETPS EEEESSTPES EESESTESEG EKARKNIVLA RRRPMVEEVK EVKGRKEEPQ





1681
EEQKEPKMEE EEHSEEEESG PAPVEESTDP EAQDIPEEGS AESASVEGGV ESEEESESGS





1741
SSSSSESQSG GPWGYQVPAY DRSKNANQKK SPGANSEGYN TAL











SEQ ID NO: 289



USHERIN (USH2A), ISOFORM A



NP_009054.5









1
MNCPVLSLGS GFLFQVIEML IFAYFASISL TESRGLFPRL ENVGAFKKVS IVPTQAVCGL






61
PDRSTFCHSS AAAESIQFCT QRFCIQDCPY RSSHPTYTAL FSAGLSSCIT PDKNDLHPNA





121
HSNSASFIFG NHKSCFSSPP SPKLMASFTL AVWLKPEQQG VMCVIEKTVD GQIVFKLTIS





181
EKETMFYYRT VNGLQPPIKV MTLGRILVKK WIHLSVQVHQ TKISFFINGV EKDHTPFNAR





241
TLSGSITDFA SGTVQIGQSL NGLEQFVGRM QDFRLYQVAL TNREILEVFS GDLLRLHAQS





301
HCRCPGSHPR VHPLAQRYCI PNDAGDTADN RVSRLNPEAH PLSFVNDNDV GTSWVSNVFT





361
NITQLNQGVT ISVDLENGQY QVFYIIIQFF SPQPTEIRIQ RKKENSLDWE DWQYFARNCG





421
AFGMKNNGDL EKPDSVNCLQ LSNFTPYSRG NVTFSILTPG PNYRPGYNNF YNTPSLQEFV





481
KATQIRFHFH GQYYTTETAV NLRHRYYAVD EITISGRCQC HGHADNCDTT SQPYRCLCSQ





541
ESFTEGLHCD RCLPLYNDKP FRQGDQVYAF NCKPCQCNSH SKSCHYNISV DPFPFEHFRG





601
GGGVCDDCEH NTTGRNCELC KDYFFRQVGA DPSAIDVCKP CDCDTVGTRN GSILCDQIGG





661
QCNCKRHVSG RQCNQCQNGF YNLQELDPDG CSPCNCNTSG TVDGDITCHQ NSGQCKCKAN





721
VIGLRCDHCN FGFKFLRSFN DVGCEPCQCN LHGSVNKFCN PHSGQCECKK EAKGLQCDTC





781
RENFYGLDVT NCKACDCDTA GSLPGTVCNA KTGQCICKPN VEGRQCNKCL EGNFYLRQNN





841
SFLCLPCNCD KTGTINGSLL CNKSTGQCPC KLGVTGLRCN QCEPHRYNLT IDNFQHCQMC





901
ECDSLGTLPG TICDPISGQC LCVPNRQGRR CNQCQPGFYI SPGNATGCLP CSCHTTGAVN





961
HICNSLTGQC VCQDASIAGQ RCDQCKDHYF GFDPQTGRCQ PCNCHLSGAL NETCHLVTGQ





1021
CFCKQFVTGS KCDACVPSAS HLDVNNLLGC SKTPFQQPPP RGQVQSSSAI NLSWSPPDSP





1081
NAHWLTYSLL RDGFEIYTTE DQYPYSIQYF LDTDLLPYTK YSYYIETTNV HGSTRSVAVT





1141
YKTKPGVPEG NLTLSYIIPI GSDSVTLTWT TLSNQSGPIE KYILSCAPLA GGQPCVSYEG





1201
HETSATIWNL VPFAKYDFSV QACTSGGCLH SLPITVTTAQ APPQRLSPPK MQKISSTELH





1261
VEWSPPAELN GIIIRYELYM RRLRSTKETT SEESRVFQSS GWLSPHSFVE SANENALKPP





1321
QTMTTITGLE PYTKYEFRVL AVNMAGSVSS AWVSERTGES APVFMIPPSV FPLSSYSLNI





1381
SWEKPADNVT RGKVVGYDIN MLSEQSPQQS IPMAFSQLLH TAKSQELSYT VEGLKPYRIY





1441
EFTITLCNSV GCVTSASGAG QTLAAAPAQL RPPLVKGINS TTIHLKWFPP EELNGPSPIY





1501
QLERRESSLP ALMTTMMKGI RFIGNGYCKF PSSTHPVNTD FTGKCV











SEQ ID NO: 290



USHERIN (USH2A), ISOFORM B PRECURSOR



NP_996816.2









1
MNCPVLSLGS GFLFQVIEML IFAYFASISL TESRGLFPRL ENVGAFKKVS IVPTQAVCGL






61
PDRSTFCHSS AAAESIQFCT QRFCIQDCPY RSSHPTYTAL FSAGLSSCIT PDKNDLHPNA





121
HSNSASFIFG NHKSCFSSPP SPKLMASFTL AVWLKPEQQG VMCVIEKTVD GQIVFKLTIS





181
EKETMFYYRT VNGLQPPIKV MTLGRILVKK WIHLSVQVHQ TKISFFINGV EKDHTPFNAR





241
TLSGSITDFA SGTVQIGQSL NGLEQFVGRM QDFRLYQVAL TNREILEVFS GDLLRLHAQS





301
HCRCPGSHPR VHPLAQRYCI PNDAGDTADN RVSRLNPEAH PLSFVNDNDV GTSWVSNVFT





361
NITQLNQGVT ISVDLENGQY QVFYIIIQFF SPQPTEIRIQ RKKENSLDWE DWQYFARNCG





421
AFGMKNNGDL EKPDSVNCLQ LSNFTPYSRG NVTFSILTPG PNYRPGYNNF YNTPSLQEFV





481
KATQIRFHFH GQYYTTETAV NLRHRYYAVD EITISGRCQC HGHADNCDTT SQPYRCLCSQ





541
ESFTEGLHCD RCLPLYNDKP FRQGDQVYAF NCKPCQCNSH SKSCHYNISV DPFPFEHFRG





601
GGGVCDDCEH NTTGRNCELC KDYFFRQVGA DPSAIDVCKP CDCDTVGTRN GSILCDQIGG





661
QCNCKRHVSG RQCNQCQNGF YNLQELDPDG CSPCNCNTSG TVDGDITCHQ NSGQCKCKAN





721
VIGLRCDHCN FGFKFLRSFN DVGCEPCQCN LHGSVNKFCN PHSGQCECKK EAKGLQCDTC





781
RENFYGLDVT NCKACDCDTA GSLPGTVCNA KTGQCICKPN VEGRQCNKCL EGNFYLRQNN





841
SFLCLPCNCD KTGTINGSLL CNKSTGQCPC KLGVTGLRCN QCEPHRYNLT IDNFQHCQMC





901
ECDSLGTLPG TICDPISGQC LCVPNRQGRR CNQCQPGFYI SPGNATGCLP CSCHTTGAVN





961
HICNSLTGQC VCQDASIAGQ RCDQCKDHYF GFDPQTGRCQ PCNCHLSGAL NETCHLVTGQ





1021
CFCKQFVTGS KCDACVPSAS HLDVNNLLGC SKTPFQQPPP RGQVQSSSAI NLSWSPPDSP





1081
NAHWLTYSLL RDGFEIYTTE DQYPYSIQYF LDTDLLPYTK YSYYIETTNV HGSTRSVAVT





1141
YKTKPGVPEG NLTLSYIIPI GSDSVTLTWT TLSNQSGPIE KYILSCAPLA GGQPCVSYEG





1201
HETSATIWNL VPFAKYDFSV QACTSGGCLH SLPITVTTAQ APPQRLSPPK MQKISSTELH





1261
VEWSPPAELN GIIIRYELYM RRLRSTKETT SEESRVFQSS GWLSPHSFVE SANENALKPP





1321
QTMTTITGLE PYTKYEFRVL AVNMAGSVSS AWVSERTGES APVFMIPPSV FPLSSYSLNI





1381
SWEKPADNVT RGKVVGYDIN MLSEQSPQQS IPMAFSQLLH TAKSQELSYT VEGLKPYRIY





1441
EFTITLCNSV GCVTSASGAG QTLAAAPAQL RPPLVKGINS TTIHLKWFPP EELNGPSPIY





1501
QLERRESSLP ALMTTMMKGI RFIGNGYCKF PSSTHPVNTD FTGIKASFRT KVPEGLIVFA





1561
ASPGNQEEYF ALQLKKGRLY FLFDPQGSPV EVTTTNDHGK QYSDGKWHEI IAIRHQAFGQ





1621
ITLDGIYTGS SAILNGSTVI GDNTGVFLGG LPRSYTILRK DPEIIQKGFV GCLKDVHFMK





1681
NYNPSAIWEP LDWQSSEEQI NVYNSWEGCP ASLNEGAQFL GAGFLELHPY MFHGGMNFEI





1741
SFKFRTDQLN GLLLFVYNKD GPDFLAMELK SGILTFRLNT SLAFTQVDLL LGLSYCNGKW





1801
NKVIIKKEGS FISASVNGLM KHASESGDQP LVVNSPVYVG GIPQELLNSY QHLCLEQGFG





1861
GCMKDVKFTR GAVVNLASVS SGAVRVNLDG CLSTDSAVNC RGNDSILVYQ GKEQSVYEGG





1921
LQPFTEYLYR VIASHEGGSV YSDWSRGRTT GAAPQSVPTP SRVRSLNGYS IEVTWDEPVV





1981
RGVIEKYILK AYSEDSTRPP RMPSASAEFV NTSNLTGILT GLLPFKNYAV TLTACTLAGC





2041
TESSHALNIS TPQEAPQEVQ PPVAKSLPSS LLLSWNPPKK ANGIITQYCL YMDGRLIYSG





2101
SEENYTVTDL AVFTPHQFLL SACTHVGCTN SSWVLLYTAQ LPPEHVDSPV LTVLDSRTIH





2161
IQWKQPRKIS GILERYVLYM SNHTHDFTIW SVIYNSTELF QDHMLQYVLP GNKYLIKLGA





2221
CTGGGCTVSE ASEALTDEDI PEGVPAPKAH SYSPDSFNVS WTEPEYPNGV ITSYGLYLDG





2281
ILIHNSSELS YRAYGFAPWS LHSFRVQACT AKGCALGPLV ENRTLEAPPE GTVNVFVKTQ





2341
GSRKAHVRWE APFRPNGLLT HSVLFTGIFY VDPVGNNYTL LNVTKVMYSG EETNLWVLID





2401
GLVPFTNYTV QVNISNSQGS LITDPITIAM PPGAPDGVLP PRLSSATPTS LQVVWSTPAR





2461
NNAPGSPRYQ LQMRSGDSTH GFLELFSNPS ASLSYEVSDL QPYTEYMFRL VASNGFGSAH





2521
SSWIPFMTAE DKPGPVVPPI LLDVKSRMML VTWQHPRKSN GVITHYNIYL HGRLYLRTPG





2581
NVTNCTVMHL HPYTAYKFQV EACTSKGCSL SPESQTVWTL PGAPEGIPSP ELFSDTPTSV





2641
IISWQPPTHP NGLVENFTIE RRVKGKEEVT TLVTLPRSHS MRFIDKTSAL SPWTKYEYRV





2701
LMSTLHGGTN SSAWVEVTTR PSRPAGVQPP VVTVLEPDAV QVTWKPPLIQ NGDILSYEIH





2761
MPDPHITLTN VTSAVLSQKV THLIPFTNYS VTIVACSGGN GYLGGCTESL PTYVTTHPTV





2821
PQNVGPLSVI PLSESYVVIS WQPPSKPNGP NLRYELLRRK IQQPLASNPP EDLNRWHNIY





2881
SGTQWLYEDK GLSRFTTYEY MLFVHNSVGF TPSREVTVTT LAGLPERGAN LTASVLNHTA





2941
IDVRWAKPTV QDLQGEVEYY TLFWSSATSN DSLKILPDVN SHVIGHLKPN TEYWIFISVF





3001
NGVHSINSAG LHATTCDGEP QGMLPPEVVI INSTAVRVIW TSPSNPNGVV TEYSIYVNNK





3061
LYKTGMNVPG SFILRDLSPF TIYDIQVEVC TIYACVKSNG TQITTVEDTP SDIPTPTIRG





3121
ITSRSLQIDW VSPRKPNGII LGYDLLWKTW YPCAKTQKLV QDQSDELCKA VRCQKPESIC





3181
GHICYSSEAK VCCNGVLYNP KPGHRCCEEK YIPFVLNSTG VCCGGRIQEA QPNHQCCSGY





3241
YARILPGEVC CPDEQHNRVS VGIGDSCCGR MPYSTSGNQI CCAGRLHDGH GQKCCGRQIV





3301
SNDLECCGGE EGVVYNRLPG MFCCGQDYVN MSDTICCSAS SGESKAHIKK NDPVPVKCCE





3361
TELIPKSQKC CNGVGYNPLK YVCSDKISTG MMMKETKECR ILCPASMEAT EHCGRCDFNF





3421
TSHICTVIRG SHNSTGKASI EEMCSSAEET IHTGSVNTYS YTDVNLKPYM TYEYRISAWN





3481
SYGRGLSKAV RARTKEDVPQ GVSPPTWTKI DNLEDTIVLN WRKPIQSNGP IIYYILLRNG





3541
IERFRGTSLS FSDKEGIQPF QEYSYQLKAC TVAGCATSSK VVAATTQGVP ESILPPSITA





3601
LSAVALHLSW SVPEKSNGVI KEYQIRQVGK GLIHTDTTDR RQHTVTGLQP YTNYSFTLTA





3661
CTSAGCTSSE PFLGQTLQAA PEGVWVTPRH IIINSTTVEL YWSLPEKPNG LVSQYQLSRN





3721
GNLLFLGGSE EQNFTDKNLE PNSRYTYKLE VKTGGGSSAS DDYIVQTPMS TPEEIYPPYN





3781
ITVIGPYSIF VAWIPPGILI PEIPVEYNVL LNDGSVTPLA FSVGHHQSTL LENLTPFTQY





3841
EIRIQACQNG SCGVSSRMFV KTPEAAPMDL NSPVLKALGS ACIEIKWMPP EKPNGIIINY





3901
FIYRRPAGIE EESVLFVWSE GALEFMDEGD TLRPFTLYEY RVRACNSKGS VESLWSLTQT





3961
LEAPPQDFPA PWAQATSAHS VLLNWTKPES PNGIISHYRV VYQERPDDPT FNSPTVHAFT





4021
VKGTSHQAHL YGLEPFTTYR IGVVAANHAG EILSPWTLIQ TLESSPSGLR NFIVEQKENG





4081
RALLLQWSEP MRTNGVIKTY NIFSDGFLEY SGLNRQFLFR RLDPFTLYTL TLEACTRAGC





4141
AHSAPQPLWT DEAPPDSQLA PTVHSVKSTS VELSWSEPVN PNGKIIRYEV IRRCFEGKAW





4201
GNQTIQADEK IVFTEYNTER NTFMYNDTGL QPWTQCEYKI YTWNSAGHTC SSWNVVRTLQ





4261
APPEGLSPPV ISYVSMNPQK LLISWIPPEQ SNGIIQSYRL QRNEMLYPFS FDPVTFNYTD





4321
EELLPFSTYS YALQACTSGG CSTSKPTSIT TLEAAPSEVS PPDLWAVSAT QMNVCWSPPT





4381
VQNGKITKYL VRYDNKESLA GQGLCLLVSH LQPYSQYNFS LVACTNGGCT ASVSKSAWTM





4441
EALPENMDSP TLQVTGSESI EITWKPPRNP NGQIRSYELR RDGTIVYTGL ETRYRDFTLT





4501
PGVEYSYTVT ASNSQGGILS PLVKDRTSPS APSGMEPPKL QARGPQEILV NWDPPVRTNG





4561
DIINYTLFIR ELFERETKII HINTTHNSFG MQSYIVNQLK PFHRYEIRIQ ACTTLGCASS





4621
DWTFIQTPEI APLMQPPPHL EVQMAPGGFQ PTVSLLWTGP LQPNGKVLYY ELYRRQIATQ





4681
PRKSNPVLIY NGSSTSFIDS ELLPFTEYEY QVWAVNSAGK APSSWTWCRT GPAPPEGLRA





4741
PTFHVISSTQ AVVNISAPGK PNGIVSLYRL FSSSAHGAET VLSEGMATQQ TLHGLQAFTN





4801
YSIGVEACTC FNCCSKGPTA ELRTHPAPPS GLSSPQIGTL ASRTASFRWS PPMFPNGVIH





4861
SYELQFHVAC PPDSALPCTP SQIETKYTGL GQKASLGGLQ PYTTYKLRVV AHNEVGSTAS





4921
EWISFTTQKE LPQYRAPFSV DSNLSVVCVN WSDTFLLNGQ LKEYVLTDGG RRVYSGLDTT





4981
LYIPRTADKT FFFQVICTTD EGSVKTPLIQ YDTSTGLGLV LTTPGKKKGS RSKSTEFYSE





5041
LWFIVLMAML GLILLAIFLS LILQRKIHKE PYIRERPPLV PLQKRMSPLN VYPPGENHMG





5101
LADTKIPRSG TPVSIRSNRS ACVLRIPSQN QTSLTYSQGS LHRSVSQLMD IQDKKVLMDN





5161
SLWEAIMGHN SGLYVDEEDL MNAIKDFSSV TKERTTFTDT HL











SEQ ID NO: 291



USHERIN (USH2A), TYPE IIA



AAC23748.2









1
MNCPVLSLGS GFLFQVIEML IFAYFASISL TESRGLFPRL ENVGAFKKVS IVPTQAVCGL






61
PDRSTFCHSS AAAESIQFCT QRFCIQDCPY RSSHPTYTAL FSAGLSSCIT PDKNDLHPNA





121
HSNSASFIFG NHKSCFSSPP SPKLMASFTL AVWLKPEQQG VMCVIEKTVD GQIVFKLTIS





181
EKETMFYYRT VNGLQPPIKV MTLGRILVKK WIHLSVQVHQ TKISFFINGV EKDHTPFNAR





241
TLSGSITDFA SGTVQIGQSL NGLEQFVGRM QDFRLYQVAL TNREILEVFS GDLLRLHAQS





301
HCRCPGSHPR VHPLAQRYCI PNDAGDTADN RVSRLNPEAH PLSFVNDNDV GTSWVSNVFT





361
NITQLNQGVT ISVDLENGQY QVFYIIIQFF SPQPTEIRIQ RKKENSLDWE DWQYFARNCG





421
AFGMKNNGDL EKPDSVNCLQ LSNFTPYSRG NVTFSILTPG PNYRPGYNNF YNTPSLQESV





481
KATQIRFHFH GQYYTTETAV NLRHRYYAVD EITISGRCQC HGHADNCDTT SQPYRCLCSQ





541
ESFTEGLHCD RCLPLYNDKP FRQGDQVYAF NCKPCQCNSH SKSCHYNISV DPFPFEHFRG





601
GGGVCDDCEH NTTGRNCELC KDYFFRQVGA DPSAIDVCKP CDCDTVGTRN GSILCDQIGG





661
QCNCKRHVSG RQCNQCQNGF YNLQELDPDG CSPCNCNTSG TVDGDITCHQ NSGQCKCKAN





721
VIGLRCDHCN FGFKFLRSFN DVGCEPCQCN LHGSVNKFCN PHSGQCECKK EAKGLQCDTC





781
RENFYGLDVT NCKACDCDTA GSLPGTVCNA KTGQCICKPN VEGRQCNKCL EGNFYLRQNN





841
SFLCLPCNCD KTGTINGSLL CNKSTGQCPC KLGVTGLRCN QCEPHRYNLT IDNFQHCQMC





901
ECDSLGTLPG TICDPISGQC LCVPNRQGRR CNQCQPGFYI SPGNATGCLP CSCHTTGAVN





961
HICNSLTGQC VCQDASIAGQ RCDQCKDHYF GFDPQTGRCQ PCNCHLSGAL NETCHLVTGQ





1021
CFCKQFVTGS KCDACVPSAS HLDVNNLLGC SKTPFQQPPP RGQVQSSSAI NLSWSPPDSP





1081
NAHWLTYSLL RDGFEIYTTE DQYPYSIQYF LDTDLLPYTK YSYYIETTNV HGSTRSVAVT





1141
YKTKPGVPEG NLTLSYIIPI GSDSVTLTWT TLSNQSGPIE KYILSCAPLA GGQPCVSYEG





1201
HETSATIWNL VPFAKYDFSV QACTSGGCLH SLPITVTTAQ APPQRLSPPK MQKISSTELH





1261
VEWSPPAELN GIIIRYELYM RRLRSTKETT SEESRVFQSS GWLSPHSFVE SANENALKPP





1321
QTMTTITGLE PYTKYEFRVL AVNMAGSVSS AWVSERTGES APVFMIPPSV FPLSSYSLNI





1381
SWEKPADNVT RGKVVGYDIN MLSEQSPQQS IPMAFSQLLH TAKSQELSYT VEGLKPYRIY





1441
EFTITLCNSV GCVTSASGAG QTLAAAPAQL RPPLVKGINS TTIHLKWFPP EELNGPSPIY





1501
QLERRESSLP ALMTIMMKGI RFIGNGYCKF PSSTHPVNTD FTGKCV











SEQ ID NO: 292



CLARIN 1 (CLRN1)



AAH74971.1









1
MPSQQKKIIF CMAGVFSFAC ALGVVTALGT PLWIKATVLC KTGALLVNAS GQELDKFMGE






61
MQYGLFHGEG VRQCGLGARP FRFSFFPDLL KAIPVSIHVN VILFSAILIV LTMVGTAFFM





121
YNAFGKPFET LHGPLGLYLL SFISGSCGCL VMILFASEVK IHHLSEKIAN YKEGTYVYKT





181
QSEKYTTSFW VIFFCFFVHF LNGLLIRLAG FQFPFAKSKD AETTNVAADL MY











SEQ ID NO: 293



CLARIN 1 (CLRN1), ISOFORM A



NP_777367.1









1
MPSQQKKIIF CMAGVFSFAC ALGVVTALGT PLWIKATVLC KTGALLVNAS GQELDKFMGE






61
MQYGLFHGEG VRQCGLGARP FRFSFFPDLL KAIPVSIHVN VILFSAILIV LTMVGTAFFM





121
YNAFGKPFET LHGPLGLYLL SFISGSCGCL VMILFASEVK IHHLSEKIAN YKEGTYVYKT





181
QSEKYTTSFW VIFFCFFVHF LNGLLIRLAG FQFPFAKSKD AETTNVAADL MY











SEQ ID NO: 294



CLARIN 1 (CLRN1), ISOFORM D



NP_001182723.1









1
MPSQQKKIIF CMAGVFSFAC ALGVVTALGT PLWIKATVLC KTGALLVNAS GQELDKFMGE






61
MQYGLFHGEG VRQCGLGARP FRFSFFPDLL KAIPVSIHVN VILFSAILIV LTMVGTAFFM





121
YNAFGKPFET LHGPLGLYLL SFISVALWLP ATRHQAQGSC GCLVMILFAS EVKIHHLSEK





181
IANYKEGTYV YKTQSEKYTT SFWVIFFCFF VHFLNGLLIR LAGFQFPFAK SKDAETTNVA





241
ADLMY











SEQ ID NO: 295



CLARIN 1 (CLRN1), ISOFORM C



NP_443721.1









1
MQALQQQPVF PDLLKAIPVS IHVNVILFSA ILIVLTMVGT AFFMYNAFGK PFETLHGPLG






61
LYLLSFISGS CGCLVMILFA SEVKIHHLSE KIANYKEGTY VYKTQSEKYT TSFWLTKGHS











SEQ ID NO: 296



CLARIN 1 (CLRN1), ISOFORM E



NP_001243748.1









1
MPSQQKKIIF CMAGVFSFAC ALGVVTALGT PLWIKATVLC KTGALLVNAS GQELDKFMGE






61
MQYGLFHGEG VRQCGLGARP FRFSCYFLDP FMGLPTGVPH LLSLPCSTSC RREHTSERVQ





121
EPAGCFSAVR SKLHAGPAAA TSFSRFAQSN PSEHPRQCHS LLCHPYCVNH GGDSLLHVQC





181
FWKTF











SEQ ID NO: 297



ATP BINDING CASSETTE SUBFAMILY A MEMBER 4 (ABCA4)



P78363.3









1
MGFVRQIQLL LWKNWTLRKR QKIRFVVELV WPLSLFLVLI WLRNANPLYS HHECHFPNKA






61
MPSAGMLPWL QGIFCNVNNP CFQSPTPGES PGIVSNYNNS ILARVYRDFQ ELLMNAPESQ





121
HLGRIWTELH ILSQFMDTLR THPERIAGRG IRIRDILKDE ETLTLFLIKN IGLSDSVVYL





181
LINSQVRPEQ FAHGVPDLAL KDIACSEALL ERFIIFSQRR GAKTVRYALC SLSQGTLQWI





241
EDTLYANVDF FKLFRVLPTL LDSRSQGINL RSWGGILSDM SPRIQEFIHR PSMQDLLWVT





301
RPLMQNGGPE TFTKLMGILS DLLCGYPEGG GSRVLSFNWY EDNNYKAFLG IDSTRKDPIY





361
SYDRRTTSFC NALIQSLESN PLTKIAWRAA KPLLMGKILY TPDSPAARRI LKNANSTFEE





421
LEHVRKLVKA WEEVGPQIWY FFDNSTQMNM IRDTLGNPTV KDFLNRQLGE EGITAEAILN





481
FLYKGPRESQ ADDMANFDWR DIFNITDRTL RLVNQYLECL VLDKFESYND ETQLTQRALS





541
LLEENMFWAG VVFPDMYPWT SSLPPHVKYK IRMDIDVVEK TNKIKDRYWD SGPRADPVED





601
FRYIWGGFAY LQDMVEQGIT RSQVQAEAPV GIYLQQMPYP CFVDDSFMII LNRCFPIFMV





661
LAWIYSVSMT VKSIVLEKEL RLKETLKNQG VSNAVIWCTW FLDSFSIMSM SIFLLTIFIM





721
HGRILHYSDP FILFLFLLAF STATIMLCFL LSTFFSKASL AAACSGVIYF TLYLPHILCF





781
AWQDRMTAEL KKAVSLLSPV AFGFGTEYLV RFEEQGLGLQ WSNIGNSPTE GDEFSFLLSM





841
QMMLLDAAVY GLLAWYLDQV FPGDYGTPLP WYFLLQESYW LGGEGCSTRE ERALEKTEPL





901
TEETEDPEHP EGIHDSFFER EHPGWVPGVC VKNLVKIFEP CGRPAVDRLN ITFYENQITA





961
FLGHNGAGKT TTLSILTGLL PPTSGTVLVG GRDIETSLDA VRQSLGMCPQ HNILFHHLTV





1021
AEHMLFYAQL KGKSQEEAQL EMEAMLEDTG LHHKRNEEAQ DLSGGMQRKL SVAIAFVGDA





1081
KVVILDEPTS GVDPYSRRSI WDLLLKYRSG RTIIMSTHHM DEADLLGDRI AIIAQGRLYC





1141
SGTPLFLKNC FGTGLYLTLV RKMKNIQSQR KGSEGTCSCS SKGFSTTCPA HVDDLTPEQV





1201
LDGDVNELMD VVLHHVPEAK LVECIGQELI FLLPNKNFKH RAYASLFREL EETLADLGLS





1261
SFGISDTPLE EIFLKVTEDS DSGPLFAGGA QQKRENVNPR HPCLGPREKA GQTPQDSNVC





1321
SPGAPAAHPE GQPPPEPECP GPQLNTGTQL VLQHVQALLV KRFQHTIRSH KDFLAQIVLP





1381
ATFVFLALML SIVIPPFGEY PALTLHPWIY GQQYTFFSMD EPGSEQFTVL ADVLLNKPGF





1441
GNRCLKEGWL PEYPCGNSTP WKTPSVSPNI TQLFQKQKWT QVNPSPSCRC STREKLTMLP





1501
ECPEGAGGLP PPQRTQRSTE ILQDLTDRNI SDFLVKTYPA LIRSSLKSKF WVNEQRYGGI





1561
SIGGKLPVVP ITGEALVGFL SDLGRIMNVS GGPITREASK EIPDFLKHLE TEDNIKVWFN





1621
NKGWHALVSF LNVAHNAILR ASLPKDRSPE EYGITVISQP LNLTKEQLSE ITVLTTSVDA





1681
VVAICVIFSM SFVPASFVLY LIQERVNKSK HLQFISGVSP TTYWVTNFLW DIMNYSVSAG





1741
LVVGIFIGFQ KKAYTSPENL PALVALLLLY GWAVIPMMYP ASFLFDVPST AYVALSCANL





1801
FIGINSSAIT FILELFENNR TLLRFNAVLR KLLIVFPHFC LGRGLIDLAL SQAVTDVYAR





1861
FGEEHSANPF HWDLIGKNLF AMVVEGVVYF LLTLLVQRHF FLSQWIAEPT KEPIVDEDDD





1921
VAEERQRIIT GGNKTDILRL HELTKIYPGT SSPAVDRLCV GVRPGECFGL LGVNGAGKTT





1981
TFKMLTGDTT VTSGDATVAG KSILTNISEV HQNMGYCPQF DAIDELLTGR EHLYLYARLR





2041
GVPAEEIEKV ANWSIKSLGL TVYADCLAGT YSGGNKRKLS TAIALIGCPP LVLLDEPTTG





2101
MDPQARRMLW NVIVSIIREG RAVVLTSHSM EECEALCTRL AIMVKGAFRC MGTIQHLKSK





2161
FGDGYIVTMK IKSPKDDLLP DLNPVEQFFQ GNFPGSVQRE RHYNMLQFQV SSSSLARIFQ





2221
LLLSHKDSLL IEEYSVTQTT LDQVFVNFAK QQTESHDLPL HPRAAGASRQ AQD











SEQ ID NO: 298



ATP BINDING CASSETTE SUBFAMILY A MEMBER 4 (ABCA4), ISOFORM CRA_A



EAW73056.1









1
MGFVRQIQLL LWKNWTLRKR QKIRFVVELV WPLSLFLVLI WLRNANPLYS HHECHFPNKA






61
MPSAGMLPWL QGIFCNVNNP CFQSPTPGES PGIVSNYNNS ILARVYRDFQ ELLMNAPESQ





121
HLGRIWTELH ILSQFMDTLR THPERIAGRG IRIRDILKDE ETLTLFLIKN IGLSDSVVYL





181
LINSQVRPEQ FAHGVPDLAL KDIACSEALL ERFIIFSQRR GAKTVRYALC SLSQGTLQWI





241
EDTLYANVDF FKLFRVLPTL LDSRSQGINL RSWGGILSDM SPRIQEFIHR PSMQDLLWVT





301
RPLMQNGGPE TFTKLMGILS DLLCGYPEGG GSRVLSFNWY EDNNYKAFLG IDSTRKDPIY





361
SYDRRTTSFC NALIQSLESN PLTKIAWRAA KPLLMGKILY TPDSPAARRI LKNANSTFEE





421
LEHVRKLVKA WEEVGPQIWY FFDNSTQMNM IRDTLGNPTV KDFLNRQLGE EGITAEAILN





481
FLYKGPRESQ ADDMANFDWR DIFNITDRTL RLVNQYLECL VLDKFESYND ETQLTQRALS





541
LLEENMFWAG VVFPDMYPWT SSLPPHVKYK IRMDIDVVEK TNKIKDRYWD SGPRADPVED





601
FRYIWGGFAY LQDMVEQGIT RSQVQAEAPV GIYLQQMPYP CFVDDSFMII LNRCFPIFMV





661
LAWIYSVSMT VKSIVLEKEL RLKETLKNQG VSNAVIWCTW FLDSFSIMSM SIFLLTIFIM





721
HGRILHYSDP FILFLFLLAF STATIMLCFL LSTFFSKASL AAACSGVIYF TLYLPHILCF





781
AWQDRMTAEL KKAVSLLSPV AFGFGTEYLV RFEEQGLGLQ WSNIGNSPTE GDEFSFLLSM





841
QMMLLDAAVY GLLAWYLDQV FPGDYGTPLP WYFLLQESYW LGGEGCSTRE ERALEKTEPL





901
TEETEDPEHP EGIHDSFFER EHPGWVPGVC VKNLVKIFEP CGRPAVDRLN ITFYENQITA





961
FLGHNGAGKT TTLSILTGLL PPTSGTVLVG GRDIETSLDA VRQSLGMCPQ HNILFHHLTV





1021
AEHMLFYAQL KGKSQEEAQL EMEAMLEDTG LHHKRNEEAQ DLSGGMQRKL SVAIAFVGDA





1081
KVVILDEPTS GVDPYSRRSI WDLLLKYRSG RTIIMSTHHM DEADLLGDRI AIIAQGRLYC





1141
SGTPLFLKNC FGTGLYLTLV RKMKNIQSQR KGSEGTCSCS SKGFSTTCPA HVDDLTPEQV





1201
LDGDVNELMD VVLHHVPEAK LVECIGQELI FLLPNKNFKH RAYASLFREL EETLADLGLS





1261
SFGISDTPLE EIFLKVTEDS DSGPLFAGGA QQKRENVNPR HPCLGPREKA GQTPQDSNVC





1321
SPGAPAAHPE GQPPPEPECP GPQLNTGTQL VLQHVQALLV KRFQHTIRSH KDFLAQIVLP





1381
ATFVFLALML SIVIPPFGEY PALTLHPWIY GQQYTFFSMD EPGSEQFTVL ADVLLNKPGF





1441
GNRCLKEGWL PEYPCGNSTP WKTPSVSPNI TQLFQKQKWT QVNPSPSCRC STREKLTMLP





1501
ECPEGAGGLP PPQRTQRSTE ILQDLTDRNI SDFLVKTYPA LIRSSLKSKF WVNEQRYGGI





1561
SIGGKLPVVP ITGEALVGFL SDLGRIMNVS GGPITREASK EIPDFLKHLE TEDNIKVWFN





1621
NKGWHALVSF LNVAHNAILR ASLPKDRSPE EYGITVISQP LNLTKEQLSE ITVLTTSVDA





1681
VVAICVIFSM SFVPASFVLY LIQERVNKSK HLQFISGVSP TTYWVTNFLW DIMNYSVSAG





1741
LVVGIFIGFQ KKAYTSPENL PALVALLLLY GWAVIPMMYP ASFLFDVPST AYVALSCANL





1801
FIGINSSAIT FILELFENNR TLLRFNAVLR KLLIVFPHFC LGRGLIDLAL SQAVTDVYAR





1861
FGEEHSANPF HWDLIGKNLF AMVVEGVVYF LLTLLVQRHF FLSQWIAEPT KEPIVDEDDD





1921
VAEERQRIIT GGNKTDILRL HELTKIYPGT SSPAVDRLCV GVRPGECFGL LGVNGAGKTT





1981
TFKMLTGDTT VTSGDATVAG KSILTNISEV HQNMGYCPQF DAIDELLTGR EHLYLYARLR





2041
GVPAEEIEKV ANWSIKSLGL TVYADCLAGT YSGGNKRKLS TAIALIGCPP LVLLDEPTTG





2101
MDPQARRMLW NVIVSIIREG RAVVLTSHSM EECEALCTRL AIMVKGAFRC MGTIQHLKSK





2161
FGDGYIVTMK IKSPKDDLLP DLNPVEQFFQ GNFPGSVQRE RHYNMLQFQV SSSSLARIFQ





2221
LLLSHKDSLL IEEYSVTQTT LDQVFVNFAK QQTESHDLPL HPRAAGASRQ AQD











SEQ ID NO: 299



ATP BINDING CASSETTE SUBFAMILY A MEMBER 4 (ABCA4), ISOFORM CRA_B



EAW73057.1









1
MGFVRQIQLL LWKNWTLRKR QKIRFVVELV WPLSLFLVLI WLRNANPLYS HHECHFPNKA






61
MPSAGMLPWL QGIFCNVNNP CFQSPTPGES PGIVSNYNNS ILARVYRDFQ ELLMNAPESQ





121
HLGRIWTELH ILSQFMDTLR THPERIAGRG IRIRDILKDE ETLTLFLIKN IGLSDSVVYL





181
LINSQVRPEQ FAHGVPDLAL KDIACSEALL ERFIIFSQRR GAKTVRYALC SLSQGTLQWI





241
EDTLYANVDF FKLFRVLPTL LDSRSQGINL RSWGGILSDM SPRIQEFIHR PSMQDLLWVT





301
RPLMQNGGPE TFTKLMGILS DLLCGYPEGG GSRVLSFNWY EDNNYKAFLG IDSTRKDPIY





361
SYDRRTTSFC NALIQSLESN PLTKIAWRAA KPLLMGKILY TPDSPAARRI LKNANSTFEE





421
LEHVRKLVKA WEEVGPQIWY FFDNSTQMNM IRDTLGNPTV KDFLNRQLGE EGITAEAILN





481
FLYKGPRESQ ADDMANFDWR DIFNITDRTL RLVNQYLECL VLDKFESYND ETQLTQRALS





541
LLEENMFWAG VVFPDMYPWT SSLPPHVKYK IRMDIDVVEK TNKIKDRYWD SGPRADPVED





601
FRYIWGGFAY LQDMVEQGIT RSQVQAEAPV GIYLQQMPYP CFVDDSFMII LNRCFPIFMV





661
LAWIYSVSMT VKSIVLEKEL RLKETLKNQG VSNAVIWCTW FLDSFSIMSM SIFLLTIFIM





721
HGRILHYSDP FILFLFLLAF STATIMLCFL LSTFFSKASL AAACSGVIYF TLYLPHILCF





781
AWQDRMTAEL KKAVSLLSPV AFGFGTEYLV RFEEQGLGLQ WSNIGNSPTE GDEFSFLLSM





841
QMMLLDAAVY GLLAWYLDQV FPGDYGTPLP WYFLLQESYW LGGEGCSTRE ERALEKTEPL





901
TEETEDPEHP EGIHDSFFER EHPGWVPGVC VKNLVKIFEP CGRPAVDRLN ITFYENQITA





961
FLGHNGAGKT TTLSILTGLL PPTSGTVLVG GRDIETSLDA VRQSLGMCPQ HNILFHHLTV





1021
AEHMLFYAQL KGKSQEEAQL EMEAMLEDTG LHHKRNEEAQ DLSGGMQRKL SVAIAFVGDA





1081
KVVILDEPTS GVDPYSRRSI WDLLLKYRSG RTIIMSTHHM DEADLLGDRI AIIAQGRLYC





1141
SGTPLFLKNC FGTGLYLTLV RKMKNIQSQR KGSEVVIPSI CCRGPAAARL RVSPPRVQPT





1201
SMT











SEQ ID NO: 300



ATP BINDING CASSETTE SUBFAMILY A MEMBER 4 (ABCA4), ISOFORM CRA_C



EAW73058.1









1
MGFVRQIQLL LWKNWTLRKR QKIRFVVELV WPLSLFLVLI WLRNANPLYS HHECHFPNKA






61
MPSAGMLPWL QGIFCNVNNP CFQSPTPGES PGIVSNYNNS ILARVYRDFQ ELLMNAPESQ





121
HLGRIWTELH ILSQFMDTLR THPERIAGRG IRIRDILKDE ETLTLFLIKN IGLSDSVVYL





181
LINSQVRPEQ FAHGVPDLAL KDIACSEALL ERFIIFSQRR GAKTVRYALC SLSQGTLQWI





241
EDTLYANVDF FKLFRVLPTL LDSRSQGINL RSWGGILSDM SPRIQEFIHR PSMQDLLWVT





301
RPLMQNGGPE TFTKLMGILS DLLCGYPEGG GSRVLSFNWY EDNNYKAFLG IDSTRKDPIY





361
SYDRRTTSFC NALIQSLESN PLTKIAWRAA KPLLMGKILY TPDSPAARRI LKNANSTFEE





421
LEHVRKLVKA WEEVGPQIWY FFDNSTQMNM IRDTLGNPTV KDFLNRQLGE EGITAEAILN





481
FLYKGPRESQ ADDMANFDWR DIFNITDRTL RLVNQYLECL VLDKFESYND ETQLTQRALS





541
LLEENMFWAG VVFPDMYPWT SSLPPHVKYK IRMDIDVVEK TNKIKDRYWD SGPRADPVED





601
FRYIWGGFAY LQDMVEQGIT RSQVQAEAPV GIYLQQMPYP CFVDDSFMII LNRCFPIFMV





661
LAWIYSVSMT VKSIVLEKEL RLKETLKNQG VSNAVIWCTW FLDSFSIMSM SIFLLTIFIM





721
HGRILHYSDP FILFLFLLAF STATIMLCFL LSTFFSKASL AAACSGVIYF TLYLPHILCF





781
AWQDRMTAEL KKAVSLLSPV AFGFGTEYLV RFEEQGLGLQ WSNIGNSPTE GDEFSFLLSM





841
QMMLLDAAVY GLLAWYLDQV FPGDYGTPLP WYFLLQESYW LGGEGCSTRE ERALEKTEPL





901
TEETEDPEHP EGIHDSFFER EHPGWVPGVC VKNLVKIFEP CGRPAVDRLN ITFYENQITA





961
FLGHNGAGKT TTLSILTGLL PPTSGTVLVG GRDIETSLDA VRQSLGMCPQ HNILFHHLTV





1021
AEHMLFYAQL KGKSQEEAQL EMEAMLEDTG LHHKRNEEAQ DLSGGMQRKL SVAIAFVGDA





1081
KVVILDEPTS GVDPYSRRSI WDLLLKYRSG RTIIMSTHHM DEADLLGDRI AIIAQGRLYC





1141
SGTPLFLKNC FGTGLYLTLV RKMKNIQSQR KGSEGTCSCS SKGFSTTCPA HVDDLTPEQV





1201
LDGDVNELMD VVLHHVPEAK LVECIGQELI FLLPNKNFKH RAYASLFREL EETLADLGLS





1261
SFGISDTPLE EIFLKVTEDS DSGPLFAGGA QQKRENVNPR HPCLGPREKA GQTPQDSNVC





1321
SPGAPAAHPE GQPPPEPECP GPQLNTGTQL VLQHVQALLV KRFQHTIRSH KDFLAQIVLP





1381
ATFVFLALML SIVIPPFGEY PALTLHPWIY GQQYTFFSMD EPGSEQFTVL ADVLLNKPGF





1441
GNRCLKEGWL PEYPCGNSTP WKTPSVSPNI TQLFQKQKWT QVNPSPSCRC STREKLTMLP





1501
ECPEGAGGLP PPQRTQRSTE ILQDLTDRNI SDFLVKTYPA LIRSSLKSKF WVNEQRYGGI





1561
SIGGKLPVVP ITGEALVGFL SDLGRIMNVS GGPITREASK EIPDFLKHLE TEDNIKVWFN





1621
NKGWHALVSF LNVAHNAILR ASLPKDRSPE EYGITVISQP LNLTKEQLSE ITVLTTSVDA





1681
VVAICVIFSM SFVPASFVLY LIQERVNKSK HLQFISGVSP TTYWVTNFLW DIMNYSVSAG





1741
LVVGIFIGFQ KKAYTSPENL PALVALLLLY GWAVIPMMYP ASFLFDVPST AYVALSCANL





1801
FIGINSSAIT FILELFENNR TLLRFNAVLR KLLIVFPHFC LGRGLIDLAL SQAVTDVYAR





1861
FGEEHSANPF HWDLIGKNLF AMVVEGVVYF LLTLLVQRHF FLSQWIAEPT KEPIVDEDDD





1921
VAEERQRIIT GGNKTDILRL HELTKIYPGT SSPAVDRLCV GVRPGECFGL LGVNGAGKTT





1981
TFKMLTGDTT VTSGDATVAG KSILTNISEV HQNMGYCPQF DAIDELLTGR EHLYLYARLR





2041
GVPAEEIEKV ANWSIKSLGL TVYADCLAGT YSGGNKRKLS TAIALIGCPP LVLLDEPTTG





2101
MDPQARRMLW NVIVSIIREG RAVVLTSHRQ EIPRAGEECE ALCTRLAIMV KGAFRCMGTI





2161
QHLKSKFGDG YIVTMKIKSP KDDLLPDLNP VEQFFQGNFP GSVQRERHYN MLQFQVSSSS





2221
LARIFQLLLS HKDSLLIEEY SVTQTTLDQA SVCKFC











SEQ ID NO: 301



ELOVL FATTY ACID ELONGASE 4 (ELOVL4)



NP_073563.1









1
MGLLDSEPGS VLNVVSTALN DTVEFYRWTW SIADKRVENW PLMQSPWPTL SISTLYLLFV






61
WLGPKWMKDR EPFQMRLVLI IYNFGMVLLN LFIFRELFMG SYNAGYSYIC QSVDYSNNVH





121
EVRIAAALWW YFVSKGVEYL DTVFFILRKK NNQVSFLHVY HHCTMFTLWW IGIKWVAGGQ





181
AFFGAQLNSF IHVIMYSYYG LTAFGPWIQK YLWWKRYLTM LQLIQFHVTI GHTALSLYTD





241
CPFPKWMHWA LIAYAISFIF LFLNFYIRTY KEPKKPKAGK TAMNGISANG VSKSEKQLMI





301
ENGKKQKNGK AKGD











SEQ ID NO: 302



INTERLEUKIN 6 (IL6)



AAC41704.1









1
MNSFSTSAFG PVAFSLGLLL VLPAAFPAPV PPGEDSKDVA APHRQPLTSS ERIDKQIRYI






61
LDGISALRKE TCNKSNMCES SKEALAENNL NLPKMAEKDG CFQSGFNEET CLVKIITGLL





121
EFEVYLEYLQ NRFESSEEQA RAVQMSTKVL IQFLQKKAKN LDAITTPDPT TNASLLTKLQ





181
AQNQWLQDMT THLILRSFKE FLQSSLRALR QM











SEQ ID NO: 303



TNF-ALPHA (TNF)



CAA26669.1









1
MSTESMIRDV ELAEEALPKK TGGPQGSRRC LFLSLFSFLI VAGATTLFCL LHFGVIGPQR






61
EEFPRDLSLI SPLAQAVRSS SRTPSDKPVA HVVANPQAEG QLQWLNRRAN ALLANGVELR





121
DNQLVVPSEG LYLIYSQVLF KGQGCPSTHV LLTHTISRIA VSYQTKVNLL SAIKSPCQRE





181
TPEGAEAKPW YEPIYLGGVF QLEKGDRLSA EINRPDYLDF AESGQVYFGI IAL











SEQ ID NO: 304



L OPSIN (OPN1LW)



NP_064445.2









1
MAQQWSLQRL AGRHPQDSYE DSTQSSIFTY TNSNSTRGPF EGPNYHIAPR WVYHLTSVWM






61
IFVVTASVFT NGLVLAATMK FKKLRHPLNW ILVNLAVADL AETVIASTIS IVNQVSGYFV





121
LGHPMCVLEG YTVSLCGITG LWSLAIISWE RWMVVCKPFG NVRFDAKLAI VGIAFSWIWA





181
AVWTAPPIFG WSRYWPHGLK TSCGPDVFSG SSYPGVQSYM IVLMVTCCII PLAIIMLCYL





241
QVWLAIRAVA KQQKESESTQ KAEKEVTRMV VVMIFAYCVC WGPYTFFACF AAANPGYAFH





301
PLMAALPAYF AKSATIYNPV IYVFMNRQFR NCILQLFGKK VDDGSELSSA SKTEVSSVSS





361
VSPA











SEQ ID NO: 305



M OPSIN (OPN1MW)



NP_000504.1









1
MAQQWSLQRL AGRHPQDSYE DSTQSSIFTY TNSNSTRGPF EGPNYHIAPR WVYHLTSVWM






61
IFVVIASVFT NGLVLAATMK FKKLRHPLNW ILVNLAVADL AETVIASTIS VVNQVYGYFV





121
LGHPMCVLEG YTVSLCGITG LWSLAIISWE RWMVVCKPFG NVRFDAKLAI VGIAFSWIWA





181
AVWTAPPIFG WSRYWPHGLK TSCGPDVFSG SSYPGVQSYM IVLMVTCCIT PLSIIVLCYL





241
QVWLAIRAVA KQQKESESTQ KAEKEVTRMV VVMVLAFCFC WGPYAFFACF AAANPGYPFH





301
PLMAALPAFF AKSATIYNPV IYVFMNRQFR NCILQLFGKK VDDGSELSSA SKTEVSSVSS





361
VSPA











SEQ ID NO: 306



GUANYLATE CYCLASE 2D, RETINAL (GUCY2D)



Q02846.2









1
MTACARRAGG LPDPGLCGPA WWAPSLPRLP RALPRLPLLL LLLLLQPPAL SAVFTVGVLG






61
PWACDPIFSR ARPDLAARLA AARLNRDPGL AGGPRFEVAL LPEPCRTPGS LGAVSSALAR





121
VSGLVGPVNP AACRPAELLA EEAGIALVPW GCPWTQAEGT TAPAVTPAAD ALYALLRAFG





181
WARVALVTAP QDLWVEAGRS LSTALRARGL PVASVTSMEP LDLSGAREAL RKVRDGPRVT





241
AVIMVMHSVL LGGEEQRYLL EAAEELGLTD GSLVFLPFDT IHYALSPGPE ALAALANSSQ





301
LRRAHDAVLT LTRHCPSEGS VLDSLRRAQE RRELPSDLNL QQVSPLFGTI YDAVFLLARG





361
VAEARAAAGG RWVSGAAVAR HIRDAQVPGF CGDLGGDEEP PFVLLDTDAA GDRLFATYML





421
DPARGSFLSA GTRMHFPRGG SAPGPDPSCW FDPNNICGGG LEPGLVFLGF LLVVGMGLAG





481
AFLAHYVRHR LLHMQMVSGP NKIILTVDDI TFLHPHGGTS RKVAQGSRSS LGARSMSDIR





541
SGPSQHLDSP NIGVYEGDRV WLKKFPGDQH IAIRPATKTA FSKLQELRHE NVALYLGLFL





601
ARGAEGPAAL WEGNLAVVSE HCTRGSLQDL LAQREIKLDW MFKSSLLLDL IKGIRYLHHR





661
GVAHGRLKSR NCIVDGRFVL KITDHGHGRL LEAQKVLPEP PRAEDQLWTA PELLRDPALE





721
RRGTLAGDVF SLAIIMQEVV CRSAPYAMLE LTPEEVVQRV RSPPPLCRPL VSMDQAPVEC





781
ILLMKQCWAE QPELRPSMDH TFDLFKNINK GRKTNIIDSM LRMLEQYSSN LEDLIRERTE





841
ELELEKQKTD RLLTQMLPPS VAEALKTGTP VEPEYFEQVT LYFSDIVGFT TISAMSEPIE





901
VVDLLNDLYT LFDAIIGSHD VYKVETIGDA YMVASGLPQR NGQRHAAEIA NMSLDILSAV





961
GTFRMRHMPE VPVRIRIGLH SGPCVAGVVG LTMPRYCLFG DTVNTASRME STGLPYRIHV





1021
NLSTVGILRA LDSGYQVELR GRTELKGKGA EDTFWLVGRR GFNKPIPKPP DLQPGSSNHG





1081
ISLQEIPPER RRKLEKARPG QFS











SEQ ID NO: 307



RETINOID ISOMEROHYDROLASE RPE65 (RPE65)



NP_000320.1









1
MSIQVEHPAG GYKKLFETVE ELSSPLTAHV TGRIPLWLTG SLLRCGPGLF EVGSEPFYHL






61
FDGQALLHKF DFKEGHVTYH RRFIRTDAYV RAMTEKRIVI TEFGTCAFPD PCKNIFSRFF





121
SYFRGVEVTD NALVNVYPVG EDYYACTETN FITKINPETL ETIKQVDLCN YVSVNGATAH





181
PHIENDGTVY NIGNCFGKNF SIAYNIVKIP PLQADKEDPI SKSEIVVQFP CSDRFKPSYV





241
HSFGLTPNYI VFVETPVKIN LFKFLSSWSL WGANYMDCFE SNETMGVWLH IADKKRKKYL





301
NNKYRTSPFN LFHHINTYED NGFLIVDLCC WKGFEFVYNY LYLANLRENW EEVKKNARKA





361
PQPEVRRYVL PLNIDKADTG KNLVTLPNTT ATAILCSDET IWLEPEVLFS GPRQAFEFPQ





421
INYQKYCGKP YTYAYGLGLN HFVPDRLCKL NVKTKETWVW QEPDSYPSEP IFVSHPDALE





481
EDDGVVLSVV VSPGAGQKPA YLLILNAKDL SEVARAEVEI NIPVTFHGLF KKS











SEQ ID NO: 308



RETINOID ISOMEROHYDROLASE RPE65 (RPE65), ISOFORM X1



XP_016857516.1









1
MTEKRIVITE FGTCAFPDPC KNIFSRFFSY FRGVEVTDNA LVNVYPVGED YYACTETNFI






61
TKINPETLET IKQVDLCNYV SVNGATAHPH IENDGTVYNI GNCFGKNFSI AYNIVKIPPL





121
QADKEDPISK SEIVVQFPCS DRFKPSYVHS FGLTPNYIVF VETPVKINLF KFLSSWSLWG





181
ANYMDCFESN ETMGVWLHIA DKKRKKYLNN KYRTSPFNLF HHINTYEDNG FLIVDLCCWK





241
GFEFVYNYLY LANLRENWEE VKKNARKAPQ PEVRRYVLPL NIDKADTGKN LVTLPNTTAT





301
AILCSDETIW LEPEVLFSGP RQAFEFPQIN YQKYCGKPYT YAYGLGLNHF VPDRLCKLNV





361
KTKETWVWQE PDSYPSEPIF VSHPDALEED DGVVLSVVVS PGAGQKPAYL LILNAKDLSE





421
VARAEVEINI PVTFHGLFKK S











SEQ ID NO: 309



ARYL HYDROCARBON RECEPTOR INTERACTING PROTEIN LIKE 1 (AIPL1)



CAH25996.1









1
MDAALLLNVE GVKKTILHGG TGELPNFITG SRVIFHFRTM KCDEERTVID DSRQVGQPMH






61
IIIGNMFKLE VWEILLTSMR VHEVAEFWCD TIHTGVYPIL SRSLRQMAQG KDPTEWHVHT





121
CGLANMFAYH TLGYEDLDEL QKEPQPLVFV IELLQVDAPS DYQRETWNLS NHEKMKAVPV





181
LHGEGNRLFK LGRYEEASSK YQEAIICLRN LQTKCLLKKE EYYEVLEHTS DILRHHPGIV





241
KAYYVRARAH AEVWNEAEAK ADLQKVLELE PSMQKAVRRE LRLLENRMAE KQEEERLRCR





301
NMLSQGATQP PAEPPTEPPA QSSTEPPAEP PTAPSAELSA GPPAEPATEP PPSPGHSLQH











SEQ ID NO: 310



ARYL HYDROCARBON RECEPTOR INTERACTING PROTEIN LIKE 1 (AIPL1)



CAH25995.1









1
MDAALLLNVE GVKKTILHGG TGELPNFITG SRVGQPMHII IGNMFKLEVW EILLTSMRVH






61
EVAEFWCDTI HTGVYPILSR SLRQMAQGKD PTEWHVHTCG LANMFAYHTL GYEDLDELQK





121
EPQPLVFVIE LLQVDAPSDY QRETWNLSNH EKMKAVPVLH GEGNRLFKLG RYEEASSKYQ





181
EAIICLRNLQ TKEKPWEVQW LKLEKMINTL ILNYCQCLLK KEEYYEVLEH TSDILRHHPG





241
IVKAYYVRAR AHAEVWNEAE AKADLQKVLE LEPSMQKAVR RELRLLENRM AEKQEEERLR





301
CRNMLSQGAT QPPAEPPTEP PAQSSTEPPA EPPTAPSAEL SAGPPAEPAT EPPPSPGHSL





361
QH











SEQ ID NO: 311



ARYL HYDROCARBON RECEPTOR INTERACTING PROTEIN LIKE 1 (AIPL1)



CAG17883.1









1
MDAALLLNVE GVKKTILHGG TGELPNFITG SRVIFHFRTM KCDEERTVID DSRQVGQPMH






61
IIIGNMFKLE VWEILLTSMR VHEVAEFWCH TIVDAPSDYQ RETWNLSNHE KMKAVPVLHG





121
EGNRLFKLGR YEEASSKYQE AIICLRNLQT KEKPWEVQWL KLEKMINTLI LNYCQCLLKK





181
EEYYEVLEHT SDILRHHPGI VKAYYVRARA HAEVWNEAEA KADLQKVLEL EPSMQKAVRR





241
ELRLLENRMA EKQEEERLRC RNMLSQGATQ PPAEPPTEPP AQSSTEPPAE PPTAPSAELS





301
AGPPAEPATE PPPSPGHSLQ H











SEQ ID NO: 312



ARYL HYDROCARBON RECEPTOR INTERACTING PROTEIN LIKE 1 (AIPL1)



CAG17882.1









1
MDAALLLNVE GVKKTILHGG TGELPNFITG SRHTGVYPIL SRSLRQMAQG KDPTEWHVHT






61
CGLANMFAYH TLGYEDLDEL QKEPQPLVFV IELLQVDAPS DYQRETWNLS NHEKMKAVPV





121
LHGEGNRLFK LGRYEEASSK YQEAIICLRN LQTKEKPWEV QWLKLEKMIN TLILNYCQCL





181
LKKKEYYEVL EHTSDILRHH PGIVKAYYVR ARAHAEVWNE AEAKADLQKV LELEPSMQKA





241
VRRELRLLEN RMAEKQEEER LRCRNMLSQG ATQPPAEPPT EPPAQSSTEP PAEPPTAPSA





301
ELSAGPPAEP ATEPPPSPGH SLQH











SEQ ID NO: 313



ARYL HYDROCARBON RECEPTOR INTERACTING PROTEIN LIKE 1 (AIPL1)



AAH12055.1









1
MDAALLLNVE GVKKTILHGG TGELPNFITG SRVIFHFRTM KCDEERTVID DSRQVGQPMH






61
IIIGNMFKLE VWEILLTSMR VHEVAEFWCD TIHTGVYPIL SRSLRQMAQG KDPTEWHVHT





121
CGLANMFAYH TLGYEDLDEL QKEPQPLVFV IELLQVDAPS DYQRETWNLS NHEKMKAVPV





181
LHGEGNRLFK LGRYEEASSK YQEAIICLRN LQTKEKPWEV QWLKLEKMIN TLILNYCQCL





241
LKKEEYYEVL EHTSDILRHH PGIVKAYYVR ARAHAEVWNE AEAKADLQKV LELEPSMQKA





301
VRRELRLLEN RMAEKQEEER LRCRNMLSQG ATQPPAEPPT EPPAQSSTEP PAEPPTAPSA





361
ELSAGPPAEP ATEPPPSPGH SLQH











SEQ ID NO: 314



C5B isoform 1



NP_001726.2









1
MGLLGILCFL IFLGKTWGQE QTYVISAPKI FRVGASENIV IQVYGYTEAF DATISIKSYP






61
DKKFSYSSGH VHLSSENKFQ NSAILTIQPK QLPGGQNPVS YVYLEVVSKH FSKSKRMPIT





121
YDNGFLFIHT DKPVYTPDQS VKVRVYSLND DLKPAKRETV LTFIDPEGSE VDMVEEIDHI





181
GIISFPDFKI PSNPRYGMWT IKAKYKEDFS TTGTAYFEVK EYVLPHFSVS IEPEYNFIGY





241
KNFKNFEITI KARYFYNKVV TEADVYITFG IREDLKDDQK EMMQTAMQNT MLINGIAQVT





301
FDSETAVKEL SYYSLEDLNN KYLYIAVTVI ESTGGFSEEA EIPGIKYVLS PYKLNLVATP





361
LFLKPGIPYP IKVQVKDSLD QLVGGVPVTL NAQTIDVNQE TSDLDPSKSV TRVDDGVASF





421
VLNLPSGVTV LEFNVKTDAP DLPEENQARE GYRAIAYSSL SQSYLYIDWT DNHKALLVGE





481
HLNIIVTPKS PYIDKITHYN YLILSKGKII HFGTREKFSD ASYQSINIPV TQNMVPSSRL





541
LVYYIVTGEQ TAELVSDSVW LNIEEKCGNQ LQVHLSPDAD AYSPGQTVSL NMATGMDSWV





601
ALAAVDSAVY GVQRGAKKPL ERVFQFLEKS DLGCGAGGGL NNANVFHLAG LTFLTNANAD





661
DSQENDEPCK EILRPRRTLQ KKIEEIAAKY KHSVVKKCCY DGACVNNDET CEQRAARISL





721
GPRCIKAFTE CCVVASQLRA NISHKDMQLG RLHMKTLLPV SKPEIRSYFP ESWLWEVHLV





781
PRRKQLQFAL PDSLTTWEIQ GVGISNTGIC VADTVKAKVF KDVFLEMNIP YSVVRGEQIQ





841
LKGTVYNYRT SGMQFCVKMS AVEGICTSES PVIDHQGTKS SKCVRQKVEG SSSHLVTFTV





901
LPLEIGLHNI NFSLETWFGK EILVKTLRVV PEGVKRESYS GVTLDPRGIY GTISRRKEFP





961
YRIPLDLVPK TEIKRILSVK GLLVGEILSA VLSQEGINIL THLPKGSAEA ELMSVVPVFY





1021
VFHYLETGNH WNIFHSDPLI EKQKLKKKLK EGMLSIMSYR NADYSYSVWK GGSASTWLTA





1081
FALRVLGQVN KYVEQNQNSI CNSLLWLVEN YQLDNGSFKE NSQYQPIKLQ GTLPVEAREN





1141
SLYLTAFTVI GIRKAFDICP LVKIDTALIK ADNFLLENTL PAQSTFTLAI SAYALSLGDK





1201
THPQFRSIVS ALKREALVKG NPPIYRFWKD NLQHKDSSVP NTGTARMVET TAYALLTSLN





1261
LKDINYVNPV IKWLSEEQRY GGGFYSTQDT INAIEGLTEY SLLVKQLRLS MDIDVSYKHK





1321
GALHNYKMTD KNFLGRPVEV LLNDDLIVST GFGSGLATVH VTTVVHKTST SEEVCSFYLK





1381
IDTQDIEASH YRGYGNSDYK RIVACASYKP SREESSSGSS HAVMDISLPT GISANEEDLK





1441
ALVEGVDQLF TDYQIKDGHV ILQLNSIPSS DFLCVRFRIF ELFEVGFLSP ATFTVYEYHR





1501
PDKQCTMFYS TSNIKIQKVC EGAACKCVEA DCGQMQEELD LTISAETRKQ TACKPEIAYA





1561
YKVSITSITV ENVFVKYKAT LLDIYKTGEA VAEKDSEITF IKKVICTNAE LVKGRQYLIM





1621
GKEALQIKYN FSFRYIYPLD SLTWIEYWPR DTTCSSCQAF LANLDEFAED IFLNGC











SEQ ID NO: 315



CSB, isoform 2



NP_001304092.1









1
MPGSLGREAS GRAGPTGCGA FAFGLRCRYV ISAPKIFRVG ASENIVIQVY GYTEAFDATI






61
SIKSYPDKKF SYSSGHVHLS SENKFQNSAI LTIQPKQLPG GQNPVSYVYL EVVSKHFSKS





121
KRMPITYDNG FLFIHTDKPV YTPDQSVKVR VYSLNDDLKP AKRETVLTFI DPEGSEVDMV





181
EEIDHIGIIS FPDFKIPSNP RYGMWTIKAK YKEDFSTTGT AYFEVKEYVL PHFSVSIEPE





241
YNFIGYKNFK NFEITIKARY FYNKVVTEAD VYITFGIRED LKDDQKEMMQ TAMQNTMLIN





301
GIAQVTFDSE TAVKELSYYS LEDLNNKYLY IAVIVIESTG GFSEEAEIPG IKYVLSPYKL





361
NLVATPLFLK PGIPYPIKVQ VKDSLDQLVG GVPVTLNAQT IDVNQETSDL DPSKSVTRVD





421
DGVASFVLNL PSGVTVLEFN VKTDAPDLPE ENQAREGYRA IAYSSLSQSY LYIDWTDNHK





481
ALLVGEHLNI IVTPKSPYID KITHYNYLIL SKGKIIHFGT REKFSDASYQ SINIPVTQNM





541
VPSSRLLVYY IVTGEQTAEL VSDSVWLNIE EKCGNQLQVH LSPDADAYSP GQTVSLNMAT





601
GMDSWVALAA VDSAVYGVQR GAKKPLERVF QFLEKSDLGC GAGGGLNNAN VFHLAGLTFL





661
TNANADDSQE NDEPCKEILR PRRTLQKKIE EIAAKYKHSV VKKCCYDGAC VNNDETCEQR





721
AARISLGPRC IKAFTECCVV ASQLRANISH KDMQLGRLHM KTLLPVSKPE IRSYFPESWL





781
WEVHLVPRRK QLQFALPDSL TTWEIQGVGI SNTGICVADT VKAKVFKDVF LEMNIPYSVV





841
RGEQIQLKGT VYNYRTSGMQ FCVKMSAVEG ICTSESPVID HQGTKSSKCV RQKVEGSSSH





901
LVTFTVLPLE IGLHNINFSL ETWFGKEILV KTLRVVPEGV KRESYSGVTL DPRGIYGTIS





961
RRKEFPYRIP LDLVPKTEIK RILSVKGLLV GEILSAVLSQ EGINILTHLP KGSAEAELMS





1021
VVPVFYVFHY LETGNHWNIF HSDPLIEKQK LKKKLKEGML SIMSYRNADY SYSVWKGGSA





1081
STWLTAFALR VLGQVNKYVE QNQNSICNSL LWLVENYQLD NGSFKENSQY QPIKLQGTLP





1141
VEARENSLYL TAFTVIGIRK AFDICPLVKI DTALIKADNF LLENTLPAQS TFTLAISAYA





1201
LSLGDKTHPQ FRSIVSALKR EALVKGNPPI YRFWKDNLQH KDSSVPNTGT ARMVETTAYA





1261
LLTSLNLKDI NYVNPVIKWL SEEQRYGGGF YSTQDTINAI EGLTEYSLLV KQLRLSMDID





1321
VSYKHKGALH NYKMTDKNFL GRPVEVLLND DLIVSTGFGS GLATVHVTTV VHKTSTSEEV





1381
CSFYLKIDTQ DIEASHYRGY GNSDYKRIVA CASYKPSREE SSSGSSHAVM DISLPTGISA





1441
NEEDLKALVE GVDQLFTDYQ IKDGHVILQL NSIPSSDFLC VRFRIFELFE VGFLSPATFT





1501
VYEYHRPDKQ CTMFYSTSNI KIQKVCEGAA CKCVEADCGQ MQEELDLTIS AETRKQTACK





1561
PEIAYAYKVS ITSITVENVF VKYKATLLDI YKTGEAVAEK DSEITFIKKV TCTNAELVKG





1621
RQYLIMGKEA LQIKYNFSFR YIYPLDSLTW IEYWPRDTTC SSCQAFLANL DEFAEDIFLN





1681
GC











SEQ ID NO: 316



C5B, isoform 3



NP_001304093.1









1
MGLLGILCFL IFLGKTWGQE QTYVISAPKI FRVGASENIV IQVYGYTEAF DATISIKSYP






61
DKKFSYSSGH VHLSSENKFQ NSAILTIQPK QLPGGQNPVS YVYLEVVSKH FSKSKRMPIT





121
YDNGFLFIHT DKPVYTPDQS VKVRVYSLND DLKPAKRETV LTFIDPEGSE VDMVEEIDHI





181
GIISFPDFKI PSNPRYGMWT IKAKYKEDFS TTGTAYFEVK EYVLPHFSVS IEPEYNFIGY





241
KNFKNFEITI KARYFYNKVV TEADVYITFG IREDLKDDQK EMMQTAMQNT MLINGIAQVT





301
FDSETAVKEL SYYSLEDLNN KYLYIAVTVI ESTGGFSEEA EIPGIKYVLS PYKLNLVATP





361
LFLKPGIPYP IKVQVKDSLD QLVGGVPVTL NAQTIDVNQE TSDLDPSKSV TRVDDGVASF





421
VLNLPSGVTV LEFNVKTDAP DLPEENQARE GYRAIAYSSL SQSYLYIDWT DNHKALLVGE





481
HLNIIVTPKS PYIDKITHYN YLILSKGKII HFGTREKFSD ASYQSINIPV TQNMVPSSRL





541
LVYYIVTGEQ TAELVSDSVW LNIEEKCGNQ LQVHLSPDAD AYSPGQTVSL NMATGMDSWV





601
ALAAVDSAVY GVQRGAKKPL ERVFQFLEKS DLGCGAGGGL NNANVFHLAG LTFLTNANAD





661
DSQENDEPCK EILRPRRTLQ KKIEEIAAKY KHSVVKKCCY DGACVNNDET CEQRAARISL





721
GPRCIKAFTE CCVVASQLRA NISHKDMQLG RLHMKTLLPV SKPEIRSYFP ESWLWEVHLV





781
PRRKQLQFAL PDSLTTWEIQ GVGISNTGIC VADTVKAKVF KDVFLEMNIP YSVVRGEQIQ





841
LKGTVYNYRT SGMQSLALSP RLECNGKISG HCKLRLPGSS DSPASASQVA GITGTHHHAQ





901
PT











SEQ ID NO: 317



C6



NP_001108603.2









1
MARRSVLYFI LLNALINKGQ ACFCDHYAWT QWTSCSKTCN SGTQSRHRQI VVDKYYQENF






61
CEQICSKQET RECNWQRCPI NCLLGDFGPW SDCDPCIEKQ SKVRSVLRPS QFGGQPCTAP





121
LVAFQPCIPS KLCKIEEADC KNKFRCDSGR CIARKLECNG ENDCGDNSDE RDCGRTKAVC





181
TRKYNPIPSV QLMGNGFHFL AGEPRGEVLD NSFTGGICKT VKSSRTSNPY RVPANLENVG





241
FEVQTAEDDL KTDFYKDLTS LGHNENQQGS FSSQGGSSFS VPIFYSSKRS ENINHNSAFK





301
QAIQASHKKD SSFIRIHKVM KVLNFTTKAK DLHLSDVFLK ALNHLPLEYN SALYSRIFDD





361
FGTHYFTSGS LGGVYDLLYQ FSSEELKNSG LTEEEAKHCV RIETKKRVLF AKKTKVEHRC





421
TTNKLSEKHE GSFIQGAEKS ISLIRGGRSE YGAALAWEKG SSGLEEKTFS EWLESVKENP





481
AVIDFELAPI VDLVRNIPCA VTKRNNLRKA LQEYAAKFDP CQCAPCPNNG RPTLSGTECL





541
CVCQSGTYGE NCEKQSPDYK SNAVDGQWGC WSSWSTCDAT YKRSRTRECN NPAPQRGGKR





601
CEGEKRQEED CTFSIMENNG QPCINDDEEM KEVDLPEIEA DSGCPQPVPP ENGFIRNEKQ





661
LYLVGEDVEI SCLTGFETVG YQYFRCLPDG TWRQGDVECQ RTECIKPVVQ EVLTITPFQR





721
LYRIGESIEL TCPKGFVVAG PSRYTCQGNS WTPPISNSLT CEKDTLTKLK GHCQLGQKQS





781
GSECICMSPE EDCSHHSEDL CVFDTDSNDY FTSPACKFLA EKCLNNQQLH FLHIGSCQDG





841
RQLEWGLERT RLSSNSTKKE SCGYDTCYDW EKCSASTSKC VCLLPPQCFK GGNQLYCVKM





901
GSSTSEKTLN ICEVGTIRCA NRKMEILHPG KCLA











SEQ ID NO: 318



C7



NP_000578.2









1
MKVISLFILV GFIGEFQSFS SASSPVNCQW DFYAPWSECN GCTKTQTRRR SVAVYGQYGG






61
QPCVGNAFET QSCEPTRGCP TEEGCGERFR CFSGQCISKS LVCNGDSDCD EDSADEDRCE





121
DSERRPSCDI DKPPPNIELT GNGYNELTGQ FRNRVINTKS FGGQCRKVFS GDGKDFYRLS





181
GNVLSYTFQV KINNDFNYEF YNSTWSYVKH TSTEHTSSSR KRSFFRSSSS SSRSYTSHTN





241
EIHKGKSYQL LVVENTVEVA QFINNNPEFL QLAEPFWKEL SHLPSLYDYS AYRRLIDQYG





301
THYLQSGSLG GEYRVLFYVD SEKLKQNDFN SVEEKKCKSS GWHFVVKFSS HGCKELENAL





361
KAASGTQNNV LRGEPFIRGG GAGFISGLSY LELDNPAGNK RRYSAWAESV TNLPQVIKQK





421
LTPLYELVKE VPCASVKKLY LKWALEEYLD EFDPCHCRPC QNGGLATVEG THCLCHCKPY





481
TFGAACEQGV LVGNQAGGVD GGWSCWSSWS PCVQGKKTRS RECNNPPPSG GGRSCVGETT





541
ESTQCEDEEL EHLRLLEPHC FPLSLVPTEF CPSPPALKDG FVQDEGTMFP VGKNVVYTCN





601
EGYSLIGNPV ARCGEDLRWL VGEMHCQKIA CVLPVLMDGI QSHPQKPFYT VGEKVTVSCS





661
GGMSLEGPSA FLCGSSLKWS PEMKNARCVQ KENPLTQAVP KCQRWEKLQN SRCVCKMPYE





721
CGPSLDVCAQ DERSKRILPL TVCKMHVLHC QGRNYTLTGR DSCTLPASAE KACGACPLWG





781
KCDAESSKCV CREASECEEE GFSICVEVNG KEQTMSECEA GALRCRGQSI SVTSIRPCAA





841
ETQ











SEQ ID NO: 319



C8 ALPHA SUBUNIT



NP_000553.1









1
MFAVVFFILS LMTCQPGVTA QEKVNQRVRR AATPAAVTCQ LSNWSEWTDC FPCQDKKYRH






61
RSLLQPNKFG GTICSGDIWD QASCSSSTTC VRQAQCGQDF QCKETGRCLK RHLVCNGDQD





121
CLDGSDEDDC EDVRAIDEDC SQYEPIPGSQ KAALGYNILT QEDAQSVYDA SYYGGQCETV





181
YNGEWRELRY DSTCERLYYG DDEKYFRKPY NFLKYHFEAL ADTGISSEFY DNANDLLSKV





241
KKDKSDSFGV TIGIGPAGSP LLVGVGVSHS QDTSFLNELN KYNEKKFIFT RIFTKVQTAH





301
FKMRKDDIML DEGMLQSLME LPDQYNYGMY AKFINDYGTH YITSGSMGGI YEYILVIDKA





361
KMESLGITSR DITTCFGGSL GIQYEDKINV GGGLSGDHCK KFGGGKTERA RKAMAVEDII





421
SRVRGGSSGW SGGLAQNRST ITYRSWGRSL KYNPVVIDFE MQPIHEVLRH TSLGPLEAKR





481
QNLRRALDQY LMEFNACRCG PCFNNGVPIL EGTSCRCQCR LGSLGAACEQ TQTEGAKADG





541
SWSCWSSWSV CRAGIQERRR ECDNPAPQNG GASCPGRKVQ TQAC











SEQ ID NO: 320



C8 BETA SUBUNIT



AAA51862.1









1
MKNSRTWAWR APVELFLLCA ALGCLSLPGS RGERPHSFGS NAVNKSFAKS RQMRSVDVTL






61
MPIDCELSSW SSWTTCDPCQ KKRYRYAYLL QPSQFHGEPC NFSDKEVEDC VTNRPCGSQV





121
RCEGFVCAQT GRCVNRRLLC NGDNDCGDQS DEANCRRIYK KCQHEMDQYW GIGSLASGIN





181
LFTNSFEGPV LDHRYYAGGC SPHYILNTRF RKPYNVESYT PQTQGKYEFI LKEYESYSDF





241
ERNVTEKMAS KSGFSFGFKI PGIFELGISS QSDRGKHYIR RTKRFSHTKS VFLHARSDLE





301
VAHYKLKPRS LMLHYEFLQR VKRLPLEYSY GEYRDLFRDF GTHYITEAVL GGIYEYTLVM





361
NKEAMERGDY TLNNVHACAK NDFKIGGAIE EVYVSLGVSV GKCRGILNEI KDRNKRDTMV





421
EDLVVLVRGG ASEHITTLAY QELPTADLMQ EWGDAVQYNP AIIKVKVEPL YELVTATDFA





481
YSSTVRQNMK QALEEFQKEV SSCHCAPCQG NGVPVLKGSR CDCICPVGSQ GLACEVSYRK





541
NTPIDGKWNC WSNWSSCSGR RKTRQRQCNN PPPQNGGSPC SGPASETLDC S











SEQ ID NO: 321



C8 GAMMA SUBUNIT



AAA51888.1









1
MLPPGTATLL TLLLAAGSLG QKPQRPRRPA SPISTIQPKA NFDAQQFAGT WLLVAVGSAC






61
RFLQEQGHRA EATTLHVAPQ GTAMAVSTFR KLDGICWQVR QLYGDTGVLG RFLLQARGAR





121
GAVHVVVAET DYQSFAVLYL ERAGQLSVKL YARSLPVSDS VLSGFEQRVQ EAHLTEDQIF





181
YFPKYGFCEA ADQFHVLDEV RR






8. EXAMPLES
8.1 Example 1: Bevacizumab Fab cDNA-Based Vector

A bevacizumab Fab cDNA-based vector is constructed comprising a transgene comprising bevacizumab Fab portion of the light and heavy chain cDNA sequences (SEQ ID NOs. 10 and 11, respectively). The transgene also comprises nucleic acids comprising a signal peptide chosen from the group listed in Table 1. The nucleotide sequences encoding the light chain and heavy chain are separated by IRES elements or 2A cleavage sites to create a bicistronic vector. Optionally, the vector additionally comprises a hypoxia-inducible promoter.


8.2 Example 2: Ranibizumab cDNA-Based Vector

A ranibizumab Fab cDNA-based vector is constructed comprising a transgene comprising ranibizumab Fab light and heavy chain cDNAs (the portions of SEQ ID NOs. 12 and 13, respectively not encoding the signal peptide). The transgene also comprises nucleic acids comprising a signal peptide chosen from the group listed in Table 1. The nucleotide sequences encoding the light chain and heavy chain are separated by IRES elements or 2A cleavage sites to create a bicistronic vector. Optionally, the vector additionally comprises a hypoxia-inducible promoter.


8.3 Example 3: Hyperglycosylated Bevacizumab Fab cDNA-Based Vector

A hyperglycosylated bevacizumab Fab cDNA-based vector is constructed comprising a transgene comprising bevacizumab Fab portion of the light and heavy chain cDNA sequences (SEQ ID NOs. 10 and 11, respectively) with mutations to the sequence encoding one or more of the following mutations: L118N (heavy chain), E195N (light chain), or Q160N or Q1605 (light chain). The transgene also comprises nucleic acids comprising a signal peptide chosen from the group listed in Table 1. The nucleotide sequences encoding the light chain and heavy chain are separated by IRES elements or 2A cleavage sites to create a bicistronic vector. Optionally, the vector additionally comprises a hypoxia-inducible promoter.


8.4 Example 4: Hyperglycosylated Ranibizumab cDNA-Based Vector

A hyperglycosylated ranibizumab Fab cDNA-based vector is constructed comprising a transgene comprising ranibizumab Fab light and heavy chain cDNAs (the portions of SEQ ID NOs.12 and 13, respectively not encoding the signal peptide), with mutations to the sequence encoding one or more of the following mutations: L118N (heavy chain), E195N (light chain), or Q160N or Q1605 (light chain). The transgene also comprises nucleic acids comprising a signal peptide chosen from the group listed in Table 1. The nucleotide sequences encoding the light chain and heavy chain are separated by IRES elements or 2A cleavage sites to create a bicistronic vector. Optionally, the vector additionally comprises a hypoxia-inducible promoter.


8.5 Example 5: Ranibizumab Based HuGlyFabVEGFi

A ranibizumab Fab cDNA-based vector (see Example 2) is expressed in the PER.C6® Cell Line (Lonza) in the AAV8 background. The resultant product, ranibizumab-based HuGlyFabVEGFi is determined to be stably produced. N-glycosylation of the HuGlyFabVEGFi is confirmed by hydrazinolysis and MS/MS analysis. See, e.g., Bondt et al., Mol. & Cell. Proteomics 13.11:3029-3039. Based on glycan analysis, HuGlyFabVEGFi is confirmed to be N-glycosylated, with 2,6 sialic acid a predominant modification. Advantageous properties of the N-glycosylated HuGlyFabVEGFi are determined using methods known in the art. The HuGlyFabVEGFi can be found to have increased stability and increased affinity for its antigen (VEGF). See Sola and Griebenow, 2009, J Pharm Sci., 98(4): 1223-1245 for methods of assessing stability and Wright et al., 1991, EMBO J. 10:2717-2723 and Leibiger et al., 1999, Biochem. J. 338:529-538 for methods of assessing affinity.


8.6 Example 6: Treatment of Wet AMD with Ranibizumab Based HuGlyFabVEGFi by Peripheral Injection

Based on determination of advantageous characteristics of ranibizumab-based HuGlyFabVEGFi (see Example 5), a ranibizumab Fab cDNA-based vector is deemed useful for treatment of wet AMD when expressed as a transgene. A subject presenting with wet AMD is administered AAV8 that encodes ranibizumab Fab at a dose sufficient to produce a concentration of the transgene product at a Cmin of at least 0.330 μg/mL in the Vitreous humour for three months. The administration is done by subretinal administration via peripheral injection into the retina (i.e., peripheral to the optic disc, fovea and macula located in the back of the eye), which is accomplished by transvitreal injection. Following treatment, the subject is evaluated for improvement in symptoms of wet AMD.


8.7 Example 7: Palmitoyl-Protein Thioesterase 1 cDNA-Based Vector

A Palmitoyl-Protein Thioesterase 1 (PPT1) cDNA-based vector is constructed comprising a transgene comprising the nucleotide sequences corresponding to the amino acid sequence of SEQ ID NO. 273. Optionally, the vector additionally comprises a hypoxia-inducible promoter.


8.8 Example 8: Treatment of Batten-CLN1-Associated Vision Loss with

Palmitoyl-Protein Thioesterase 1 cDNA-Based Vector by Peripheral Injection


A subject presenting with Batten-CLN1-associated vision loss is administered AAV8 or AAV9 that encodes Palmitoyl-Protein Thioesterase 1 at a dose sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The administration is done by subretinal administration via peripheral injection into the retina (i.e., peripheral to the optic disc, fovea and macula located in the back of the eye), which is accomplished by transvitreal injection. Following treatment, the subject is evaluated for improvement in Batten-CLN1-associated vision loss.


Effects of the methods provided herein on visual deficits are measured by one or more visual acuity screenings, including OptoKinetic Nystagmus (OKN). OKN visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN is used to measure visual acuity in pre-verbal and/or non-verbal patients, including patients that are 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. The percentage change in OKN screening results before and after the said treatment is calculated.


8.9 Example 9: Treatment of Batten-CLN1-Associated Vision Loss with Palmitoyl-Protein Thioesterase 1 cDNA-Based Vector by Suprachoroidal Injection

A subject presenting with Batten-CLN1-associated vision loss is administered AAV8 or AAV9 that encodes Palmitoyl-Protein Thioesterase 1 at a dose sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The administration is done by administration to the suprachoroidal space. Following treatment, the subject is evaluated for improvement in Batten-CLN1-associated vision loss.


Effects of the methods provided herein on visual deficits are measured by one or more visual acuity screenings, including OptoKinetic Nystagmus (OKN). OKN visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN is used to measure visual acuity in pre-verbal and/or non-verbal patients, including patients that are 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. The percentage change in OKN screening results before and after the said treatment is calculated.


8.10 Example 10: Treatment of Batten-CLN1-Associated Vision Loss with Palmitoyl-Protein Thioesterase 1 cDNA-Based Vector by Subretinal Injection Via Vitrectomy

A subject presenting with Batten-CLN1-associated vision loss is administered AAV8 or AAV9 that encodes Palmitoyl-Protein Thioesterase 1 at a dose sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The administration is done by administration to the subretinal space via vitrectomy. Following treatment, the subject is evaluated for improvement in Batten-CLN1-associated vision loss.


Effects of the methods provided herein on visual deficits are measured by one or more visual acuity screenings, including OptoKinetic Nystagmus (OKN). OKN visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN is used to measure visual acuity in pre-verbal and/or non-verbal patients, including patients that are 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. The percentage change in OKN screening results before and after the said treatment is calculated.


8.11 Example 11: Treatment of Batten-CLN1-Associated Vision Loss with Palmitoyl-Protein Thioesterase 1 cDNA-Based Vector by Subretinal Administrate Via the Suprachoroidal Space

A subject presenting with Batten-CLN1-associated vision loss is administered AAV8 or AAV9 that encodes Palmitoyl-Protein Thioesterase 1 at a dose sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The administration is done by administration to the subretinal space via the suprachoroidal space. Following treatment, the subject is evaluated for improvement in Batten-CLN1-associated vision loss.


Effects of the methods provided herein on visual deficits are measured by one or more visual acuity screenings, including OptoKinetic Nystagmus (OKN). OKN visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN is used to measure visual acuity in pre-verbal and/or non-verbal patients, including patients that are 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. The percentage change in OKN screening results before and after the said treatment is calculated.


8.12 Example 12: Tripeptidyl-Peptidase 1 (TPP1) cDNA-Based Vector

A Tripeptidyl-Peptidase 1 (TPP1) cDNA-based vector is constructed comprising a transgene comprising the nucleotide sequences corresponding to the amino acid sequence of SEQ ID NO. 274. Optionally, the vector additionally comprises a hypoxia-inducible promoter.


8.13 Example 13: Treatment of Batten-CLN2-Associated Vision Loss with Tripeptidyl-Peptidase 1 (TPP1) cDNA-Based Vector by Peripheral Injection

A subject presenting with Batten-CLN2-associated vision loss is administered AAV8 or AAV9 that encodes Tripeptidyl-Peptidase 1 at a dose sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The administration is done by subretinal administration via peripheral injection into the retina (i.e., peripheral to the optic disc, fovea and macula located in the back of the eye), which is accomplished by transvitreal injection. Following treatment, the subject is evaluated for improvement in Batten-CLN2-associated vision loss.


Effects of the methods provided herein on visual deficits are measured by one or more visual acuity screenings, including OptoKinetic Nystagmus (OKN). OKN visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN is used to measure visual acuity in pre-verbal and/or non-verbal patients, including patients that are 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. The percentage change in OKN screening results before and after the said treatment is calculated.


8.14 Example 14: Treatment of Batten-CLN2-Associated Vision Loss with Tripeptidyl-Peptidase 1 (TPP1) cDNA-Based Vector by Suprachoroidal Injection

A subject presenting with Batten-CLN2-associated vision loss is administered AAV8 or AAV9 that encodes Tripeptidyl-Peptidase 1 at a dose sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The administration is done by administration to the suprachoroidal space. Following treatment, the subject is evaluated for improvement in Batten-CLN2-associated vision loss.


Effects of the methods provided herein on visual deficits are measured by one or more visual acuity screenings, including OptoKinetic Nystagmus (OKN). OKN visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN is used to measure visual acuity in pre-verbal and/or non-verbal patients, including patients that are 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. The percentage change in OKN screening results before and after the said treatment is calculated.


8.15 Example 15: Treatment of Batten-CLN2-Associated Vision Loss with Tripeptidyl-Peptidase 1 cDNA-Based Vector by Subretinal Injection via Vitrectomy

A subject presenting with Batten-CLN2-associated vision loss is administered AAV8 or AAV9 that encodes Tripeptidyl-Peptidase 1 at a dose sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The administration is done by administration to the subretinal space via vitrectomy. Following treatment, the subject is evaluated for improvement in Batten-CLN2-associated vision loss.


Effects of the methods provided herein on visual deficits are measured by one or more visual acuity screenings, including OptoKinetic Nystagmus (OKN). OKN visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN is used to measure visual acuity in pre-verbal and/or non-verbal patients, including patients that are 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. The percentage change in OKN screening results before and after the said treatment is calculated.


8.16 Example 16: Treatment of Batten-CLN2-Associated Vision Loss with Tripeptidyl-Peptidase 1 cDNA-Based Vector by Subretinal Administrate Via the Suprachoroidal Space

A subject presenting with Batten-CLN2-associated vision loss is administered AAV8 or AAV9 that encodes Tripeptidyl-Peptidase 1 at a dose sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The administration is done by administration to the subretinal space via the suprachoroidal space. Following treatment, the subject is evaluated for improvement in Batten-CLN2-associated vision loss.


Effects of the methods provided herein on visual deficits are measured by one or more visual acuity screenings, including OptoKinetic Nystagmus (OKN). OKN visual acuity screening uses the principles of the OKN involuntary reflex to objectively assess whether a patient's eyes can follow a moving target. By using OKN, no verbal communication is needed between the tester and the patient. As such, OKN is used to measure visual acuity in pre-verbal and/or non-verbal patients, including patients that are 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 1 year old, 1.5 years old, 2 years old, 2.5 years old, 3 years old, 3.5 years old, 4 years old, 4.5 years old, or 5 years old. The percentage change in OKN screening results before and after the said treatment is calculated.


8.17 Example 17: A Randomized, Partially Masked, Controlled, Phase 2b Clinical Study to Evaluate the Safety and Efficacy of Construct II Gene Therapy in Participants with nAMD

8.17.1 Synopsis


Primary Objectives.


To evaluate mean change in best-corrected visual acuity (BCVA) for Construct II compared with ranibizumab at Week 50.


Secondary Objectives.


To evaluate the safety and tolerability of Construct II through Week 102. To evaluate the effect of Construct II on BCVA. To evaluate the effect of Construct II on central retinal thickness (CRT) as measured by spectral domain-optical coherence tomography (SD-OCT). To assess the need for supplemental anti-vascular endothelial growth factor (VEGF) therapy in the Construct II treatment arms. To assess aqueous protein concentrations of Construct II. To evaluate the immunogenicity of Construct II.


Exploratory Objectives.


To evaluate changes over time in the area of geographic atrophy and to assess, in participants with no evidence at baseline, the incidence of new areas of geographic atrophy. To assess the proportion of participants with no fluid on SD-OCT. To assess aqueous VEGF-A concentrations. To evaluate visual function and treatment satisfaction using patient reported outcome (PRO) questionnaires


Study Design.


This phase 2b partially masked, randomized, multicenter study will include 3 periods: an Active Run-in Period (i.e., screening), a Treatment Period, and an Extension Period. Participants who receive Construct II will be asked to participate in a long-term follow-up study after completion of or early discontinuation from the current study and will sign a separate informed consent for the follow-up study at that time.


The Active Run-in Period, which will last up to 10 weeks, will begin when the participant signs the informed consent form and will end once the participant has been evaluated for eligibility and has received 3 monthly intravitreal injections of ranibizumab 0.5 mg. The Treatment Period will last up to 12 months, beginning when the participant is randomized to study treatment and ending at Week 50. The Extension Period will last up to 12 months, beginning after Week 50 and ending at Week 102.


At Screening Visit 1 (Week −10), participants who meet the inclusion/exclusion criteria will enter the study and receive a 0.5-mg intravitreal injection of ranibizumab in the study eye. At Screening Visit 2 (Week −6), participants will receive a second 0.5-mg intravitreal injection of ranibizumab in the study eye. One week later, at Screening Visit 3 (Week −5), participants' anatomic response on SD-OCT will be evaluated against prespecified response criteria. Participants not meeting response criteria will be exited from the study. If participants meet all inclusion criteria, at Screening Visit 4 (Week −2), participants will be randomized. Any participants who withdraw or become ineligible for randomization during the Screening Period and have an adverse event (AE) associated with the intravitreal ranibizumab injections will be followed until the AE resolves (up to 30 days postinjection). Participants who are identified at Screening Visit 4 as being eligible will receive a third 0.5-mg intravitreal injection of ranibizumab in the study eye. Once the Central Reading Center (CRC) has verified the CRT, participants will be randomized (1:1:1) using an interactive response technology system to receive a single dose of Construct II (Dose 1), a single dose of Construct II (Dose 2), or monthly intravitreal ranibizumab 0.5 mg; Construct II will be administered by subretinal delivery. Participants will be stratified by baseline (Screening Visit 4) BCVA score (>58 letters vs ≤58 letters) in the randomization.


Participants randomized to the Construct II treatment arms will undergo the surgical procedure on Day 1 followed by visits on Day 2 and Day 8 to assess postoperative safety. At Week 2, participants will receive intravitreal ranibizumab to supplement any anti-VEGF that may have been removed during the vitrectomy surgery and to provide anti-VEGF therapy coverage while potential production of the gene therapy mediated protein escalates. The participants will then be seen at monthly intervals, beginning with Week 6, during which supplemental intravitreal ranibizumab 0.5-mg therapy may be administered if needed, as determined by the fully masked CRC evaluation of the SD-OCT data and the fully masked visual acuity assessor's evaluation of BCVA. Note that the SD-OCT and BCVA results from the masked assessors, together with predefined retreatment criteria, will inform the investigator's decision to provide supplemental anti-VEGF therapy.


Participants randomized to the ranibizumab control arm will have their first postrandomization visit at Week 2 and will receive intravitreal ranibizumab 0.5 mg. Following the Week 2 visit, the participants will have monthly (˜28 day) study visits during which they will receive an intravitreal injection of ranibizumab 0.5 mg.


At the Week 50 primary endpoint, participants in the ranibizumab control arm will be offered the opportunity to receive Construct II treatment if they still meet key inclusion/exclusion criteria. The treating physician will determine if the participant is eligible and a good candidate for the procedure. Qualified participants will then be administered the highest tolerated dose evaluated in this protocol. Participants in the ranibizumab control arm who switch to Construct II following Week 50 will follow the same visit schedule as the one started on Day 1 for participants originally randomized to receive Construct II. Those participants who either choose not to have treatment with Construct II or are ineligible for treatment with Construct II will be discontinued from the study.


Throughout the study, participants will be evaluated through the assessment of ocular and nonocular AEs including serious adverse events (SAEs) and adverse events of special interest (AESIs) (ocular inflammation deemed by the investigator to be unrelated to the surgical/study procedure and is graded as 2+ or greater on the ocular inflammation grading scales, ocular infections [including endophthalmitis], retinal tears or detachment, retinal thinning, and new arterial thromboembolic events [nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause)]), as well as assessments of clinical laboratory testing (chemistry, hematology, coagulation, urinalysis), ocular examinations and imaging (BCVA, intraocular pressure, slit-lamp biomicroscopy, indirect ophthalmoscopy, fluorescein angiography [FA], fundus autofluorescence [FAF], and SD-OCT), and vital signs. Note that AEs will be collected at all study visits. Immunogenicity to the vector and transgene product (TP) of Construct II will also be assessed. Patient reported outcomes will be collected using the supplemented National Eye Institute Visual Functioning Questionnaire 25-item version (NEI-VFQ-25) (also comprises the Rasch-scored version, NEI-VFQ-28-R) and Macular Disease Treatment Satisfaction Questionnaire (MacTSQ).


Planned safety monitoring of the study participants will be conducted on an ongoing basis. These include reviews conducted by the partially masked Medical Monitor and routine reviews conducted by the partially masked Sponsor's Internal Safety Committee. Separately, an Independent Data Monitoring Committee (IDMC) will also be established and will meet on a periodic basis to independently review the clinical data. If unmasked reviews are needed to understand a potential safety signal, these reviews will be conducted by the IDMC.


Diagnosis and Main Criteria for Inclusion.


To be eligible for enrollment in this study, participants, aged ≥50 and ≤89 years, must have a diagnosis of subfoveal choroidal neovascularization secondary to age-related macular degeneration in the study eye. Optical coherence tomography documentation from a current image of center subfield fluid must be confirmed by the CRC. Participants must have a BCVA letter score in the study eye between ≤78 and ≥44 and be pseudophakic (status postcataract surgery) in the study eye. Participants also must be willing and able to provide written, signed informed consent for this study after the nature of the study has been explained, and prior to any research-related procedures being conducted.


Investigational Product, Dosage, and Mode of Administration.


Construct II Dose 1: 1.6×1011 GC/eye (6.2×1011 GC/mL). Construct II Dose 2: 2.5×1011 GC/eye (1.0×1012 GC/mL). Construct II is administered via subretinal delivery (250 μL in a single dose).


Duration of Treatment.


In the Construct II treatment arms: 1 day. In the ranibizumab control arm: 50 weeks


Reference Therapy, Dosage and Mode of Administration.


Ranibizumab (LUCENTIS®, Genentech) 0.5 mg (0.05 mL of 10 mg/mL solution) will be administered by intravitreal injection approximately every 28 days.


Intravitreal ranibizumab 0.5 mg will also be administered as supplemental anti-VEGF therapy in all treatment arms during the Run-in Period (Screening Visits 1, 2, and 4) and at Week 2. Participants in the Construct II arm will be evaluated for intravitreal ranibizumab 0.5 mg as supplemental anti-VEGF therapy starting at Week 6 according to retreatment criteria; participants in the ranibizumab control arm who switch to Construct II after Week 50 will receive intravitreal ranibizumab 0.5 mg at Week 54 and will be evaluated for intravitreal ranibizumab 0.5 mg as supplemental anti-VEGF therapy starting at Week 58 according to retreatment criteria.


Criteria for Evaluation.


Primary Endpoint:


Mean change from baseline in BCVA to Week 50 (as the average of Week 46 and Week 50) based on the Early Treatment Diabetic Retinopathy Study (ETDRS) score


Secondary Endpoints:


Incidences of ocular and nonocular AEs over 50 weeks.


Incidences of ocular and nonocular AEs over 102 weeks.


Mean change from baseline in BCVA to Week 102 (as the average of Week 98 and Week 102).


Proportion of participants with BCVA of 43 letters (20/160 approximate Snellen equivalent) or worse at Week 50 (as the average of Week 46 and Week 50) and Week 102 (as the average of Week 98 and Week 102).


Proportion of participants with BCVA of 84 letters (20/20 approximate Snellen equivalent) or better at Week 50 (as the average of Week 46 and Week 50) and Week 102 (as the average of Week 98 and Week 102).


Proportion of participants (1) gaining or losing ≥15, ≥10, ≥5, or ≥0 letters; (2) maintaining vision (not losing ≥15 letters) compared with baseline as per BCVA at Week 50 (as the average of Week 46 and Week 50) and Week 102 (as the average of Week 98 and Week 102).


Mean change from baseline in BCVA to Week 50 (as the average of Week 46 and Week 50) for participants who received ≤2 supplemental anti-VEGF injections, 2 supplemental anti-VEGF injections, 1 supplemental anti-VEGF injection, or 0 supplemental anti-VEGF injections (Construct II randomized participants).


Mean change from Week 50 to Week 102 (as the average of Week 98 and Week 102) in BCVA (control arm participants who switch to Construct II).


Mean change from baseline in CRT as measured by SD-OCT to Week 50 (as the average of Week 46 and Week 50) and Week 102 (as the average of Week 98 and Week 102).


Mean change from Week 50 to Week 102 (as the average of Week 98 and Week 102) in CRT as measured by SD-OCT (control arm participants who switch to Construct II).


Proportion of participants who have a reduction of ≥50% in supplemental anti-VEGF injection rate through Week 50 and Week 102 compared with the prior 50 weeks preceding the first intravitreal ranibizumab injection received as part of the Active Run-in Period (Construct II randomized participants).


Mean reduction in supplemental anti VEGF injection rate through Week 50 and Week 102 compared with the prior 50 weeks preceding the first ranibizumab injection received as part of the Active Run-in Period (Construct II randomized participants).


Mean number of supplemental anti-VEGF injections in the Construct II arms through Week 50 and Week 102; Mean number of supplemental anti-VEGF injections after Week 50 through Week 102 relative to the prior 50 weeks in the study (control arm participants who switch to Construct II).


Time to first supplemental anti-VEGF injection after the Week 2 injection in the Construct II arms.


Proportion of participants in the Construct II arms who receive supplemental anti-VEGF injection after Week 2 through Week 26, after Week 26 through Week 50, after Week 50 through Week 74, after Week 74 through Week 102, after Week 2 through Week 50, and after Week 2 through Week 10


Aqueous Construct II TP concentrations at assessed time points; Immunogenicity measurements (serum neutralizing antibodies to AAV8 and serum antibodies to Construct II TP) at assessed time points.


Exploratory Endpoints:


Mean change from baseline in area of geographic atrophy based on FAF at assessed time points.


Incidence of new area of geographic atrophy by FAF (in participants with no geographic atrophy at baseline).


Incidence of retinal thinning in the area of the bleb.


Proportion of participants with no fluid on SD-OCT.


VEGF-A concentrations (aqueous) at assessed time points.


Mean change from baseline in NEI-VFQ-28-R (composite score; activity limitation domain score; and socio-emotional functioning domain score) at assessed time points.


Mean change from baseline in NEI-VFQ-25 (composite score and mental health subscale score) at assessed time points.


Mean change from baseline in MacTSQ (composite score; safety, efficacy, and discomfort domain score; and information provision and convenience domain score) at assessed time points.









TABLE 3







Objectives and Endpoints










Objectives
Endpoints











Primary









Efficacy
To evaluate mean change
Mean change from baseline in BCVA to Week 50



in BCVA for Construct II
(as the average of Week 46 and Week 50) based on



compared with
the ETDRS score



ranibizumab at Week 50







Secondary









Safety
To evaluate the safety and
Incidences of ocular and nonocular AEs over 50



tolerability of Construct II
weeks



through Week 102
Incidences of ocular and nonocular AEs over




102 weeks


Efficacy
To evaluate the
Mean change from baseline in BCVA to Week 102



effect of Construct
(as the average of Week 98 and Week 102)



II on BCVA
Proportion of participants with BCVA of 43 letters




(20/160 approximate Snellen equivalent) or worse




at Week 50 (as the average of Week 46 and Week




50) and Week 102 (as the average of Week 98 and




Week 102)




Proportion of participants with BCVA of 84 letters




(20/20 approximate Snellen equivalent) or better at




Week 50 (as the average of Week 46 and Week 50)




and Week 102 (as the average of Week 98 and




Week 102)




Proportion of participants (1) gaining or




losing ≥15, ≥10, ≥5, or ≥0 letters;




(2) maintaining vision (not losing ≥15




letters) compared with baseline as




per BCVA at Week 50 (as the average of Week 46




and Week 50) and Week 102 (as the average of




Week 98 and Week 102)




Mean change from baseline in BCVA to Week 50




(as the average of Week 46 and Week 50) for




participants who received ≤2 supplemental anti-




VEGF injections, 2 supplemental anti-VEGF




injections, 1 supplemental anti-VEGF injection, or




0 supplemental anti- VEGF injections (Construct II




randomized participants)




Mean change from Week 50 to Week 102 (as the




average of Week 98 and Week 102) in BCVA




(control arm participants who switch to Construct II)


Efficacy
To evaluate the effect of
Mean change from baseline in CRT as measured by



Construct II on CRT as
SD-OCT to Week 50 (as the average of Week 46



measured by SD-OCT
and Week 50) and Week 102 (as the average of




Week 98 and Week 102)




Mean change from Week 50 to Week 102 (as the




average of Week 98 and Week 102) in CRT as




measured by SD-OCT (control arm participants who




switch to Construct II)


Efficacy
To assess the need
Proportion of participants who have a reduction



for supplemental
of ≥50% in supplemental anti-VEGF injection rate



anti-VEGF therapy
through Week 50 and Week 102 compared with the



in the Construct II
prior 50 weeks preceding the first ranibizumab



treatment arms
injection received as part of the Active Run-in




Period (Construct II randomized participants)




Mean reduction in supplemental anti-VEGF




injection rate through Week 50 and Week 102




compared with the prior 50 weeks preceding




the first ranibizumab injection received as part




of the Active Run-in Period (Construct II




randomized participants)




Mean number of supplemental anti-VEGF injections




in the Construct II arms through Week 50 and Week




102




Mean number of supplemental anti-VEGF injections




after Week 50 through Week 102 relative to the prior




50 weeks in the study (control arm participants who




switch to Construct II)




Time to first supplemental anti-VEGF injection after




the Week 2 injection in the Construct II arms




Proportion of participants in the Construct II arm




who receive supplemental anti-VEGF injection




after Week 2 through Week 26, after Week 26




through Week 50, after Week 50 through Week




74, after Week 74 through Week 102, after Week




2 through Week 50, and after Week 2 through




Week 102


Pharmacodynamics
To assess aqueous
Aqueous Construct II TP concentrations at assessed



protein concentrations
time points



of Construct II


Immunogenicity
To evaluate the
Immunogenicity measurements (serum



immunogenicity of
neutralizing antibodies to AAV8 and serum



Construct II
antibodies to Construct II TP) at assessed time




points


Efficacy
To evaluate changes over
Mean change from baseline in area of geographic



time in the area of
atrophy based on FAF at assessed time points



geographic atrophy and to
Incidence of new area of geographic atrophy by



assess, in participants with
FAF (in participants with no geographic atrophy at



no evidence at baseline, the
baseline)



incidence of new areas of
Incidence of retinal thinning in the area of the



geographic atrophy
bleb


Efficacy
To assess the
Proportion of participants with no fluid on SD-



proportion of
OCT



participants with no



fluid on SD-OCT


Biomarkers
To assess aqueous
VEGF-A concentrations (aqueous) at assessed



VEGF-A
time points



concentrations


PRO
To evaluate visual function
Mean change from baseline in NEI-VFQ-28-R


Questionnaires
and treatment satisfaction
(composite score; activity limitation domain



using PRO questionnaires
score; and socio-emotional functioning domain




score) at assessed time points




Mean change from baseline in NEI-VFQ-25




(composite score and mental health subscale score)




at assessed time points




Mean change from baseline in MacTSQ




(composite score; safety, efficacy, and discomfort




domain score; and information provision and




convenience domain score) at assessed time points





AAV8 = adeno-associated virus serotype 8;


AE = adverse event;


BCVA = best-corrected visual acuity;


CRT = central retinal thickness;


ETDRS = Early Treatment Diabetic Retinopathy Study;


FAF = fundus autofluorescence;


MacTSQ = Macular Disease Treatment Satisfaction Questionnaire;


NEI-VFQ-25 = National Eye Institute Visual Functioning Questionnaire 25-item Version;


NEI-VFQ-28-R = National Eye Institute Visual Functioning Questionnaire 28-item Rasch-scored Version;


PRO = patient reported outcome;


SD-OCT = spectral domain-optical coherence tomography;


TP = transgene product;


VEGF = vascular endothelial growth factor






8.17.2 Study Design


Overall Study Design


This phase 2b partially masked, randomized, multicenter study will include 3 periods: an Active Run-in Period (i.e., screening), a Treatment Period, and an Extension Period. Participants who receive Construct II will be asked to participate in a long-term follow-up study after completion of or early discontinuation from the current study and will sign a separate informed consent for the follow-up study at that time.


The Active Run-in Period, which will last up to 10 weeks, will begin when the participant signs the Informed consent form (ICF) and will end once the participant has been evaluated for eligibility and has received 3 monthly injections of intravitreal ranibizumab. The Treatment Period will last up to 12 months, beginning when the participant is randomized to study treatment and ending at Week 50. The Extension Period will last up to 12 months, beginning after Week 50 and ending at Week 102.


At Screening Visit 1 (Week −10), participants who meet the inclusion/exclusion criteria will enter the study and receive a 0.5-mg intravitreal injection of ranibizumab in the study eye. At Screening Visit 2 (Week −6), participants will receive a second 0.5-mg intravitreal injection of ranibizumab in the study eye. One week later, at Screening Visit 3 (Week −5), participants' anatomic response on SD-OCT will be evaluated against prespecified response criteria. Participants not meeting response criteria will be exited from the study. If participants meet all inclusion criteria, at Screening Visit 4 (Week −2), participants will be randomized. Any participants who withdraw or become ineligible for randomization during the Screening Period and have an AE associated with the intravitreal ranibizumab injections will be followed until the AE resolves (up to 30 days postinjection). Participants who are identified at Screening Visit 4 as being eligible will receive a third 0.5-mg intravitreal injection of ranibizumab in the study eye. Once the Central Reading Center (CRC) has verified the central retinal thickness (CRT), participants will be randomized (1:1:1) using an interactive response technology (IRT) system to receive a single dose of Construct II (Dose 1), a single dose of Construct II (Dose 2), or monthly intravitreal ranibizumab 0.5 mg; Construct II will be administered by subretinal delivery. Participants will be stratified by baseline (Screening Visit 4) best-corrected visual acuity (BCVA) score (>58 letters vs ≤58 letters) in the randomization.


Participants randomized to the Construct II treatment arms will undergo the surgical procedure on Day 1 followed by visits on Day 2 and Day 8 to assess postoperative safety. At Week 2, participants will receive intravitreal ranibizumab to supplement any anti-VEGF that may have been removed during the vitrectomy surgery to provide anti-VEGF therapy coverage while potential production of the gene therapy mediated protein escalates. The participants will then be seen at monthly intervals, beginning with Week 6, during which supplemental intravitreal ranibizumab 0.5-mg therapy may be administered if needed, as determined by the fully masked CRC evaluation of the SD-OCT data and the fully masked VA assessor's evaluation of BCVA. Note that the SD-OCT and BCVA results, together with predefined retreatment criteria, will inform the investigator's decision to provide supplemental anti-VEGF therapy.


Participants randomized to the ranibizumab control arm will have their first postrandomization visit at Week 2 and will receive intravitreal ranibizumab 0.5 mg. Following the Week 2 visit, the participants will have monthly (˜28 day) study visits during which they will receive an injection of ranibizumab 0.5 mg.


At the Week 50 primary endpoint, participants in the ranibizumab control arm will be offered the opportunity to receive Construct II treatment if they still meet key inclusion/exclusion criteria. The treating physician will determine if the participant is eligible and a good candidate for the procedure. Qualified participants will then be administered the highest tolerated dose evaluated in this protocol. Participants in the ranibizumab control arm who switch to Construct II following Week 50 will follow the same visit schedule as the one started on Day 1 for participants originally randomized to receive Construct II. Those participants who either choose not to have treatment with Construct II or are ineligible for treatment with Construct II will be discontinued from the study.


Throughout the study, participants will be evaluated through the assessment of ocular and nonocular AEs including serious adverse events (SAEs) and adverse events of special interest (AESIs) (ocular inflammation deemed by the investigator to be unrelated to the surgical/study procedure and is graded as 2+ or greater on the ocular inflammation grading scales (see Section 8.17.7), ocular infections [including endophthalmitis], retinal tears or detachment, retinal thinning, and new arterial thromboembolic events [nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause)]), as well as assessments of clinical laboratory testing (chemistry, hematology, coagulation, urinalysis), ocular examinations and imaging (BCVA, IOP, slit-lamp biomicroscopy, indirect ophthalmoscopy, fluorescein angiography [FA], fundus autofluorescence [FAF], and SD-OCT), and vital signs. Note that AEs will be collected at all study visits. Immunogenicity to the vector and TP of Construct II will also be assessed. Patient reported outcomes (PROs) will be collected using the supplemented National Eye Institute Visual Functioning Questionnaire 25-item version (NEI-VFQ-25) (also comprises the Rasch-scored version, NEI-VFQ-28-R) and Macular Disease Treatment Satisfaction Questionnaire (MacTSQ).


Planned safety monitoring of the study participants will be conducted on an ongoing basis. These include reviews conducted by the partially masked Medical Monitor and routine reviews conducted by the partially masked Sponsor's Internal Safety Committee (ISC). Separately, an Independent Data Monitoring Committee (IDMC) will also be established and will meet on a periodic basis to independently review the clinical data. If unmasked reviews are needed to understand a potential safety signal, these reviews will be conducted by the IDMC.


8.17.3 Study Population


(a) General Considerations

Approximately 300 participants with nAMD who meet the inclusion/exclusion criteria will be randomized. It is expected that up to 50 study centers in the United States will participate in this study. Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.


(b) Inclusion Criteria

Participants must meet all the following criteria in order to be eligible for this study:


1. Males or females aged ≥50 years and ≤89 years.


2. An Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA letter score between ≤78 and ≥44 in the study eye at Screening Visit 1.


3. If both eyes are eligible, the study eye must be the participant's worse-seeing eye, as determined by the investigator prior to randomization.


4. Must have a diagnosis of subfoveal CNV secondary to AMD in the study eye, along with fluid within the parafovea (3-mm center of the macula, based on the early treatment diabetic retinopathy grid) at Screening Visit 1. CNV lesion characteristics as assessed by the CRC: lesion size needs to be less than 10-disc areas (typical disc area=2.54 mm2).


5. Must be pseudophakic (at least 12 weeks postcataract surgery) in the study eye


6. Must be willing and able to comply with all study procedures and be available for the duration of the study.


7. Women must be postmenopausal (defined as being at least 12 consecutive months without menses) or surgically sterilized (ie, having a bilateral tubal ligation/bilateral salpingectomy, bilateral tubal occlusive procedure, hysterectomy, or bilateral oophorectomy). If not, women must have a negative serum pregnancy test at Screening Visit 1, have negative urine pregnancy test results at Screening Visit 4, and be willing to have additional pregnancy tests during the study.


8. Women of childbearing potential (and their male partners) must be willing to use a highly effective method of contraception and male participants engaged in a sexual relationship with a woman of childbearing potential must be willing to use condoms from Screening Visit 1 until 24 weeks after Construct II administration. For the purpose of this study, highly effective methods of contraception for women of childbearing potential include the following: combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injecteable, implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; or sexual abstinence, when it is preferred and usual lifestyle of the participant.


9. Must be willing and able to provide written, signed informed consent.


10. Based on the Screening Visit 3 SD-OCT, participants must have improvement in fluid (see Response Criterion below) and have a CRT <400 Note that, if the participant has disease other than fluid contributing to an increase (ie, PED or SHRM) in CRT, they will be enrolled if they have <75 μm of fluid (intraretinal or subretinal), as determined by the CRC. Response Criterion: Subjects must have an improvement in inner retinal (parafovea 3 mm) fluid relative to Screening Visit 1 of >50 μm or 30%; or an improvement in center subfield thickness of >50 μm or 30% as determined by the CRC.


(c) Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:


1. CNV or macular edema in the study eye secondary to any causes other than AMD.


2. Subfoveal fibrosis or atrophy as determined by the CRC.


3. Participants who required >10 anti-VEGF injections in the 12 months prior to the Screening Visit 1.


4. Any condition in the investigator's opinion that could limit VA improvement in the study eye.


5. Active or history of retinal detachment in the study eye.


6. Advanced glaucoma in the study eye defined as IOP of >23 mmHg not controlled by 2 IOP-lowering medications or any invasive procedure to treat glaucoma (e.g., shunt, tube, or MIGS devices; selective laser trabeculectomy and argon laser trabeculoplasty are permitted).


7. Any condition in the study eye that, in the opinion of the investigator, may increase the risk to the participant, require either medical or surgical intervention during the course of the study to prevent or treat vision loss, or interfere with study procedures or assessments.


8. History of intraocular surgery in the study eye within 12 weeks prior to Screening Visit 1. Yttrium aluminum garnet capsulotomy is permitted if performed >10 weeks prior to the Screening Visit 1.


9. History of intravitreal therapy in the study eye, such as intravitreal steroid injection or investigational product, other than anti-VEGF therapy, in the 6 months prior to Screening Visit 1.


10. Presence of any implant in the study eye at Screening Visit 1 (excluding intraocular lens).


11. History of malignancy or hematologic malignancy that may compromise the immune system requiring chemotherapy and/or radiation in the 5 years prior to Screening Visit 1. Localized basal cell carcinoma will be permitted.


12. Receipt of any investigational product within the 30 days of enrollment or 5 half-lives of the investigational product, whichever is longer.


13. Received gene therapy.


14. History of retinal toxicity caused by a therapy, or concomitant therapy with any drug that may affect VA or with known retinal toxicity, e.g., chloroquine or hydroxychloroquine.


15. Ocular or periocular infection in the study eye that may interfere with the surgical procedure.


16. Myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months.


17. Uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg, diastolic BP >100 mmHg) despite maximal medical treatment.


18. Any participant with the following laboratory values at Screening Visit 1 will be withdrawn from study:

    • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5×upper limit of normal (ULN).
    • Total bilirubin >1.5×ULN, unless the participant has a previously known history of Gilbert's syndrome and a fractionated bilirubin that shows conjugated bilirubin <35% of total bilirubin.
    • Prothrombin time >1.5×ULN, unless the participant is anticoagulated. Participants who are anticoagulated will be monitored by local labs and managed per local practice to hold or bridge anticoagulant therapy for the study procedure; consultation with the Medical Monitor is also required.
    • Hemoglobin <10 g/dL for male participants and <9 g/dL for female participants.
    • Platelets <100×103/μL.
    • Estimated glomerular filtration rate <30 mL/min/1.73 m2.


19. Any concomitant treatment that, in the opinion of the investigator, may interfere with ocular surgical procedure or healing process.


20. Known hypersensitivity to ranibizumab or any of its components.


21. Has a serious, chronic, or unstable medical or psychological condition that, in the opinion of the investigator or Sponsor, may compromise the participant's safety or ability to complete all assessments and follow-up in the study.


22. Currently taking anticoagulation therapy for which holding anticoagulation therapy for Construct II administration is not indicated or considered to be unsafe in the opinion of the treating investigator (ie, retinal surgeon), as well as the physician prescribing anticoagulation for the participant.


Criteria for Participants in the Control Arm to Obtain Construct II After Week 50


(a) Inclusion Criteria

1. Study eye will be the eye that qualified at randomization.


2. Participant has a CRT <400 μm of subretinal/intraretinal fluid or (in cases where a participant may have nonfluid elevation in the CRT, eg, pigment epithelial defect)<75 μm of excess fluid, as confirmed by the masked CRC.


3. Women of childbearing potential (and their male partners) must be willing to use a highly effective method of contraception and male participants engaged in a sexual relationship with a woman of childbearing potential must be willing to use condoms from the surgical visit until 24 weeks after Construct II administration. For the purpose of this study, highly effective methods of contraception for women of childbearing potential include the following: combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injecteable, implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; or sexual abstinence, when it is preferred and usual lifestyle of the participant.


4. Women of childbearing potential must have a negative urine pregnancy test at Week 52 and be willing to have additional pregnancy tests during the study.


(b) Exclusion Criteria

1. CNV or macular edema in the study eye secondary to any causes other than AMD.


2. Subfoveal fibrosis or atrophy as determined by the CRC, or any condition preventing VA improvement in the study eye.


3. Ocular or periocular infection in the study eye that may interfere with the surgical procedure.


4. Myocardial infarction, cerebrovascular accident, or transient ischemic attacks since randomization.


5. Uncontrolled hypertension (systolic BP >180 mmHg, diastolic BP >100 mmHg) despite maximal medical treatment.


6. Any concomitant treatment that, in the opinion of the investigator, may interfere with ocular surgical procedure or healing process.


7. History of malignancy or hematologic malignancy that may compromise the immune system requiring chemotherapy and/or radiation in the past year. Localized basal cell carcinoma will be permitted.


8. Currently taking anticoagulation therapy for which holding anticoagulation therapy for Construct II administration is not indicated or considered to be unsafe in the opinion of the treating investigator as well as the physician prescribing anticoagulation for the participant.


8.17.4 Study Intervention


Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol.


(a) Study Intervention(s) Administered

Eligible participants will be randomized 1:1:1 to receive a single dose of Construct II (Dose 1), a single dose of Construct II (Dose 2), or monthly intravitreal injections of ranibizumab.


Participants in either of the Construct II arms will receive Construct II on Day 1 via subretinal delivery in an operating room. During the study, participants in the Construct II arms will receive ranibizumab 0.5 mg, administered by intravitreal injection, on Screening Visits 1, 2, and 4, at Week 2, and then as needed every 4 weeks starting at Week 6.


Participants in the ranibizumab control arm will receive ranibizumab 0.5 mg, administered by intravitreal injection, on Screening Visits 1, 2, and 4, at Week 2, and then monthly (˜28 days) thereafter.









TABLE 4







Study Intervention(s) Administered









Arm Name











Construct II Dose 1
Construct II Dose 2
Ranibizumab (LUCENTIS)













Type
Gene therapy
Drug








Dose
Solution


Formulation










Unit Dose
6.2 × 1011 GC/mL
1.0 × 1012GC/mL
10 mg/mL


Strength


Dose Level(s)
250 μL
250 μL
0.5 mg (0.05 mL of 10 mg/mL



(1.6 × 1011 GC/eye)
(2.5 × 1011 GC/eye)
solution) once a month



one-time dose
one-time dose
(approximately every 28 days)









Route of
Subretinal delivery
Intravitreal injection


Administration


Physical
Construct II investigational product is supplied
LUCENTIS is supplied as a


Description
as a frozen, sterile, single-use solution of the
preservative-free, sterile



AAV vector active ingredient in a formulation
solution in a single-use



buffer. The solution appears clear to opalescent,
container designed to deliver



colorless, and free of visible particulates at
0.05 mL of 10 mg/mL



room temperature.
LUCENTIS (0.5 mg dose




prefilled syringe or vial)




aqueous solution. The




solution appears colorless to




pale yellow.


Manufacturer
Advanced Bioscience Laboratories, Inc
Genentech, Inc


Packaging and
Construct II will be supplied as a sterile, single-
Study intervention will be


Labeling
use solution in 2-mL Crystal Zenith ® vials
obtained in commercial



sealed with latex free rubber stoppers and
packaging, either the prefilled



aluminum flip-off seals. Each vial will be
syringe (NDC 50242-080-03) or



labeled as required per country regulatory
single-use 2-mL glass vial (NDC



requirements.
50242-080-02) designed to




deliver 0.05 mL of 10 mg/mL




ranibizumab solution.









8.17.5 Ocular Inflammation Grading Scale


Ocular inflammation will be assessed during slit-lamp biomicroscopy and independent ophthalmoscopy and graded using the following scales. The standard practice for slit-lamp biomicroscopy and indirect ophthalmoscopy assessment should be used.









TABLE 5





Grading Scale for Ocular Inflammation: Anterior


Chamber Cells and Anterior Chamber Flare







Anterior Chamber Cells










Grade
Cells in Field (1 mm × 1 mm slit beam)







0
None



+0.5
1-5



+1
 6-15



+2
16-25



+3
26-50



+4
>50











Anterior Chamber Flare








Grade
Description





0
None


+1
Trace


+2
Moderate (iris and lens detail clear)


+3
Marked (iris and lens detail hazy)


+4
Intense (fibrin or plastic aqueous)





Source: Jabs et al., 2005, Am J Ophthalmol 140(3): 509-516.













TABLE 6







Grading Scale for Vitreous Haze








Grade
Amount of Vitreal Haze











0
None


+0.5
Trace


+1
Clear optic disc and vessels; hazy nerve fiber layer


+2
Hazy optic disc and vessels


+3
Optic disk visible


+4
Optic disc not visible





Source: Nussenblatt et al., 1985, Ophthalmology, 92(4): 467-471.






8.18 Example 18: A Phase 2, Randomized, Dose-Escalation, Ranibizumab-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Construct II Gene Therapy Delivered Via One or Two Suprachoroidal Space (SCS) Injections in Participants with Neovascular Age-Related Macular Degeneration (nAMD)

8.18.1 Synopsis


(a) Objectives and Endpoints









TABLE 7







Objectives and Endpoints









Measure
Objectives
Endpoints










Primary









Efficacy
To evaluate the mean change in
Mean change from baseline in



BCVA for Construct II
BCVA to Week 40 based on the



compared with ranibizumab
ETDRS score



monthly at Week 40







Secondary









Safety
To evaluate the safety and
Incidences of overall and ocular



tolerability of Construct II
AEs and SAEs through




Week 52




Vector shedding analysis in serum,




urine, and tears



To evaluate the effect of
Mean change from baseline in



Construct II on CNV lesion
CNV lesion size and leakage



growth and leakage as
area based on FA at Week 40



measured by FA
and Week 52


Efficacy
To evaluate the effect of
Mean change from baseline in



Construct II on BCVA
BCVA to Week 52




Proportion of participants (1) gaining




or losing ≥15, ≥10, ≥5, or ≥0 letters;




(2) maintaining vision (not




losing ≥15 letters) compared




with baseline as per BCVA at




Week 40 and Week 52




Mean change from baseline in




BCVA to Week 40 and




Week 52 for participants who




received ≤2 supplemental




anti-VEGF injections,




2 supplemental anti-VEGF




injections, 1 supplemental




anti-VEGF injection, or




0 supplemental anti-VEGF




injections (Construct II




randomized participants)



To evaluate the effect of
Mean change from baseline in CRT



Construct II on CRT, as
as measured by SD-OCT to



measured by SD-OCT
Week 40 and Week 52



To assess the need for
Annualized supplemental



supplemental anti-VEGF
anti-VEGF injection rate



therapy in participants who
through Week 40 and Week 52



receive Construct II treatment
Proportion of participants who have




a reduction of ≥50% in the




annualized supplemental




anti-VEGF injection rate




through Week 40 and Week 52




compared with the prior




52 weeks preceding the first




intravitreal ranibizumab




injection received as part of the




Screening Period (Construct II




randomized participants)




Mean reduction in the annualized




supplemental anti-VEGF




injection rate through Week 40




and Week 52 compared with




the prior 52 weeks preceding




the first ranibizumab injection




received as part of the




Screening Period (Construct II




randomized participants)




Time to first supplemental




anti-VEGF injection


Pharmacodynamics
To evaluate the concentration of
Mean change from baseline in



Construct II TP in aqueous
aqueous Construct II TP



humor
concentrations over time


Immunogenicity
To evaluate the immunogenicity
Immunogenicity measurements



of Construct II
(AAV8: NAbs, TAbs, and




ELISpot; Construct II protein:




TAbs and ELISpot)







Exploratory









Efficacy
To evaluate the effect of
Proportion of participants with no



Construct II on fluid
fluid on SD-OCT



accumulation as assessed by
Proportion of participants with



SD-OCT
stable fluid on SD-OCT within




30 μm of baseline


Safety
To assess changes in visual
Changes in visual field testing over



function by visual fields
time



To evaluate the incidences of new
Incidence of new area of



areas of geographic atrophy,
geographic atrophy by FAF (in



as assessed by FAF
participants with no geographic




atrophy at baseline)


Biomarker
To assess aqueous humor VEGF
VEGF-A concentrations (aqueous)



concentrations
at assessed time points





AAV8 = adeno-associated virus serotype 8;


AE = adverse event;


BCVA = best-corrected visual acuity;


CNV = choroidal neovascularization;


CRT = central retinal thickness;


ELISpot = enzyme-linked ImmunoSpot;


ETDRS = Early Treatment Diabetic Retinopathy Study;


FA = fluorescein angiography;


FAF = fundus autofluorescence;


NAbs = neutralizing antibodies;


SAE = serious adverse event;


SCS = suprachoroidal space;


SD-OCT = spectral domain-optical coherence tomography;


TAbs = total binding antibodies;


TP = transgene product;


VEGF = vascular endothelial growth factor






(b) Study Design

In this phase 2, randomized (3:1), dose-escalation, ranibizumab-controlled, study, approximately 40 participants with nAMD will be enrolled into 2 dose cohorts. Within each dose cohort, participants will receive a one-time administration of Construct II in the SCS (n=15 participants) or an intravitreal injection of ranibizumab 0.5 mg every 4 weeks up to Week 52 (n=5 participants).


Participants who receive Construct II will strongly be encouraged to enroll in a long-term follow-up study after completion of the current study at Week 52 (or early discontinuation) and will sign a separate informed consent for the follow-up study at that time. Participants in the ranibizumab control arm will be offered an opportunity following the Week 52 visit to be included in a future Construct II dose cohort.


Screening will comprise 3 visits to select for eligible participants with qualifying AAV8 neutralizing antibodies (NAbs) titers (Visit 1) who demonstrate anatomic responsiveness to ranibizumab during a ranibizumab run-in phase (Visits 2 and 3). During Visit 1, participants who sign the informed consent form (ICF) will be evaluated for eligibility and will have serum samples collected to screen for pre-existing NAbs or will confirm NAb status from a NAb screening protocol. Participants who have negative or low (≤300) titer results for serum AAV8 NAbs will return to the study center to confirm the remaining inclusion/exclusion criteria. Participants continuing to meet eligibility criteria will receive a 0.5-mg intravitreal injection of ranibizumab in the study eye at Visit 2 (Day 1). At Visit 3 (Week 1), participants will be evaluated by spectral domain-optical coherence tomography (SD-OCT) to confirm their anatomic response to the screening anti-VEGF injection via comparison against their Day 1 SD-OCT assessment taken prior to the screening ranibizumab injection. Anatomic response will be determined by a central reading center (CRC) according to pre-specified criteria. Once the CRC has verified anatomic eligibility, 2 sentinel participants in each cohort will be randomized one to Construct II or ranibizumab control. Participants who do not have an anatomic response will be considered screen failures. For screen-failed participants, anyone who has an AE associated with the ranibizumab injections on Day 1 will be followed until the AE resolves (up to 30 days post injection).


At the Week 2 visit, Construct II randomized participants will receive either 1 or 2 injections of Construct II, depending on dose level, administered at the study center by SCS delivery using the Clearside SCS Microinjector™ investigational device; note that the Treatment Period of the study begins at the time of Construct II administration. All investigators will be trained on the SCS procedure. A detailed description of the procedure can be found in the SCS Administration Manual. Following Construct II administration to the sentinel participant who is randomized to Construct II, a 2-week observation period will be conducted for safety. The Sponsor's Internal Safety Committee (ISC) will review the safety data for this participant and, if there are no safety concerns, up to 18 additional participants (14 Construct II and 4 ranibizumab controls) may be randomized. If no safety review triggers (SRTs) are observed, then, following a 2-week observation period for the last dosed participant within the cohort, all available safety data will be evaluated by the Independent Data Monitoring Committee (IDMC). Additionally, if any event meets the criteria of a Stopping Rule, dosing of any new participants will be suspended until a complete review of all safety data has been performed. At any given IDMC meeting, whether planned or called for due to an SRT, the IDMC may recommend stopping the study, proceeding to the next dosing cohort, or proceeding to a lower dose (up to a half-log).


Participants randomized to Construct II will have 2 visits for post injection safety (1-day post procedure and 1-week post procedure). Starting 2 weeks after Construct II administration, participants will have monthly study visits and may receive intravitreal ranibizumab supplemental therapy if they meet predefined supplemental injection criteria. For participants in the Construct II treatment arms, immunogenicity to the vector (as assessed by AAV8 NAbs, AAV8 TAbs, antibodies to Construct II protein, and enzyme-linked ImmunoSpot [ELISpot]), VEGF-A concentrations, and anti-Construct II antibodies will be assessed throughout the study.


Participants randomized to the ranibizumab control arm will have their first post randomization visit at Week 4 and will receive intravitreal ranibizumab 0.5 mg. Following the Week 4 visit, the participants will have monthly (˜every 28 days) study visits during which they will receive an intravitreal injection of ranibizumab 0.5 mg.


Efficacy will be the primary focus of the initial 40 weeks (primary study period). Following completion of the primary study period, participants will continue to be assessed until Week 52. At the end of the Week 52 study visit, participants who received Construct II will be invited to enroll into a long-term follow-up study, while participants who were in the ranibizumab control arm, if eligible, will be offered an opportunity to be included in a future Construct II dose cohort. Participants will be evaluated for safety through the assessment of AEs, including SAEs and adverse events of special interest (AESIs) (ocular inflammation deemed by the investigator to be unrelated to the surgical/study procedure and graded as 2+ or greater on the ocular inflammation grading scales, ocular infections [including endophthalmitis], retinal tears or detachment, retinal thinning, and new arterial thromboembolic events [nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause)]), as well as assessments of clinical laboratory tests (chemistry, hematology, coagulation, urinalysis), and ocular examinations and imaging (BCVA, IOP, slit-lamp biomicroscopy, indirect ophthalmoscopy, fluorescein angiography [FA], ultra-wide field Optos fundus auto fluorescence [FAF], ultra-wide field Optos color fundus photography [CFP], Humphrey visual field 120, or microperimetry, and SD-OCT). Note that AEs will be collected at all study visits. Participants who show evidence of new retinal hypo/hyper pigmentation changes as compared with baseline will be monitored using SD-OCT scans. Radial SD-OCT scans that transverse the margin of the hypo/hyper pigmentary area will be captured when possible.


Planned safety monitoring of the study participants will be conducted on an ongoing basis. The monitoring will include reviews conducted by the Medical Monitor and routine reviews conducted by the Sponsor's ISC. Separately, an IDMC will also be established and will meet on a periodic basis to independently review the clinical data.


8.18.2 Inclusion Criteria


All Participants Entering the Study


Participants are eligible to be included in the study only if all of the following criteria apply:

    • 1. Males or females, aged ≥50 years and ≤89 years.
    • 2. Must have a diagnosis of subfoveal CNV secondary to AMD in the study eye, along with retinal fluid (either subretinal or intraretinal) within the parafovea (3-mm center of the macula, based on the early treatment diabetic retinopathy grid), as assessed by the CRC.
      • CNV lesion characteristics: lesion size needs to be less than 10-disc areas (typical disc area=2.54 mm2).
    • 3. May be phakic or pseudophakic.
    • 4. Must have a negative or low serum titer result (≤300) for AAV8 NAbs.
    • 5. BCVA between ≤20/25 and ≥20/125 (≤83 and ≥44 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) in the study eye.
    • 6. Based on the SD-OCT image obtained at Week 1, participants must have improvement in fluid (see Response Criterion below) and have a central retinal thickness (CRT) <400 μm. Note that, if the participant has disease other than fluid contributing to an increase (ie, PED or SHRM) in CRT, they will be enrolled if they have <75 μm of total fluid (intraretinal or subretinal), as determined by the CRC.
      • Response Criterion: Participants must have an improvement in inner retinal (parafovea 3 mm) fluid relative to Visit 2 of >50 μm or 50%; or an improvement in center subfield thickness of >50 μm or 50%, as determined by the CRC.
    • 7. If both eyes are eligible, the study eye must be the participant's worse-seeing eye, as determined by the investigator.
    • 8. Women must be postmenopausal (defined as being at least 12 consecutive months without menses) or surgically sterilized (i.e., having a bilateral tubal ligation/bilateral salpingectomy, bilateral tubal occlusive procedure, hysterectomy, or bilateral oophorectomy). If not, women must have negative serum and urine pregnancy tests at Day 1 and be willing to undergo additional pregnancy testing during the study.
    • 9. Women of childbearing potential (WOCBP) (and their male partners) must be willing to use a highly effective method of contraception (Section 8.5) and male participants engaged in a sexual relationship with a WOCBP must be willing to use condoms from Week 2 until 24 weeks after Construct II administration.
    • 10. Must be willing and able to provide signed informed consent, comply with all study procedures, and be available for the duration of the study.


8.18.3 Exclusion Criteria


Participants are excluded from the study if any of the following criteria apply:

    • 1. CNV or macular edema in the study eye secondary to any causes other than AMD.
    • 2. Subfoveal fibrosis or atrophy, as determined by the CRC.
    • 3. Participants who required >10 anti-VEGF injections in the 12 months prior to Visit 2.
    • 4. Participants who had a prior vitrectomy.
    • 5. Any condition in the investigator's opinion that could limit VA improvement in the study eye.
    • 6. Active or history of retinal detachment in the study eye.
    • 7. Advanced glaucoma in the study eye, defined as IOP of >23 mmHg not controlled by 2 IOP-lowering medications or any invasive procedure to treat glaucoma (eg, shunt, tube, or MIGS devices; however, selective laser trabeculectomy and argon laser trabeculoplasty are permitted).
    • 8. Any condition in the study eye that, in the opinion of the investigator, may increase the risk to the participant, require either medical or surgical intervention during the course of the study to prevent or treat vision loss, or interfere with study procedures or assessments.
    • 9. History of intravitreal therapy in the study eye, such as intravitreal steroid injection or investigational product, other than anti-VEGF therapy, in the 6 months prior to Visit 2.
    • 10. Presence of an implant in the study eye at screening (excluding an intraocular lens).
    • 11. History of malignancy requiring chemotherapy and/or radiation in the 5 years prior to screening. Localized basal cell carcinoma will be permitted.
    • 12. Received any gene therapy.
    • 13. History of therapy known to have caused retinal toxicity, or concomitant therapy with any drug that may affect VA or with known retinal toxicity, e.g., chloroquine or hydroxychloroquine.
    • 14. Any concomitant treatment that, in the opinion of the investigator, may interfere with the ocular procedure or healing process.
    • 15. Known hypersensitivity to ranibizumab or any of its components or past hypersensitivity (in the investigator's opinion) to agents like Construct II.
    • 16. Has a serious, chronic, or unstable medical or psychological condition that, in the opinion of the investigator, may compromise the participant's safety or ability to complete all assessments and follow-up in the study.
    • 17. Any condition preventing visualization of the fundus or VA improvement in the study eye, e.g., cataract, vitreous opacity, fibrosis, atrophy, or retinal epithelial tear in the center of the fovea.
    • 18. History of intraocular surgery in the study eye within 12 weeks prior to Visit 2. Yttrium aluminum garnet capsulotomy is permitted if performed >10 weeks prior to Visit 2.
    • 19. Receipt of any investigational product within 30 days of Visit 2 or 5 half-lives of the investigational product, whichever is longer.
    • 20. Ocular or periocular infection in the study eye that may interfere with the administration of Construct II.
    • 21. Myocardial infarction, cerebrovascular accident, or transient ischemic attacks within the 6 months prior to Visit 2.
    • 22. Uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg, diastolic BP >100 mmHg) despite maximal medical treatment.
    • 23. Any participant with the following laboratory values collected at Visit 2 and confirmed at Visit 3:
      • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5×upper limit of normal (ULN).
      • Total bilirubin >1.5×ULN, unless the participant has a previously known history of Gilbert's syndrome and a fractionated bilirubin that shows conjugated bilirubin <35% of total bilirubin.
      • Prothrombin time >1.5×ULN, unless the participant is anticoagulated.
      • Hemoglobin <10 g/dL for male participants and <9 g/dL for female participants.
      • Platelets <100×103/μL.
      • Estimated glomerular filtration rate <30 mL/min/1.73 m2.


8.18.4 Study Intervention(s) Administered


Eligible participants will be assigned either to receive Construct II (Dose 1 or Dose 2) or ranibizumab in the study eye. Information regarding Construct II and ranibizumab follows.









TABLE 8







Information regarding Construct II and ranibizumab









Arm Name











Construct II Dose 1
Construct II Dose 2
Ranibizumab (LUCENTIS)













Type
Gene therapy (AAV8.CB7.CI.amd42.RBG)
Drug (control treatment arm




and run-in/rescue)


Dose
Solution


Formulation










Unit Dose
1.0 × 1012 GC/mL
2.5 × 1012 GC/mL
10 mg/mL


Strength


Dose Level(s)
100 μL
100 μL
0.5 mg (0.05 mL of



(2.5 × 1011 GC/eye)
(5.0 × 1011 GC/eye)
10 mg/mL solution) once at



delivered via a single
delivered via 2 SCS
Visit 2 or as rescue starting 2



SCS injection
injections at the
weeks post Construct II




same visit
administration, provided





according to rescue criteria









Route of
Suprachoroidal space injection(s) in the study eye using the
Intravitreal injection in the


Administration
Clearside SCS Microinjector ™ investigational device
study eye


Physical
Construct II investigational product is supplied as a frozen,
LUCENTIS is supplied as a


Description
sterile, single-use solution of the AAV vector active
preservative-free, sterile



ingredient (AAV8.CB7.CI.amd42.RBG) in a formulation
solution in a single-use



buffer. The solution appears clear to opalescent, colorless,
container designed to deliver



and free of visible particulates at room temperature.
0.05 mL of 10 mg/mL




LUCENTIS (0.5-mg dose




prefilled syringe or vial)




aqueous solution. The




solution appears colorless to




pale yellow.


Manufacturer
Advanced BioScience Laboratories, Inc
Genentech, Inc


Packaging and
Construct II will be supplied as a sterile, single-use solution
Study intervention will be


Labeling
in 2-mL Crystal Zenith ® vials sealed with latex-free robber
obtained in commercial



stoppers and aluminum flip-off seals. Each vial will be
packaging, either the



labeled as required per country regulatory requirements.
prefilled syringe (NDC




50242-080-03) or single-use




2-mL glass vial (NDC




50242-080-02) designed to




deliver 0.05 mL of




10 mg/mL ranibizumab




solution.









8.19 Example 19: Treatment of Batten-CLN2-Associated Vision Loss with Tripeptidyl-Peptidase 1 (TPP1) cDNA-Based Vector in Non-Human Primates

A nonclinical toxicology study in non-human primates was initiated to evaluate Tripeptidyl-Peptidase 1 (TPP1) cDNA-based vector by two different routes of administration—subretinal and suprachoroidal. All animals were sacrificed and tissues are being analyzed


In this study, groups of cynomolgus monkeys (5 animals/group) were administered TPP1 cDNA-based vector via subretinal (SR) injection at doses of 0 (vehicle), 1×1010, 1×1011, 1×1012 or 1×1013 GC/eye (100 μL). Additional groups (5 animals/group) were administered TPP1 cDNA-based vector via injection into the suprachoroidal space (SCS) using a microneedle at a dose of 0 (vehicle) or 1×1012 GC/eye (two 50 μL injections at superior temporal or inferior nasal quadrants). All treated groups were administered TPP1 cDNA-based vector in both eyes. Control animals received an injection of vehicle into via either the SCS (OS) or the SR route (OD). Animals were euthanized either 4 weeks (2 animals/group) or 3 months (3 animals/group) after administration of the TPP1 cDNA-based vector. Endpoints included in this study were: clinical observations, body weights, ophthalmic procedures (ophthalmoscopy, intraocular pressure, optical coherence tomography, fundus ocular photography and full field electroretinography), TPP1 (aqueous and vitreous [terminal only] humor; serum), anti-AAV antibodies (nAbs), anti-transgene product antibodies (ATPA), biodistribution, organ weights, immunohistochemistry (anti-TPP1 in the eye), macroscopic and microscopic examination.


8.20 Example 20: Treatment of Batten-CLN2-Associated Vision Loss with Tripeptidyl-Peptidase 1 (TPP1) cDNA-Based Vector in Human Subject

A subject presenting with Batten-CLN2-associated vision loss is administered AAV9 that encodes Tripeptidyl-Peptidase 1 at a dose (e.g., 1×1010 to 5×1011 genome copies per eye) sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The administration is done by a dual route of administration that involves both a central nervous system (CNS) delivery (e.g., intracerebroventricular (ICV), intracisternal (IC), or intrathecal-lumbar (IT-L) delivery) and an ocular delivery (e.g., suprachoroidal, subretinal, juxtascleral, or intravitreal delivery). Following treatment, the subject is evaluated for improvement in Batten-CLN2-associated vision loss.


8.21 Example 21: Use of an Infrared Thermal Camera to Monitor Injection in Pigs

The FLIR T530 infrared thermal camera was used to characterize post ocular injection thermal profiles in live pigs. Alternatively, an FLIR T420, FLIR T440, Fluke Ti400, or FLIRE60 infrared thermal camera is used. Suprachoroidal (FIG. 6), unsuccessful suprachoroidal, intravitreal, and extraocular efflux injections of room temperature saline (68-72° F.). were assessed in the study. Dose volume was 100 μL for every injection with the solution from the refrigerator to room temperature for injection.


Infrared camera lens to ocular surface distance was established at approximately 1 ft. The manual temperature range on the camera for viewing was set to ˜80-90° F. Imaging operator held the camera and set the center screen cursor aimed at the injection site during video recordings. Pigs received a retrobulbar injection of saline to proptose the eye for better visibility, and eye lids were cut and retracted back to expose the sclera at the site of injection. The iron filter was used during thermal video recordings.


A successful suprachoroidal injection was characterized by: (a) a slow, wide radial spread of the dark color, (b) very dark color at the beginning, and (c) a gradual change of injectate to lighter color, i.e., a temperature gradient noted by a lighter color. An unsuccessful suprachoroidal injection was characterized by: (a) no spread of the dark color, and (b) a minor change in color localized to the injection site. A successful intravitreal injection was characterized by: (a) no spread of the dark color, (b) an initial change to very dark color localized to the injection site, and (c) a gradual and uniform change of the entire eye to darker color occurring after the injection developing with time. Extraocular efflux was characterized by: (a) quick flowing streams on outside exterior of the eye, (b) very dark color at the beginning, and (c) a quick change to lighter color.


8.22 Example 22: Use of an Infrared Thermal Camera to Monitor Injection in Human Patients

A subject presenting with wet AMD is administered AAV8 that encodes ranibizumab Fab (e.g., by subretinal administration, suprachoroidal administration, or intravitreal administration) at a dose sufficient to produce a concentration of the transgene product at a Cmin of at least 0.330 μg/mL in the Vitreous humour for three months. The FLIR T530 infrared thermal camera is used to evaluate the injection during the procedure and is available to evaluate after the injection to confirm either that the administration is successfully completed or misdose of the administration. Alternatively, an FLIR T420, FLIR T440, Fluke Ti400, or FLIRE60 infrared thermal camera is used. Following treatment, the subject is evaluated clinically for signs of clinical effect and improvement in signs and symptoms of wet AMD.


8.23 Example 23: Treatment of Batten-CLN2-Associated Vision Loss with Tripeptidyl-Peptidase 1 (TPP1) cDNA-Based Vector in Human Subject by Suprachoroidal Administration

A subject presenting with Batten-CLN2-associated vision loss is administered AAV9 that encodes Tripeptidyl-Peptidase 1 at a dose (e.g., 1×1010 to 5×1011 genome copies per eye) sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The TPP1 cDNA-based vector is administered by suprachoroidal administration. Following treatment, the subject is evaluated for improvement in Batten-CLN2-associated vision loss.


8.24 Example 24: Treatment of Batten-CLN2-Associated Vision Loss with Tripeptidyl-Peptidase 1 (TPP1) cDNA-Based Vector in Human Subject by Subretinal Administration

A subject presenting with Batten-CLN2-associated vision loss is administered AAV9 that encodes Tripeptidyl-Peptidase 1 at a dose (e.g., 1×1010 to 5×1011 genome copies per eye) sufficient to produce a therapeutically effective concentration of the transgene product in the vitreous humour for three months. The TPP1 cDNA-based vector is administered by subretinal administration. Following treatment, the subject is evaluated for improvement in Batten-CLN2-associated vision loss.


EQUIVALENTS

Although the invention is described in detail with reference to specific embodiments thereof, it will be understood that variations which are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.


All publications, patents and patent applications mentioned in this specification are herein incorporated by reference into the specification to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference in their entireties.

Claims
  • 1. A method of subretinal administration without vitrectomy for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient.
  • 2. The method of claim 1, wherein the administering step comprises administering to the subretinal space in the eye of said human subject the recombinant viral vector therapeutic product via the suprachoroidal space in the eye of said human subject.
  • 3. The method of claim 2, wherein the administering step is by the use of a subretinal drug delivery device comprising a catheter that can be inserted and tunneled through the suprachoroidal space toward the posterior pole, where a small needle injects into the subretinal space.
  • 4. The method of claim 3, wherein the administering step comprises inserting and tunneling the catheter of the subretinal drug delivery device through the suprachoroidal space.
  • 5. A method of suprachoroidal administration for treating a pathology of the eye, comprising administering to the suprachoroidal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye.
  • 6. The method of claim 5, wherein the administering step is by injecting the recombinant viral vector into the suprachoroidal space using a suprachoroidal drug delivery device.
  • 7. The method of claim 5 or 6, wherein the suprachoroidal drug delivery device is a microinjector.
  • 8. A method of administration to the outer space of the sclera for treating a pathology of the eye, comprising administering to the outer surface of the sclera in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye.
  • 9. The method of claim 8, wherein the administering step is by the use of a juxtascleral drug delivery device that comprises a cannula whose tip can be inserted and kept in direct apposition to the scleral surface.
  • 10. The method of claim 9, wherein the administering step comprises inserting and keeping the tip of the cannula in direct apposition to the scleral surface.
  • 11. The method of any one of claims 1-10, wherein the therapeutic product is not an anti-human vascular endothelial growth factor (hVEGF) antibody.
  • 12. The method of any one of claims 1-11, wherein the pathology of the eye is not associated with neovascular age-related macular degeneration (nAMD).
  • 13. A method of subretinal administration accompanied by vitrectomy for treating a pathology of the eye, comprising administering to the subretinal space in the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method comprises performing a vitrectomy on the eye of said human patient, and wherein the therapeutic product is not anti-human vascular endothelial growth factor (hVEGF) antibody.
  • 14. The method of claim 13, wherein the vitrectomy is a partial vitrectomy.
  • 15. A method of subretinal administration for treating a pathology of the eye, comprising administering to the subretinal space peripheral to the optic disc, fovea and macula located in the back of the eye of a human subject in need of treatment a recombinant viral vector comprising a nucleotide sequence encoding a therapeutic product such that the therapeutic product is expressed and results in treatment of the pathology of the eye, wherein the method does not comprise performing a vitrectomy on the eye of said human patient.
  • 16. The method of claim 15, wherein the administering step is by transvitreal injection.
  • 17. The method of claim 16, wherein the transvitreal injection comprises inserting a sharp needle into the sclera via the superior or inferior side of the eye and passing the sharp needle all the way through the vitreous to inject the recombinant viral vector to the subretinal space on the other side.
  • 18. The method of claim 16, wherein the transvitreal injection comprises inserting a trochar into the sclera and inserting a cannula through the trochar and through the vitreous to inject the recombinant viral vector to the subretinal space on the other side.
  • 19. The method of any one of claims 15-18, wherein the therapeutic product is an anti-hVEGF antibody.
  • 20. The method of claim 19, wherein the anti-hVEGF antibody is an anti-hVEGF antigen-binding fragment.
  • 21. The method of claim 20, wherein the anti-hVEGF antigen-binding fragment is a Fab, F(ab′)2, or single chain variable fragment (scFv).
  • 22. The method of any one of claims 19-21, wherein the anti-hVEGF antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4, and a light chain comprising the amino acid sequence of SEQ ID NO:1, or SEQ ID NO:3.
  • 23. The method of any one of claims 19-21, wherein the anti-hVEGF antibody comprises light chain CDRs 1-3 of SEQ ID NOs:14-16 and heavy chain CDRs 1-3 of SEQ ID NOs:17-19 or SEQ ID NOs:20, 18, and 21.
  • 24. The method of any one of claims 19-23, wherein the pathology of the eye is associated with nAMD, dry age-related macular degeneration (dry AMD), retinal vein occlusion (RVO), diabetic macular edema (DME), or diabetic retinopathy (DR).
  • 25. The method of any one of claims 19-23, wherein the pathology of the eye is associated with nAMD.
  • 26. The method of any one of claims 1-11 and 13-18, wherein: (1) the pathology of the eye is associated with Batten-CLN1 and the therapeutic product is Palmitoyl-Protein Thioesterase 1 (PPT1);(2) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1);(3) the pathology of the eye is associated with Batten-CLN3 and the therapeutic product is Battenin (CLN3);(4) the pathology of the eye is associated with Batten-CLN6 and the therapeutic product is CLN6 Transmembrane ER Protein (CLN6);(5) the pathology of the eye is associated with Batten-CLN7 and the therapeutic product is Major Facilitator Superfamily Domain Containing 8 (MFSD8);(6) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Myosin VIIA (MYO7A);(7) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Cadherin Related 23 (CDH23);(8) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Protocadherin Related 15 (PCDH15);(9) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Usherin (USH2A);(10) the pathology of the eye is associated with Usher's-Type 3 and the therapeutic product is Clarin 1 (CLRN1);(11) the pathology of the eye is associated with Stargardt's and the therapeutic product is ATP Binding Cassette Subfamily A Member 4 (ABCA4);(12) the pathology of the eye is associated with Stargardt's and the therapeutic product is ELOVL Fatty Acid Elongase 4 (ELOVL4);(13) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-Interleukin 6 (IL6) monoclonal antibody;(14) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF-alpha (TNF) monoclonal antibody;(15) the pathology of the eye is associated with diabetic macular edema (DME) and the therapeutic product is an anti-IL6 monoclonal antibody;(16) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);(17) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);(18) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);(19) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D);(20) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65);(21) the pathology of the eye is associated with LCA 3 and the therapeutic product is Spermatogenesis Associated 7 (SPATA7);(22) the pathology of the eye is associated with Leber congenital amaurosis-4 (LCA 4) and the therapeutic product is Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1);(23) the pathology of the eye is associated with Leber congenital amaurosis-5 (LCA 5) and the therapeutic product is Lebercilin (LCA5);(24) the pathology of the eye is associated with Leber congenital amaurosis-6 (LCA 6) and the therapeutic product is RPGR Interacting Protein 1 (RPGRIP1);(25) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX);(26) the pathology of the eye is associated with Leber congenital amaurosis-8 (LCA 8) and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);(27) the pathology of the eye is associated with Leber congenital amaurosis-9 (LCA 9) and the therapeutic product is Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1);(28) the pathology of the eye is associated with Leber congenital amaurosis-10 (LCA 10) and the therapeutic product is Centrosomal Protein 290 (CEP290);(29) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1);(30) the pathology of the eye is associated with Leber congenital amaurosis-12 (LCA 12) and the therapeutic product is Retinal Degeneration 3, GUCY2D regulator (RD3);(31) the pathology of the eye is associated with Leber congenital amaurosis-13 (LCA 13) and the therapeutic product is Retinol Dehydrogenase 12 (RDH12);(32) the pathology of the eye is associated with Leber congenital amaurosis-14 (LCA 14) and the therapeutic product is Lecithin Retinol Acyltransferase (LRAT);(33) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1);(34) the pathology of the eye is associated with Leber congenital amaurosis-16 (LCA 16) and the therapeutic product is Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13);(35) the pathology of the eye is associated with Leber's hereditary optic neuropathy (LHON) and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1);(36) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4);(37) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6);(38) the pathology of the eye is associated with neuromyelitis optica (NMO) and the therapeutic product is an anti-complement C5 monoclonal antibody;(39) the pathology of the eye is associated with NMO and the therapeutic product is an anti-IL6 monoclonal antibody;(40) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement C5 monoclonal antibody;(41) the pathology of the eye is associated with uveitis and the therapeutic product is Angiotensin I Converting Enzyme (ACE);(42) the pathology of the eye is associated with uveitis and the therapeutic product is Interleukin 10 (IL10);(43) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF monoclonal antibody;(44) the pathology of the eye is associated with choroideremia and the therapeutic product is Rab Escort Protein 1 (CHM);(45) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1);(46) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1);(47) the pathology of the eye is associated with Bardet-Biedl syndrome 2 and the therapeutic product is Bardet-Biedl Syndrome 2 (BBS2);(48) the pathology of the eye is associated with Bardet-Biedl syndrome 3 and the therapeutic product is ADP Ribosylation Factor Like GTPase 6 (ARL6);(49) the pathology of the eye is associated with Bardet-Biedl syndrome 4 and the therapeutic product is Bardet-Biedl Syndrome 4 (BBS4);(50) the pathology of the eye is associated with Bardet-Biedl syndrome 5 and the therapeutic product is Bardet-Biedl Syndrome 5 (BBS5);(51) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS);(52) the pathology of the eye is associated with Bardet-Biedl syndrome 7 and the therapeutic product is Bardet-Biedl Syndrome 7 (BBS7);(53) the pathology of the eye is associated with Bardet-Biedl syndrome 8 and the therapeutic product is Tetratricopeptide Repeat Domain 8 (TTC8);(54) the pathology of the eye is associated with Bardet-Biedl syndrome 9 and the therapeutic product is Bardet-Biedl Syndrome 9 (BBS9);(55) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10);(56) the pathology of the eye is associated with Bardet-Biedl syndrome 11 and the therapeutic product is Tripartite Motif Containing 32 (TRIM32);(57) the pathology of the eye is associated with Bardet-Biedl syndrome 12 and the therapeutic product is Bardet-Biedl Syndrome 12 (BBS12);(58) the pathology of the eye is associated with Bardet-Biedl syndrome 13 and the therapeutic product is MKS Transition Zone Complex Subunit 1 (MKS1);(59) the pathology of the eye is associated with Bardet-Biedl syndrome 14 and the therapeutic product is Centrosomal Protein 290 (CEP290);(60) the pathology of the eye is associated with Bardet-Biedl syndrome 15 and the therapeutic product is WD Repeat Containing Planar Cell Polarity Effector (WDPCP);(61) the pathology of the eye is associated with Bardet-Biedl syndrome 16 and the therapeutic product is Serologically Defined Colon Cancer Antigen 8 (SDCCAG8);(62) the pathology of the eye is associated with Bardet-Biedl syndrome 17 and the therapeutic product is Leucine Zipper Transcription Factor Like 1 (LZTFL1);(63) the pathology of the eye is associated with Bardet-Biedl syndrome 18 and the therapeutic product is BBSome Interacting Protein 1 (BBIP1);(64) the pathology of the eye is associated with Bardet-Biedl syndrome 19 and the therapeutic product is Intraflagellar Transport 27 (IFT27);(65) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A);(66) the pathology of the eye is associated with optic atrophy and the therapeutic product is OPA1 Mitochondrial Dynamin Like GTPase (OPA1);(67) the pathology of the eye is associated with retinitis pigmentosa 1 and the therapeutic product is RP1 Axonemal Microtubule Associated (RP1);(68) the pathology of the eye is associated with retinitis pigmentosa 2 and the therapeutic product is RP2 Activator of ARL3 GTPase (RP2);(69) the pathology of the eye is associated with retinitis pigmentosa 7 and the therapeutic product is Peripherin 2 (PRPH2);(70) the pathology of the eye is associated with retinitis pigmentosa 11 and the therapeutic product is Pre-mRNA Processing Factor 31(PRPF31);(71) the pathology of the eye is associated with retinitis pigmentosa 12 and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);(72) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8);(73) the pathology of the eye is associated with retinitis pigmentosa 25 and the therapeutic product is Eyes Shut Homolog (EYS);(74) the pathology of the eye is associated with retinitis pigmentosa 28 and the therapeutic product is FAM161 Centrosomal Protein A (FAM161A);(75) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3);(76) the pathology of the eye is associated with retinitis pigmentosa 38 and the therapeutic product is MER Proto-Oncogene, Tyrosine Kinase (MERTK);(77) the pathology of the eye is associated with retinitis pigmentosa 40 and the therapeutic product is Phosphodiesterase 6B (PDE6B);(78) the pathology of the eye is associated with retinitis pigmentosa 41 and the therapeutic product is Prominin 1 (PROM1);(79) the pathology of the eye is associated with retinitis pigmentosa 43 and the therapeutic product is Phosphodiesterase 6A (PDE6A);(80) the pathology of the eye is associated with retinitis pigmentosa 56 and the therapeutic product is Interphotoreceptor Matrix Proteoglycan 2 (IMPG2);(81) the pathology of the eye is associated with petinitis pigmentosa 62 and the therapeutic product is Male Germ Cell Associated Kinase (MAK);(82) the pathology of the eye is associated with retinitis pigmentosa 80 and the therapeutic product is Intraflagellar Transport 140 (IFT140);(83) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-complement C5 monoclonal antibody;(84) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-membrane attack complex (MAC) monoclonal antibody;(85) the pathology of the eye is associated with dry AMD and the therapeutic product is HtrA Serine Peptidase 1 (HTRA1);(86) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1);(87) the pathology of the eye is associated with dry AMD and the therapeutic product is a complement factor B anti sense oligonucleotide;(88) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-beta-amyloid monoclonal antibody;(89) the pathology of the eye is associated with dry AMD and the therapeutic product is CD59 glycoprotein (CD59);(90) the pathology of the eye is associated with dry AMD and the therapeutic product is Channelrhodopsin-1 (ChR1);(91) the pathology of the eye is associated with dry AMD and the therapeutic product is Channelrhodopsin-2 (ChR2), the light-sensitive protein discovered in Chlamydomonas reinhardtii; (92) the pathology of the eye is associated with dry AMD and the therapeutic product is an anti-complement factor C5a aptamer;(93) the pathology of the eye is associated with dry AMD and the therapeutic product is anti-complement factor D monoclonal antibody;(94) the pathology of the eye is associated with age-related retinal ganglion cell (RGC) degeneration and the therapeutic product is DnaJ heat shock protein family (Hsp40) member C3 (DNAJC3);(95) the pathology of the eye is associated with blue cone monochromacy (BCM) and the therapeutic product is L opsin (OPN1LW);(96) the pathology of the eye is associated with glaucoma and the therapeutic product is beta-2 adrenoceptor siRNA;(97) the pathology of the eye is associated with glaucoma and the therapeutic product is Caspase-2 (CASP2);(98) the pathology of the eye is associated with glaucoma and the therapeutic product is Insulin Receptor Substrate 1 (IRS1);(99) the pathology of the eye is associated with glaucoma and the therapeutic product is HIF-1 Responsive Protein RTP801 (RTP801);(100) the pathology of the eye is associated with glaucoma and the therapeutic product is Transforming Growth Factor Beta 2 (TGFB2);(101) the pathology of the eye is associated with glaucoma and the therapeutic product is Brain Derived Neurotrophic Factor (BDNF);(102) the pathology of the eye is associated with glaucoma and the therapeutic product is Ciliary Neurotrophic Factor (CNTF);(103) the pathology of the eye is associated with glaucoma and the therapeutic product is Prostaglandin-Endoperoxide Synthase 2 (PTGS2);(104) the pathology of the eye is associated with glaucoma and the therapeutic product is Prostaglandin F Receptor (PTGFR);(105) the pathology of the eye is associated with glaucoma and the therapeutic product is a hyaluronidase;(106) the pathology of the eye is associated with glaucoma and the therapeutic product is Pigment Epithelium-Derived Factor (PEDF);(107) the pathology of the eye is associated with glaucoma and the therapeutic product is Vascular Endothelial Growth Factor (VEGF);(108) the pathology of the eye is associated with glaucoma and the therapeutic product is Placental Growth Factor (PGF);(109) the pathology of the eye is associated with glaucoma and the therapeutic product is Myocilin (MYOC);(110) the pathology of the eye is associated with NMO and the therapeutic product is an anti-complement C5 monoclonal antibody;(111) the pathology of the eye is associated with NMO and the therapeutic product is C-C Motif Chemokine Receptor 5 (CCR5) siRNA;(112) the pathology of the eye is associated with NMO and the therapeutic product is an anti-CD19 monoclonal antibody;(113) the pathology of the eye is associated with retinitis pigmentosa that is associated with rhodopsin mutations and the therapeutic product is Channelrhodopsin-1 (ChR1);(114) the pathology of the eye is associated with retinitis pigmentosa that is associated with rhodopsin mutations and the therapeutic product is Channelrhodopsin-2 (ChR2);(115) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Ciliary Neurotrophic Factor (CNTF);(116) the pathology of the eye is associated with autosomal recessive retinitis pigmentosa and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);(117) the pathology of the eye is associated with autosomal recessive retinitis pigmentosa and the therapeutic product is Crumbs Cell Polarity Complex Component 2 (CRB2);(118) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Histone Deacetylase 4 (HDAC4);(119) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rhodopsin (RHO);(120) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Nerve Growth Factor (NGF);(121) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Nuclear Factor, Erythroid 2 Like 2 (NRF2);(122) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Pigment Epithelium-Derived Factor (PEDF);(123) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Glutathione S-Transferase PI 1 (GSTP1);(124) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rod-Derived Cone Viability Factor (RDCVF);(125) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Rhodopsin (RHO);(126) the pathology of the eye is associated with retinitis pigmentosa and the therapeutic product is Retinaldehyde Binding Protein 1 (RLBP1);(127) the pathology of the eye is associated with Stargardt's disease and the therapeutic product is an anti-complement C5 aptamer;(128) the pathology of the eye is associated with uveitis and the therapeutic product is Double Homeobox 4 (DUX4);(129) the pathology of the eye is associated with uveitis and the therapeutic product is NLR Family Pyrin Domain Containing 3 (NLRP3);(130) the pathology of the eye is associated with uveitis and the therapeutic product is Spleen Associated Tyrosine Kinase (SYK);(131) the pathology of the eye is associated with uveitis and the therapeutic product is Adrenocorticotropic Hormone (ACTH);(132) the pathology of the eye is associated with uveitis and the therapeutic product is Caspase 1 (CASP1);(133) the pathology of the eye is associated with uveitis and the therapeutic product is anti-CD59 monoclonal antibody;(134) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement C5 aptamer;(135) the pathology of the eye is associated with corneal neovascularization and the therapeutic product is Insulin Receptor Substrate 1 (IRS1);(136) the pathology of the eye is associated with corneal neovascularization and the therapeutic product is NOTCH Regulated Ankyrin Repeat Protein (NRARP);(137) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is NOTCH Regulated Ankyrin Repeat Protein (NRARP);(138) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Alpha-2-Antiplasmin (A2AP);(139) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Plasminogen (PLG);(140) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is a growth hormone;(141) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Insulin Like Growth Factor 1 (IGF1);(142) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Interleukin 1 Beta (IL1B).(143) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is Angiotensin I Converting Enzyme 2 (ACE2);(144) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is IRS1;(145) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is an anti-integrin oligopeptide;(146) the pathology of the eye is associated with diabetic retinopathy and the therapeutic product is an anti-Placental Growth Factor (PGF) monoclonal antibody;(147) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-CD40 monoclonal antibody;(148) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-Insulin-Like Growth Factor 1 Receptor (IGF1R) monoclonal antibody;(149) the pathology of the eye is associated with Graves' ophthalmopathy and the therapeutic product is an anti-Insulin-Like Growth Factor 2 Receptor (IGF2R) monoclonal antibody;(150) the pathology of the eye is associated with DME and the therapeutic product is an anti-integrin oligopeptide;(151) the pathology of the eye is associated with DME and the therapeutic product is an anti-Placental Growth Factor (PGF) monoclonal antibody;(152) the pathology of the eye is associated with DME and the therapeutic product is RTP801 siRNA;(153) the pathology of the eye is associated with multiple sclerosis (MS)-associated vision loss and the therapeutic product is ND1;(154) the pathology of the eye is associated with myopia and the therapeutic product is Matrix Metalloproteinase 2 (MMP2) RNAi;(155) the pathology of the eye is associated with X-linked recessive ocular albinism and the therapeutic product is G-Protein Coupled Receptor 143 (GPR143);(156) the pathology of the eye is associated with oculocutaneous albinism type 1 and the therapeutic product is Tyrosinase (TYR);(157) the pathology of the eye is associated with optic neuritis and the therapeutic product is Caspase 2 (CASP2);(158) the pathology of the eye is associated with optic neuritis and the therapeutic product is an anti-Leucine Rich Repeat And Ig Domain Containing Protein 1 (LINGO1) monoclonal antibody; or(159) the pathology of the eye is associated with polypoidal choroidal vasculopathy and the therapeutic product is an anti-complement C5 aptamer.
  • 27. The method of any one of claims 1-11 and 15-18, wherein: (1) the pathology of the eye is associated with X-linked retinitis pigmentosa (XLRP) and the therapeutic product is Retinitis Pigmentosa GTPase Regulator (RPGR); (2) the pathology of the eye is associated with achromatopsia (ACHM) and the therapeutic product is Cyclic Nucleotide Gated Channel Beta 3 (CNGB3);(3) the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3); or(4) the pathology of the eye is associated with biallelic RPE65 mutation-associated retinal dystrophy and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65).
  • 28. The method of any one of claims 1-11 and 13-18, wherein: (1) the pathology of the eye is associated with Batten-CLN1 and the therapeutic product is Palmitoyl-Protein Thioesterase 1 (PPT1);(2) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1);(3) the pathology of the eye is associated with Batten-CLN3 and the therapeutic product is Battenin (CLN3);(4) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-Interleukin 6 (IL6) monoclonal antibody;(5) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF-alpha (TNF) monoclonal antibody;(6) the pathology of the eye is associated with diabetic macular edema (DME) and the therapeutic product is an anti-IL6 monoclonal antibody;(7) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);(8) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);(9) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);(10) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D);(11) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65);(12) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX);(13) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1);(14) the pathology of the eye is associated with Leber congenital amaurosis-12 (LCA 12) and the therapeutic product is Retinal Degeneration 3, GUCY2D regulator (RD3);(15) the pathology of the eye is associated with Leber congenital amaurosis-13 (LCA 13) and the therapeutic product is Retinol Dehydrogenase 12 (RDH12);(16) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1);(17) the pathology of the eye is associated with Leber congenital amaurosis-16 (LCA 16) and the therapeutic product is Potassium Voltage-Gated Channel Subfamily J Member 13 (KCNJ13);(18) the pathology of the eye is associated with Leber's hereditary optic neuropathy (LHON) and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 1 (MT-ND1);(19) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4);(20) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6);(21) the pathology of the eye is associated with neuromyelitis optica (NMO) and the therapeutic product is an anti-complement C5 monoclonal antibody;(22) the pathology of the eye is associated with NMO and the therapeutic product is an anti-IL6 monoclonal antibody;(23) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-complement C5 monoclonal antibody;(24) the pathology of the eye is associated with uveitis and the therapeutic product is Angiotensin I Converting Enzyme (ACE);(25) the pathology of the eye is associated with uveitis and the therapeutic product is Interleukin 10 (IL10);(26) the pathology of the eye is associated with uveitis and the therapeutic product is an anti-TNF monoclonal antibody;(27) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1);(28) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1);(29) the pathology of the eye is associated with Bardet-Biedl syndrome 3 and the therapeutic product is ADP Ribosylation Factor Like GTPase 6 (ARL6);(30) the pathology of the eye is associated with Bardet-Biedl syndrome 5 and the therapeutic product is Bardet-Biedl Syndrome 5 (BBS5);(31) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS);(32) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10);(33) the pathology of the eye is associated with Bardet-Biedl syndrome 11 and the therapeutic product is Tripartite Motif Containing 32 (TRIM32);(34) the pathology of the eye is associated with Bardet-Biedl syndrome 13 and the therapeutic product is MKS Transition Zone Complex Subunit 1 (MKS1);(35) the pathology of the eye is associated with Bardet-Biedl syndrome 18 and the therapeutic product is BBSome Interacting Protein 1 (BBIP1);(36) the pathology of the eye is associated with Bardet-Biedl syndrome 19 and the therapeutic product is Intraflagellar Transport 27 (IFT27);(37) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A);(38) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8);(39) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3); or(40) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1).
  • 29. The method of any one of claims 1-11 and 15-18, wherein: (1) the pathology of the eye is associated with biallelic RPE65 mutation-associated retinal dystrophy and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65).
  • 30. The method of any one of claims 1-11 and 13-18, wherein: (1) the pathology of the eye is associated with Batten-CLN2 and the therapeutic product is Tripeptidyl-Peptidase 1 (TPP1);(2) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Myosin VIIA (MYO7A);(3) the pathology of the eye is associated with Usher's-Type 1 and the therapeutic product is Cadherin Related 23 (CDH23);(4) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Protocadherin Related 15 (PCDH15);(5) the pathology of the eye is associated with Usher's-Type 2 and the therapeutic product is Usherin (USH2A);(6) the pathology of the eye is associated with Usher's-Type 3 and the therapeutic product is Clarin 1 (CLRN1);(7) the pathology of the eye is associated with Stargardt's and the therapeutic product is ATP Binding Cassette Subfamily A Member 4 (ABCA4);(8) the pathology of the eye is associated with Stargardt's and the therapeutic product is ELOVL Fatty Acid Elongase 4 (ELOVL4);(9) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);(10) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);(11) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);(12) the pathology of the eye is associated with Leber congenital amaurosis-1 (LCA 1) and the therapeutic product is Guanylate Cyclase 2D, Retinal (GUCY2D);(13) the pathology of the eye is associated with Leber congenital amaurosis-2 (LCA 2) and the therapeutic product is Retinoid Isomerohydrolase RPE65 (RPE65);(14) the pathology of the eye is associated with Leber congenital amaurosis-4 (LCA 4) and the therapeutic product is Aryl Hydrocarbon Receptor Interacting Protein Like 1 (AIPL1);(15) the pathology of the eye is associated with Leber congenital amaurosis-7 (LCA 7) and the therapeutic product is Cone-Rod Homeobox (CRX);(16) the pathology of the eye is associated with Leber congenital amaurosis-8 (LCA 8) and the therapeutic product is Crumbs Cell Polarity Complex Component 1 (CRB1);(17) the pathology of the eye is associated with Leber congenital amaurosis-9 (LCA 9) and the therapeutic product is Nicotinamide Nucleotide Adenylyltransferase 1 (NMNAT1);(18) the pathology of the eye is associated with Leber congenital amaurosis-10 (LCA 10) and the therapeutic product is Centrosomal Protein 290 (CEP290);(19) the pathology of the eye is associated with Leber congenital amaurosis-11 (LCA 11) and the therapeutic product is Inosine Monophosphate Dehydrogenase 1 (IMPDH1);(20) the pathology of the eye is associated with Leber congenital amaurosis-15 (LCA 15) and the therapeutic product is Tubby Like Protein 1 (TULP1);(21) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 4 (MT-ND4);(22) the pathology of the eye is associated with LHON and the therapeutic product is Mitochondrially Encoded NADH Dehydrogenase 6 (MT-ND6);(23) the pathology of the eye is associated with choroideremia and the therapeutic product is Rab Escort Protein 1 (CHM);(24) the pathology of the eye is associated with X-linked retinoschisis (XLRS) and the therapeutic product is Retinoschisin (RS1);(25) the pathology of the eye is associated with Bardet-Biedl syndrome 1 and the therapeutic product is Bardet-Biedl Syndrome 1 (BBS1);(26) the pathology of the eye is associated with Bardet-Biedl syndrome 6 and the therapeutic product is McKusick-Kaufman Syndrome (MKKS);(27) the pathology of the eye is associated with Bardet-Biedl syndrome 10 and the therapeutic product is Bardet-Biedl Syndrome 10 (BBS10);(28) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A);(29) the pathology of the eye is associated with optic atrophy and the therapeutic product is OPA1 Mitochondrial Dynamin Like GTPase (OPA1);(30) the pathology of the eye is associated with retinitis pigmentosa 1 and the therapeutic product is RP1 Axonemal Microtubule Associated (RP1);(31) the pathology of the eye is associated with retinitis pigmentosa 2 and the therapeutic product is RP2 Activator of ARL3 GTPase (RP2);(32) the pathology of the eye is associated with retinitis pigmentosa 7 and the therapeutic product is Peripherin 2 (PRPH2);(33) the pathology of the eye is associated with retinitis pigmentosa 11 and the therapeutic product is Pre-mRNA Processing Factor 31(PRPF31);(34) the pathology of the eye is associated with retinitis pigmentosa 13 and the therapeutic product is Pre-mRNA Processing Factor 8 (PRPF8);(35) the pathology of the eye is associated with retinitis pigmentosa 37 and the therapeutic product is Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3);(36) the pathology of the eye is associated with retinitis pigmentosa 38 and the therapeutic product is MER Proto-Oncogene, Tyrosine Kinase (MERTK);(37) the pathology of the eye is associated with retinitis pigmentosa 40 and the therapeutic product is Phosphodiesterase 6B (PDE6B);(38) the pathology of the eye is associated with retinitis pigmentosa 41 and the therapeutic product is Prominin 1 (PROM1);(39) the pathology of the eye is associated with retinitis pigmentosa 56 and the therapeutic product is Interphotoreceptor Matrix Proteoglycan 2 (IMPG2);(40) the pathology of the eye is associated with petinitis pigmentosa 62 and the therapeutic product is Male Germ Cell Associated Kinase (MAK);(41) the pathology of the eye is associated with retinitis pigmentosa 80 and the therapeutic product is Intraflagellar Transport 140 (IFT140); or(42) the pathology of the eye is associated with Best disease and the therapeutic product is Bestrophin 1 (BEST1).
  • 31. The method of any one of claims 1-11 and 15-18, wherein: (1) the pathology of the eye is associated with X-linked retinitis pigmentosa (XLRP) and the therapeutic product is Retinitis Pigmentosa GTPase Regulator (RPGR);(2) the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Beta 3 (CNGB3); or(3) the pathology of the eye is associated with achromatopsia and the therapeutic product is Cyclic Nucleotide Gated Channel Alpha 3 (CNGA3).
  • 32. The method of any one of claims 1-31, wherein the recombinant viral vector further comprises a nucleotide sequence encoding a promoter or an enhancer-promoter, which nucleotide sequence encoding the promoter or enhancer-promoter is operably linked to the nucleotide sequence encoding the therapeutic product, and wherein the promoter or enhancer-promoter is: (1) a CAG promoter;(2) a CBA promoter;(3) a CMV promoter;(4) a PR1.7 promoter;(5) a Rhodopsin Kinase (GRK1) photoreceptor-specific enhancer-promoter;(6) an hCARp promoter;(7) an hRKp;(8) a cone photoreceptor specific human arrestin 3 (ARR3) promoter;(9) a rhodopsin promoter; or(10) a U6 promoter.
  • 33. The method of any one of claims 1-11 and 13-15, wherein the recombinant viral vector further comprises a nucleotide sequence encoding a cone-specific promoter, which nucleotide sequence encoding the cone-specific promoter is operably linked to the nucleotide sequence encoding the therapeutic product, and wherein: (1) the pathology of the eye is associated with red-green color blindness and the therapeutic product is L opsin (OPN1LW);(2) the pathology of the eye is associated with red-green color blindness and the therapeutic product is M opsin (OPN1MW);(3) the pathology of the eye is associated with blue cone monochromacy and the therapeutic product is M opsin (OPN1MW);(4) the pathology of the eye is associated with cone dystrophy and the therapeutic product is Guanylate Cyclase Activator 1A (GUCA1A); or(5) the pathology of the eye is associated with blue cone monochromacy (BCM) and the therapeutic product is L opsin (OPN1LW).
  • 34. The method of any one of claims 1-33, wherein the administering step delivers a therapeutically effective amount of the therapeutic product to the retina of said human subject.
  • 35. The method of claim 34, wherein the therapeutically effective amount of the therapeutic product is produced by human retinal cells of said human subject.
  • 36. The method of claim 34, wherein the therapeutically effective amount of the therapeutic product is produced by human photoreceptor cells, horizontal cells, bipolar cells, amacrine cells, retina ganglion cells, and/or retinal pigment epithelial cells in the external limiting membrane of said human subject.
  • 37. The method of claim 36, wherein the human photoreceptor cells are cone cells and/or rod cells.
  • 38. The method of claim 36, wherein the retina ganglion cells are midget cells, parasol cells, bistratified cells, giant retina ganglion cells, photosensitive ganglion cells, and/or Müller glia.
  • 39. The method of any one of claims 1-38, wherein the recombinant viral vector is an rAAV vector.
  • 40. The method of claim 39, wherein the recombinant viral vector is an rAAV8 vector.
  • 41. The method of any one of claims 1-40, which further comprises, after the administering step, a step of monitoring the post ocular injection thermal profile of the injected material in the eye using an infrared thermal camera.
  • 42. The method of claim 41, wherein the infrared thermal camera is an FLIR T530 infrared thermal camera.
  • 43. The method of any one of claims 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 6.0×1010 genome copies per eye.
  • 44. The method of any one of claims 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 1.6×1011 genome copies per eye.
  • 45. The method of any one of claims 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 2.5×1011 genome copies per eye.
  • 46. The method of any one of claims 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 5.0×1011 genome copies per eye.
  • 47. The method of any one of claims 1-43, wherein the recombinant nucleotide expression vector is administered at a dose about 3.0×1012 genome copies per eye.
1. CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application Nos. 62/828,949, filed Apr. 3, 2019, 62/856,533, filed Jun. 3, 2019, and 62/946,158, filed Dec. 10, 2019, which are incorporated by reference herein in their entireties.

PCT Information
Filing Document Filing Date Country Kind
PCT/US2020/026356 4/2/2020 WO 00
Provisional Applications (3)
Number Date Country
62828949 Apr 2019 US
62856533 Jun 2019 US
62946158 Dec 2019 US