MODULATION OF TIMP1 AND TIMP2 EXPRESSION

Abstract

Provided herein are compositions, methods and kits for modulating expression of target genes, particularly of tissue inhibitor of metalloproteinase 1 and of tissue inhibitor of metalloproteinase 2 (TIMP1 and TIMP2, respectively). The compositions, methods and kits may include nucleic acid molecules (for example, short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA) or short hairpin RNA (shRNA)) that modulate a gene encoding TIMP1 and TIMP2, for example, the gene encoding human TIMP1 and TIMP2. The composition and methods disclosed herein may also be used in treating conditions and disorders associated with TIMP1 and TIMP2 including fibrotic diseases and disorders including liver fibrosis, pulmonary fibrosis, peritoneal fibrosis and kidney fibrosis.

Description

SEQUENCE LISTING

The instant application contains a Sequence Listing which is entitled 224-PCT1_ST25.txt, said ASCII copy, created on Aug. 24, 2011 and is 910 kb in size, is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

Provided herein are compositions and methods for modulating expression of TIMP1 and TIMP2.

BACKGROUND OF THE INVENTION

Sato, Y., et al. disclose the administration of vitamin A-coupled liposomes to deliver small interfering RNA (siRNA) against gp46, the rat homolog of human heat shock protein 47, to liver cirrhosis rat animal models. Sato, Y., et al., Nature Biotechnology, vol. 26(4), p. 431-442 (2008).

Chen, J-J., et al. disclose transfecting human keloid samples with HSP-47-shRNA (small hairpin RNA) to examine proliferation of keloid fibroblast cells. Chen, J-J., et al., British Journal of Dermatology, vol. 156, p. 1188-1195 (2007).

PCT Patent Publication No. WO 2006/068232 discloses an astrocyte specific drug carrier which includes a retinoid derivative and/or a vitamin A analog.

PCT Patent Publication Nos. WO 2008/104978 and WO 2007/091269 disclose siRNA structures and compounds.

PCT Patent Publication No. WO 2011/072082 discloses double stranded RNA compounds targeting HSP47 (SERPINH1).

SUMMARY OF THE INVENTION

Compositions, methods and kits for modulating expression of target genes are provided herein. In various aspects and embodiments, compositions, methods and kits provided herein modulate expression of tissue inhibitor of metalloproteinases 1 and tissue inhibitor of metalloproteinases 2 also known as TIMP1 and TIMP2, respectively. The compositions, methods and kits may involve use of nucleic acid molecules (for example, short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA) or short hairpin RNA (shRNA)) that bind a nucleotide sequence (such as an mRNA sequence) encoding TIMP1 and TIMP2, for example, the mRNA coding sequence for human TIMP1 exemplified by SEQ ID NO:1 and the mRNA coding sequence for human TIMP2 exemplified by SEQ ID NO:2. In certain preferred embodiments, the compositions, methods and kits disclosed herein inhibit expression of TIMP1 or TIMP2. For example, siNA molecules (e.g., RISC length dsNA molecules or Dicer length dsNA molecules) are provided that down regulate, reduce or inhibit TIMP1 or TIMP2 expression. Also provided are compositions, methods and kits for treating and/or preventing diseases, conditions or disorders associated with TIMP1 and TIMP2, including organ specific fibrosis associated with at least one of brain, skin fibrosis, lung fibrosis, liver fibrosis, kidney fibrosis, heart fibrosis, vascular fibrosis, bone marrow fibrosis, eye fibrosis, intestinal fibrosis, vocal cord fibrosis or other fibrosis. Specific indications include liver fibrosis, cirrhosis, pulmonary fibrosis including Interstitial lung fibrosis (ILF), kidney fibrosis resulting from any condition (e.g., CKD including ESRD), peritoneal fibrosis, chronic hepatic damage, fibrillogenesis, fibrotic diseases in other organs, abnormal scarring (keloids) associated with all possible types of skin injury accidental and jatrogenic (operations); scleroderma; cardiofibrosis, failure of glaucoma filtering operation; brain fibrosis associated with cerebral infarction; and intestinal adhesions and Crohn's disease. The compounds are useful in treating organ specific indications including those shown in Table I infra.

In one aspect, provided are nucleic acid molecules (e.g., siNA molecules) in which (a) the nucleic acid molecule includes a sense strand (passenger strand) and an antisense strand (guide strand); (b) each strand of the nucleic acid molecule is independently 15 to 49 nucleotides in length; (c) a 15 to 49 nucleotide sequence of the antisense strand is complementary to a sequence of an mRNA encoding a human TIMP (e.g., SEQ ID NO: 1 or SEQ ID NO:2); and (d) a 15 to 49 nucleotide sequence of the sense strand is complementary to the sequence of the antisense strand and includes a 15 to 49 nucleotide sequence of an mRNA encoding human TIMP1 or TIMP2 (e.g., SEQ ID NO: 1 or SEQ ID NO:2, respectively). In various embodiments the sense and antisense strands generate a 15 to 49 base pair duplex.

In certain embodiments, the sequence of the antisense strand that is complementary to a sequence of an mRNA encoding human TIMP1 includes a sequence complimentary to a sequence between nucleotides 193-813 or 1-192; or 813-893 of SEQ ID NO: 1; or between nucleotides 1-200; or 800-893 of SEQ ID NO: 1.

In certain embodiments the sequence of the antisense comprises an antisense sequence set forth in any one of Tables A1-A8 or C. In preferred embodiments the sequence of the antisense comprises an antisense sequence set forth in Tables A3, A4, A7, A8, or C. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table A3 or Table A4. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table A7 or Table A8. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table C.

In certain embodiments, the sequence of the antisense strand that is complementary to a sequence of an mRNA encoding human TIMP2 includes a sequence complimentary to a sequence between nucleotides 303-962 or 1-303; or 962-3369; of SEQ ID NO: 2; or between nucleotides 1-350; or 950-3369 of SEQ ID NO: 2.

In certain embodiments the sequence of the antisense comprises an antisense sequence set forth in any one of Tables B1-B8 or D. In preferred embodiments the sequence of the antisense comprises an antisense sequence set forth in Tables B3, B4, B7, B8, D. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table B3 or Table B4. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table B7 or Table B8. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in Table D.

In some embodiments, the antisense strand includes a sequence that is complementary to a sequence of an mRNA encoding human TIMP1 corresponding to nucleotides 355-373 of SEQ ID NO: 1 or a portion thereof; or nucleotides 620-638 of SEQ ID NO: 1 or a portion thereof; or nucleotides 640-658 of SEQ ID NO: 1 or a portion thereof.

In some embodiments, the antisense strand includes a sequence that is complementary to a sequence of an mRNA encoding human TIMP2 corresponding to nucleotides 421-439 of SEQ ID NO: 2 or a portion thereof; or nucleotides 502-520 of SEQ ID NO: 2 or a portion thereof; or nucleotides 523-541 of SEQ ID NO: 2 or a portion thereof; or nucleotides 625-643 of SEQ ID NO: 2 or a portion thereof; or nucleotides 629-647 of SEQ ID NO: 2 or a portion thereof.

In some embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown in Table A1 or A5. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table A1. In certain preferred embodiments the antisense strand and the sense strand are selected from the sequence pairs shown in Table A5. In some preferred embodiments the antisense and sense strands are selected from the sequence pairs shown in Table A3 or Table A7.

In certain embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown in Table C.

In various embodiments of nucleic acid molecules (e.g., siNA molecules) as disclosed herein, the antisense strand may be 15 to 49 nucleotides in length (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49 nucleotides in length); or 17-35 nucleotides in length; or 17-30 nucleotides in length; or 15-25 nucleotides in length; or 18-25 nucleotides in length; or 18-23 nucleotides in length; or 19-21 nucleotides in length; or 25-30 nucleotides in length; or 26-28 nucleotides in length. Similarly the sense strand of nucleic acid molecules (e.g., siNA molecules) as disclosed herein may be 15 to 49 nucleotides in length (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49 nucleotides in length); or 17-35 nucleotides in length; or 17-30 nucleotides in length; or 15-25 nucleotides in length; or 18-25 nucleotides in length; or 18-23 nucleotides in length; or 19-21 nucleotides in length; or 25-30 nucleotides in length; or 26-28 nucleotides in length. The duplex region of the nucleic acid molecules (e.g., siNA molecules) as disclosed herein may be 15-49 nucleotides in length (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49 nucleotides in length); 18-40 nucleotides in length; or 15-35 nucleotides in length; or 15-30 nucleotides in length; or about 15-25 nucleotides in length; or 17-25 nucleotides in length; or 17-23 nucleotides in length; or 17-21 nucleotides in length; or 19-21 nucleotides in length, or 25-30 nucleotides in length; or 25-28 nucleotides in length. In some embodiments the duplex region of the nucleic acid molecules (e.g., siNA molecules) is 19 nucleotides in length.

In certain embodiments, the sense and antisense strands of a nucleic acid (e.g., an siNA nucleic acid molecule) as provided herein are separate polynucleotide strands. In some embodiments, the separate antisense and sense strands form a double stranded structure via hydrogen bonding, for example, Watson-Crick base pairing. In some embodiments the sense and antisense strands are two separate strands that are covalently linked to each other. In other embodiments, the sense and antisense strands are part of a single polynucleotide strand having both a sense and antisense region; in some preferred embodiments the polynucleotide strand has a hairpin structure.

In certain embodiments, the nucleic acid molecule (e.g., siNA molecule) is a double stranded nucleic acid (dsNA) molecule that is symmetrical with regard to overhangs, and has a blunt end on both ends. In other embodiments the nucleic acid molecule (e.g., siNA molecule) is a dsNA molecule that is symmetrical with regard to overhangs, and has an overhang on both ends of the dsNA molecule; preferably the molecule has overhangs of 1, 2, 3, 4, 5, 6, 7, or 8 nucleotides; preferably the molecule has 2 nucleotide overhangs. In some embodiments the overhangs are 5′ overhangs; in alternative embodiments the overhangs are 3′ overhangs. In certain embodiments, the overhang nucleotides are modified with modifications as disclosed herein. In some embodiments the overhang nucleotides are 2′-deoxyribonucleotides.

In some embodiments the molecules comprise non-nucleotide overhangs at one or more of the 5′ or 3′ terminus of the sense and/or antisense strands. Such non-nucleotide overhangs include abasic ribo- and deoxyribo-nucleotide moieties, alkyl moieties including C3-C3 moieties and amino carbon chains.

In certain preferred embodiments, the nucleic acid molecule (e.g., siNA molecule) is a dsNA molecule that is asymmetrical with regard to overhangs, and has a blunt end on one end of the molecule and an overhang on the other end of the molecule. In certain embodiments the overhang is 1, 2, 3, 4, 5, 6, 7, or 8 nucleotides; preferably the overhang is 2 nucleotides. In some preferred embodiments an asymmetrical dsNA molecule has a 3′-overhang (for example a two nucleotide 3′-overhang) on one side of a duplex occurring on the sense strand; and a blunt end on the other side of the molecule. In some preferred embodiments an asymmetrical dsNA molecule has a 5′-overhang (for example a two nucleotide 5′-overhang) on one side of a duplex occurring on the sense strand; and a blunt end on the other side of the molecule. In other preferred embodiments an asymmetrical dsNA molecule has a 3′-overhang (for example a two nucleotide 3′-overhang) on one side of a duplex occurring on the antisense strand; and a blunt end on the other side of the molecule. In some preferred embodiments an asymmetrical dsNA molecule has a 5′-overhang (for example a two nucleotide 5′-overhang) on one side of a duplex occurring on the antisense strand; and a blunt end on the other side of the molecule. In certain preferred embodiments, the overhangs are 2′-deoxyribonucleotides. Examples of siNA compounds having a terminal dTdT are found in Tables C and D, infra.

In some embodiments, the nucleic acid molecule (e.g., siNA molecule) has a hairpin structure (having the sense strand and antisense strand on one polynucleotide), with a loop structure on one end and a blunt end on the other end. In some embodiments, the nucleic acid molecule has a hairpin structure, with a loop structure on one end and an overhang end on the other end (for example a 1, 2, 3, 4, 5, 6, 7, or 8 nucleotide overhang); in certain embodiments, the overhang is a 3′-overhang; in certain embodiments the overhang is a 5′-overhang; in certain embodiments the overhang is on the sense strand; in certain embodiments the overhang is on the antisense strand.

The nucleic acid molecules (e.g., siNA molecule) disclosed herein may include one or more modifications or modified nucleotides such as described herein. For example, a nucleic acid molecule (e.g., siNA molecule) as provided herein may include a modified nucleotide having a modified sugar; a modified nucleotide having a modified nucleobase; or a modified nucleotide having a modified phosphate group. Similarly, a nucleic acid molecule (e.g., siNA molecule) as provided herein may include a modified phosphodiester backbone and/or may include a modified terminal phosphate group.

Nucleic acid molecules (e.g., siNA molecules) as provided may have one or more nucleotides that include a modified sugar moiety, for example as described herein. In some preferred embodiments the modified sugar moiety is selected from the group consisting of 2′-O-methyl, 2′-methoxyethoxy, 2′-deoxy, 2′-fluoro, 2′-allyl, 2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio, 4′-(CH₂)₂—O-2′-bridge, 2′-locked nucleic acid, and 2′-O—(N-methylcarbamate).

Nucleic acid molecules (e.g., siNA molecules) as provided may have one or more modified nucleobase(s) for example as described herein, which preferably may be one selected from the group consisting of xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine, and acyclonucleotides.

Nucleic acid molecules (e.g., siNA molecules) as provided may have one or more modifications to the phosphodiester backbone, for example as described herein. In some preferred embodiments the phosphodiester bond is modified by substituting the phosphodiester bond with a phosphorothioate, 3′-(or -5′)deoxy-3′-(or -5′)thio-phosphorothioate, phosphorodithioate, phosphoroselenates, 3′-(or -5′)deoxy phosphinates, borano phosphates, 3′-(or -5′)deoxy-3′-(or 5′-)amino phosphoramidates, hydrogen phosphonates, borano phosphate esters, phosphoramidates, alkyl or aryl phosphonates and phosphotriester or phosphorus linkages.

In various embodiments, the provided nucleic acid molecules (e.g., siNA molecules) may include one or modifications in the sense strand but not the antisense strand; in other embodiments the provided nucleic acid molecules (e.g., siNA molecules) include one or more modifications in the antisense strand but not the sense strand; in yet other embodiments, the provided nucleic acid molecules (e.g., siNA molecules) include one or more modifications in the both the sense strand and the antisense strand.

In some embodiments in which the provided nucleic acid molecules (e.g., siNA molecules) have modifications, the sense strand includes a pattern of alternating modified and unmodified nucleotides, and/or the antisense strand includes a pattern of alternating modified and unmodified nucleotides; in some preferred versions of such embodiments the modification is a 2′-O-methyl (2′ methoxy or 2′OMe) sugar moiety. The pattern of alternating modified and unmodified nucleotides may start with a modified nucleotide at the 5′ end or 3′ end of one of the strands; for example the pattern of alternating modified and unmodified nucleotides may start with a modified nucleotide at the 5′ end or 3′ end of the sense strand and/or the pattern of alternating modified and unmodified nucleotides may start with a modified nucleotide at the 5′ end or 3′ end of the antisense strand. When both the antisense and sense strand include a pattern of alternating modified nucleotides, the pattern of modified nucleotides may be configured such that modified nucleotides in the sense strand are opposite modified nucleotides in the antisense strand; or there may be a phase shift in the pattern such that modified nucleotides of the sense strand are opposite unmodified nucleotides in the antisense strand and vice-versa.

The nucleic acid molecules (e.g., siNA molecules) as provided herein may include 1-3 (i.e., 1, 2 or 3) deoxyribonucleotides at the 3′ end of the sense and/or the antisense strand.

The nucleic acid molecules (e.g., siNA molecules) as provided herein may include a phosphate group at the 5′ end of the sense and/or the antisense strand.

In one aspect, provided are double stranded nucleic acid molecules having the structure (A1):

(A1)  5′(N)x - Z  3′ (antisense strand)
3′ Z′-(N′)y -z″ 5′ (sense strand)

wherein each of N and N′ is a nucleotide which may be unmodified or modified, or an unconventional moiety;wherein each of (N)x and (N′)y is an oligonucleotide in which each consecutive N or N′ is joined to the next N or N′ by a covalent bond; wherein each of Z and Z′ is independently present or absent, but if present independently includes 1-5 consecutive nucleotides or non-nucleotide moieties or a combination thereof covalently attached at the 3′ terminus of the strand in which it is present;wherein z″ may be present or absent, but if present is a capping moiety covalently attached at the 5′ terminus of (N′)y;each of x and y is independently an integer from 18 to 40;wherein the sequence of (N′)y has complementarity to the sequence of (N)x; and wherein (N)x includes an antisense sequence to SEQ ID NO:1 or to SEQ ID NO:2.

In some embodiments (N)x includes an antisense sequence to SEQ ID NO:1. In some embodiments (N)x includes an antisense oligonucleotide present in any one of Tables A1, A2, A3 or A4. In other embodiments (N)x is selected from an antisense oligonucleotide present in Tables A3 or A4.

In certain preferred embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown on Table A1. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table A2. In certain preferred embodiments the antisense strand and the strand are active in more than one species (human and at least one other species) and are selected from the sequence pairs shown in Table A2. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table A3, and preferably in Table A4. In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in duplexes siTIMP1_p2; siTIMP1_p6; siTIMP1_p14; siTIMP1_p16; siTIMP1_p17; siTIMP1_p19; siTIMP1_p20; siTIMP1_p21; siTIMP1_p23; siTIMP1_p24; siTIMP1_p27; siTIMP1_p29; siTIMP1_p31; siTIMP1_p33; siTIMP1_p38; siTIMP1_p42; siTIMP1_p43; siTIMP1_p45; siTIMP1_p49; siTIMP1_p60; siTIMP1_p71; siTIMP1_p73; siTIMP1_p77; siTIMP1_p78; siTIMP1_p79; siTIMP1_p85; siTIMP1_p89; siTIMP1_p91; siTIMP1_p96; siTIMP1_p98; siTIMP1_p99 and siTIMP1_p108, shown in Table A3 infra.

In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP1_p2 (SEQ ID NOS:267 and 299); siTIMP1_p6 (SEQ ID NOS:268 and 300); siTIMP1_p14 (SEQ ID NOS:269 and 301); siTIMP1_p16 (SEQ ID NOS:270 and 302); siTIMP1_p17 (SEQ ID NOS:271 and 303); siTIMP1_p19 (SEQ ID NOS:272 and 304); siTIMP1_p20 (SEQ ID NOS:273 and 305); siTIMP1_p21 (SEQ ID NOS:274 and 306); siTIMP1_p23 (SEQ ID NOS:275 and 307; siTIMP1_p29 (278 and 310); siTIMP1_p33 (280 and 312); siTIMP1_p38 (SEQ ID NOS:281 and 313); siTIMP1_p42 (282 and 314); siTIMP1_p43 (SEQ ID NOS:283 and 315); siTIMP1_p45 (284 and 316); siTIMP1_p60 (SEQ ID NOS:286 and 318); siTIMP1_p71 (SEQ ID NOS:287 and 319); siTIMP1_p73 (SEQ ID NOS:288 and 320); siTIMP1_p78 (290 and 322); siTIMP1_p79 (SEQ ID NOS:291 and 323); siTIMP1_p85 (SEQ ID NOS:292 and 324); siTIMP1_p89 (SEQ ID NOS:293 and 325); siTIMP1_p91 (SEQ ID NOS:294 and 326); siTIMP1_p96 (SEQ ID NOS:295 and 327); siTIMP1_p98 (SEQ ID NOS:296 and 328); siTIMP1_p99 (SEQ ID NOS:297 and 329) and siTIMP1_p108 (SEQ ID NOS:298 and 330), shown in Table A4, infra.

In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p2 (SEQ ID NOS:267 and 299). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p6 (SEQ ID NOS:268 and 300). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p14 (SEQ ID NOS:269 and 301). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p16 (SEQ ID NOS:270 and 302). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p17 (SEQ ID NOS:271 and 303). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p19 (SEQ ID NOS:272 and 304). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p20 (SEQ ID NOS:273 and 305). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p21 (SEQ ID NOS:274 and 306). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p23 (SEQ ID NOS:275 and 307. In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p29 (278 and 310). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p33 (280 and 312). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p38 (SEQ ID NOS:281 and 313). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p42 (282 and 314). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p43 (SEQ ID NOS:283 and 315). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p45 (284 and 316). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p60 (SEQ ID NOS:286 and 318). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p71 (SEQ ID NOS:287 and 319). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p73 (SEQ ID NOS:288 and 320). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p78 (290 and 322). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p79 (SEQ ID NOS:291 and 323). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p85 (SEQ ID NOS:292 and 324). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p89 (SEQ ID NOS:293 and 325). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p91 (SEQ ID NOS:294 and 326). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p96 (SEQ ID NOS:295 and 327). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p98 (SEQ ID NOS:296 and 328). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p99 (SEQ ID NOS:297 and 329). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p108 (SEQ ID NOS:298 and 330), shown in Table A4.

In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p2 (SEQ ID NOS:267 and 299). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p6 (SEQ ID NOS:268 and 300). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p16 (SEQ ID NOS:270 and 302). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p17 (SEQ ID NOS:271 and 303). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p19 (SEQ ID NOS:272 and 304). I In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p20 (SEQ ID NOS:273 and 305). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p21 (SEQ ID NOS:274 and 306). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p38 (SEQ ID NOS:281 and 313).

In some embodiments (N)x includes an antisense sequence to SEQ ID NO:2. In some embodiments (N)x includes an antisense oligonucleotide present in any one of Tables B1, B2, B3 or B4. In other embodiments (N)x is selected from an antisense oligonucleotide present in Tables B3 or B4.

In certain preferred embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown on Table B1. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table B2. In certain preferred embodiments the antisense strand and the strand are active in more than one species (human and at least one other species) and are selected from the sequence pairs shown in Table B2. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table B3, and preferably in Table B4.

In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP2_p4; siTIMP2_p16; siTIMP2_p17; siTIMP2_p18; siTIMP2_p20; siTIMP2_p24; siTIMP2_p25; siTIMP2_p27; siTIMP2_p29; siTIMP2_p30; siTIMP2_p33; siTIMP2_p35; siTIMP2_p37; siTIMP2_p38; siTIMP2_p39; siTIMP2_p40; siTIMP2_p41; siTIMP2_p44; siTIMP2_p46; siTIMP2_p51; siTIMP2_p55; siTIMP2_p61; siTIMP2_p62; siTIMP2_p64; siTIMP2_p65; siTIMP2_p67; siTIMP2_p68; siTIMP2_p69; siTIMP2_p71; siTIMP2_p75; siTIMP2_p76; siTIMP2_p78; siTIMP2_p79; siTIMP2_p82; siTIMP2_p83; siTIMP2_p84; siTIMP2_p85; siTIMP2_p86; siTIMP2_p87; siTIMP2_p88; siTIMP2_p89; siTIMP2_p90; siTIMP2_p91; siTIMP2_p92; siTIMP2_p93; siTIMP2_p94; siTIMP2_p95; siTIMP2_p96; siTIMP2_p97; siTIMP2_p98; siTIMP2_p99; siTIMP2_p100; and siTIMP2_p101 and siTIMP2_p102, shown in Table B3, infra.

In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP2_p27 (SEQ ID NOS:2478 and 2531); siTIMP2_p29 (SEQ ID NOS:2479 and 2532); siTIMP2_p30 (SEQ ID NOS:2480 and 2533); siTIMP2_p39 (SEQ ID NOS:2485 and 2538); siTIMP2_p40 (SEQ ID NOS:2486 and 2539); siTIMP2_p41 (SEQ ID NOS:2487 and 2540); siTIMP2_p46 (SEQ ID NOS:2489 and 2542); siTIMP2_p55 (SEQ ID NOS:2491 and 2544); siTIMP2_p62 (SEQ ID NOS:2493 and 2546); siTIMP2_p68 (SEQ ID NOS:2497 and 2550); siTIMP2_p69 (SEQ ID NOS:2498 and 2551); siTIMP2_p71 (SEQ ID NOS:2499 and 2552); siTIMP2_p76 (SEQ ID NOS:2501 and 2554); siTIMP2_p78 (SEQ ID NOS:2502 and 2555); siTIMP2_p89 (SEQ ID NOS:2511 and 2564); siTIMP2_p91 (SEQ ID NOS:2513 and 2566); siTIMP2_p93 (SEQ ID NOS:2515 and 2568); siTIMP2_p95 (SEQ ID NOS:2517 and 2570); siTIMP2_p97 (SEQ ID NOS:2519 and 2572); siTIMP2_p98 (SEQ ID NOS:2520 and 2573); and siTIMP2_p100 (SEQ ID NOS:2522 and 2575), shown in Table B4, infra

In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p27 (SEQ ID NOS:2478 and 2531). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p29 (SEQ ID NOS:2479 and 2532). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p30 (SEQ ID NOS:2480 and 2533). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p39 (SEQ ID NOS:2485 and 2538). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p40 (SEQ ID NOS:2486 and 2539). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p41 (SEQ ID NOS:2487 and 2540). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p46 (SEQ ID NOS:2489 and 2542). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p55 (SEQ ID NOS:2491 and 2544). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p62 (SEQ ID NOS:2493 and 2546). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p68 (SEQ ID NOS:2497 and 2550). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p69 (SEQ ID NOS:2498 and 2551). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p71 (SEQ ID NOS:2499 and 2552). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p76 (SEQ ID NOS:2501 and 2554). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p78 (SEQ ID NOS:2502 and 2555). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p89 (SEQ ID NOS:2511 and 2564). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p91 (SEQ ID NOS:2513 and 2566). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p93 (SEQ ID NOS:2515 and 2568). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p95 (SEQ ID NOS:2517 and 2570). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p97 (SEQ ID NOS:2519 and 2572). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p98 (SEQ ID NOS:2520 and 2573). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p100 (SEQ ID NOS:2522 and 2575). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p102 (SEQ ID NOS:1007 and 1622).

In some embodiments the covalent bond joining each consecutive N or N′ is a phosphodiester bond.

In some embodiments x=y and each of x and y is 19, 20, 21, 22 or 23. In various embodiments x=y=19. In some embodiments the antisense and sense strands form a duplex by base pairing.

According to one embodiment provided are modified nucleic acid molecules having a structure (A2) set forth below:

	(A2)	5′ N1-(N)x-Z	3′ (antisense strand)
		3′ Z′-N2-(N′)y-z″	5′ (sense strand)

wherein each of N2, N and N′ is independently an unmodified or modified nucleotide, or an unconventional moiety;wherein each of (N)x and (N′)y is an oligonucleotide in which each consecutive N or N′ is joined to the adjacent N or N′ by a covalent bond;wherein each of x and y is independently an integer of from 17 to 39;wherein the sequence of (N′)y has complementarity to the sequence of (N)x and (N)x has complementarity to a consecutive sequence in a target mRNA selected from SEQ ID NO:1 and SEQ ID NO:2;wherein N1 is covalently bound to (N)x and is mismatched to SEQ ID NO:1 or to SEQ ID NO:2,wherein N1 is a moiety selected from the group consisting of uridine, modified uridine, ribothymidine, modified ribothymidine, deoxyribothymidine, modified deoxyribothymidine, riboadenine, modified riboadenine, deoxyriboadenine or modified deoxyriboadenine;wherein N1 and N2 form a base pair;wherein each of Z and Z′ is independently present or absent, but if present is independently 1-5 consecutive nucleotides or non-nucleotide moieties or a combination thereof covalently attached at the 3′ terminus of the strand in which it is present; andwherein z″ may be present or absent, but if present is a capping moiety covalently attached at the 5′ terminus of (N′)y.

Molecules covered by the description of Structure A2 are also referred to herein as “18+1” or “18+1 mer”. In some embodiments the N2-(N′)y and N1-(N)x oligonucleotide strands useful in generating dsRNA compounds are presented in Tables A5, A6, A7, A8, B5, B6, B7 or B8. In some embodiments (N)x has complementarity to a consecutive sequence in SEQ ID NO:1 (human TIMP1 mRNA). In some embodiments (N)x includes an antisense oligonucleotide present in any one of Tables A5, A6, A7, and A8. In some embodiments x=y=18 and N1-(N)x includes an antisense oligonucleotide present in any one of Tables A3 or A4. In some embodiments x=y=19 or x=y=20. In certain preferred embodiments x=y=18.

In certain preferred embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown on Table A5. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table A6. In certain preferred embodiments the antisense strand and the strand are active in more than one species (human and at least one other species) and are selected from the sequence pairs shown in Table A6. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table A7, and preferably in Table A8.

In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP1_p1; siTIMP1_p3; siTIMP1_p4; siTIMP1_p5; siTIMP1_p7; siTIMP1_p8; siTIMP1_p9; siTIMP1_p10; siTIMP1_p11; siTIMP1_p12; siTIMP1_p13; siTIMP1_p15; siTIMP1_p18; siTIMP1_p22; siTIMP1_p25; siTIMP1_p26; siTIMP1_p28; siTIMP1_p30; siTIMP1_p32; siTIMP1_p34; siTIMP1_p35; siTIMP1_p36; siTIMP1_p37; siTIMP1_p39; siTIMP1_p40; siTIMP1_p41; siTIMP1_p44; siTIMP1_p46; siTIMP1_p47; siTIMP1_p48; siTIMP1_p50; siTIMP1_p51; siTIMP1_p52; siTIMP1_p53; siTIMP1_p54; siTIMP1_p55; siTIMP1_p56; siTIMP1_p57; siTIMP1_p58; siTIMP1_p59; siTIMP1_p61; siTIMP1_p62; siTIMP1_p63; siTIMP1_p64; siTIMP1_p65; siTIMP1_p66; siTIMP1_p67; siTIMP1_p68; siTIMP1_p69; siTIMP1_p70; siTIMP1_p72; siTIMP1_p74; siTIMP1_p75; siTIMP1_p76; siTIMP1_p80; siTIMP1_p81; siTIMP1_p82; siTIMP1_p83; siTIMP1_p84; siTIMP1_p86; siTIMP1_p87; siTIMP1_p88; siTIMP1_p90; siTIMP1_p92; siTIMP1_p93; siTIMP1_p94; siTIMP1_p95; siTIMP1_p97; siTIMP1_p100; siTIMP1_p101; siTIMP1_p102; siTIMP1_p103; siTIMP1_p104; siTIMP1_p105; siTIMP1_p106; siTIMP1_p109; siTIMP1_p110; siTIMP1_p111; siTIMP1_p112; siTIMP1_p113 and siTIMP1_p114, shown in Table A7, infra.

In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP1_p1 (SEQ ID NOS:845 and 926); siTIMP1_p4 (SEQ ID NOS:847 and 928; siTIMP1_p5 (SEQ ID NOS:848 and 929); siTIMP1_p7 (SEQ ID NOS:849 and 930); siTIMP1_p8 (SEQ ID NOS:850 and 931); siTIMP1_p9 (SEQ ID NOS:850 and 931); siTIMP1_p10 (SEQ ID NOS:852 and 933); siTIMP1_p11 (SEQ ID NOS:853 and 934); siTIMP1_p12 (SEQ ID NOS:854 and 935); siTIMP1_p13 (SEQ ID NOS:855 and 936); siTIMP1_p15 (SEQ ID NOS:856 and 937); siTIMP1_p18 (SEQ ID NOS:857 and 938); siTIMP1_p22 (SEQ ID NOS:858 and 939); siTIMP1_p26 (SEQ ID NOS:860 and 941); siTIMP1_p36 (SEQ ID NOS:866 and 947); siTIMP1_p37 (SEQ ID NOS:867 and 948); siTIMP1_p39 (SEQ ID NOS:868 and 949); siTIMP1_p40 (SEQ ID NOS:869 and 950); siTIMP1_p41 (SEQ ID NOS:870 and 951); siTIMP1_p44 (SEQ ID NOS:871 and 952); siTIMP1_p47 (SEQ ID NOS:873 and 954); siTIMP1_p48 (SEQ ID NOS:874 and 955); siTIMP1_p50 (SEQ ID NOS:875 and 956); siTIMP1_p51 (SEQ ID NOS:876 and 957); siTIMP1_p52 (SEQ ID NOS:877 and 958); siTIMP1_p55 (SEQ ID NOS:880 and 961); siTIMP1_p56 (SEQ ID NOS:881 and 962); siTIMP1_p58 (SEQ ID NOS:883 and 964); siTIMP1_p61 (SEQ ID NOS:885 and 966); siTIMP1_p64 (SEQ ID NOS:888 and 969); siTIMP1_p66 (SEQ ID NOS:890 and 971); siTIMP1_p68 (SEQ ID NOS:892 and 973); siTIMP1_p70 (SEQ ID NOS:894 and 975); siTIMP1_p75 (SEQ ID NOS:897 and 978); siTIMP1_p83 (SEQ ID NOS:902 and 983); siTIMP1_p86 (SEQ ID NOS:904 and 985); siTIMP1_p88 (SEQ ID NOS:906 and 987); siTIMP1_p92 (SEQ ID NOS:908 and 989); siTIMP1_p93 (SEQ ID NOS:909 and 990); siTIMP1_p95 (SEQ ID NOS:911 and 992); siTIMP1_p97 (SEQ ID NOS:912 and 993); siTIMP1_p102 (SEQ ID NOS:915 and 996); siTIMP1_p104 (SEQ ID NOS:917 and 998); siTIMP1_p105 (SEQ ID NOS:918 and 999); siTIMP1_p106 (SEQ ID NOS:919 and 1000); siTIMP1_p110 (SEQ ID NOS:921 and 1002) and siTIMP1_p112 (SEQ ID NOS:923 and 1004), shown in Table A8, infra.

In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p1 (SEQ ID NOS:845 and 926). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p4 (SEQ ID NOS:847 and 928. In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p5 (SEQ ID NOS:848 and 929). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p7 (SEQ ID NOS:849 and 930). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p8 (SEQ ID NOS:850 and 931). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p9 (SEQ ID NOS:850 and 931). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p10 (SEQ ID NOS:852 and 933). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p11 (SEQ ID NOS:853 and 934). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p12 (SEQ ID NOS:854 and 935). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p13 (SEQ ID NOS:855 and 936). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p15 (SEQ ID NOS:856 and 937). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p18 (SEQ ID NOS:857 and 938). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p22 (SEQ ID NOS:858 and 939). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p26 (SEQ ID NOS:860 and 941). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p36 (SEQ ID NOS:866 and 947). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p37 (SEQ ID NOS:867 and 948). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p39 (SEQ ID NOS:868 and 949). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p40 (SEQ ID NOS:869 and 950). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p41 (SEQ ID NOS:870 and 951). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p44 (SEQ ID NOS:871 and 952). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p47 (SEQ ID NOS:873 and 954). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p48 (SEQ ID NOS:874 and 955). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p50 (SEQ ID NOS:875 and 956). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p51 (SEQ ID NOS:876 and 957). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p52 (SEQ ID NOS:877 and 958). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p55 (SEQ ID NOS:880 and 961). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p56 (SEQ ID NOS:881 and 962). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p58 (SEQ ID NOS:883 and 964). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p61 (SEQ ID NOS:885 and 966). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p64 (SEQ ID NOS:888 and 969). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p66 (SEQ ID NOS:890 and 971). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p68 (SEQ ID NOS:892 and 973). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p70 (SEQ ID NOS:894 and 975). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p75 (SEQ ID NOS:897 and 978). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p83 (SEQ ID NOS:902 and 983). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p86 (SEQ ID NOS:904 and 985). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p88 (SEQ ID NOS:906 and 987). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p92 (SEQ ID NOS:908 and 989). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p93 (SEQ ID NOS:909 and 990). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p95 (SEQ ID NOS:911 and 992). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p97 (SEQ ID NOS:912 and 993). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p102 (SEQ ID NOS:915 and 996). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p104 (SEQ ID NOS:917 and 998). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p105 (SEQ ID NOS:918 and 999). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p106 (SEQ ID NOS:919 and 1000). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p110 (SEQ ID NOS:921 and 1002). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP1_p112 (SEQ ID NOS:923 and 1004).

In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p1 (SEQ ID NOS:845 and 926). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p4 (SEQ ID NOS:847 and 928. In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p5 (SEQ ID NOS:848 and 929). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p7 (SEQ ID NOS:849 and 930). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p9 (SEQ ID NOS:850 and 931). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p10 (SEQ ID NOS:852 and 933). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p11 (SEQ ID NOS:853 and 934). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p12 (SEQ ID NOS:854 and 935). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p13 (SEQ ID NOS:855 and 936). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p15 (SEQ ID NOS:856 and 937). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p18 (SEQ ID NOS:857 and 938). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p44 (SEQ ID NOS:871 and 952). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p48 (SEQ ID NOS:874 and 955). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p51 (SEQ ID NOS:876 and 957). In some preferred embodiments the nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the antisense strand and the sense strand of a sequence pair set forth in siTIMP1_p52 (SEQ ID NOS:877 and 958).

In some embodiments (N)x has complementarity to a consecutive sequence in SEQ ID NO:2 (human TIMP2 mRNA). In some embodiments (N)x includes an antisense oligonucleotide present in any one of Tables B5, B6, B7, and B8. In some embodiments x=y=18 and N1-(N)x includes an antisense oligonucleotide present in any one of Tables B3 or B4. In some embodiments x=y=19 or x=y=20. In certain preferred embodiments x=y=18.

In certain preferred embodiments, the antisense strand of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes a sequence corresponding to any one of the antisense sequences shown on Table B5. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table B6. In certain preferred embodiments the antisense strand and the strand are active in more than one species (human and at least one other species) and are selected from the sequence pairs shown in Table B6. In certain preferred embodiments the antisense strand and the strand are selected from the sequence pairs shown in Table B7, and preferably from Table B8.

In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP2_p1; siTIMP2_p2; siTIMP2_p3; siTIMP2_p5; siTIMP2_p6; siTIMP2_p7; siTIMP2_p8; siTIMP2_p9; siTIMP2_p10; siTIMP2_p11; siTIMP2_p12; siTIMP2_p13; siTIMP2_p14; siTIMP2_p15; siTIMP2_p19; siTIMP2_p21; siTIMP2_p22; siTIMP2_p23; siTIMP2_p26; siTIMP2_p28; siTIMP2_p31; siTIMP2_p32; siTIMP2_p34; siTIMP2_p36; siTIMP2_p42; siTIMP2_p43; siTIMP2_p45; siTIMP2_p47; siTIMP2_p48; siTIMP2_p49; siTIMP2_p50; siTIMP2_p52; siTIMP2_p53; siTIMP2_p54; siTIMP2_p56; siTIMP2_p57; siTIMP2_p58; siTIMP2_p59; siTIMP2_p60; siTIMP2_p63; siTIMP2_p66; siTIMP2_p70; siTIMP2_p72; siTIMP2_p73; siTIMP2_p74; siTIMP2_p77; siTIMP2_p80 and siTIMP2_p81, shown in Table B7, infra.

In some embodiments the antisense and sense strands are selected from the sequence pairs set forth in siTIMP2_p6 (SEQ ID NOS:4771 and 4819); siTIMP2_p9 (SEQ ID NOS:4774 and 4822); siTIMP2_p15 (SEQ ID NOS:4780 and 4828); siTIMP2_p19 (SEQ ID NOS:4781 and 4829); siTIMP2_p21 (SEQ ID NOS:4782 and 4830); siTIMP2_p22 (SEQ ID NOS:4783 and 4831); siTIMP2_p23 (SEQ ID NOS:4784 and 4832); siTIMP2_p28 (SEQ ID NOS:4786 and 4834); siTIMP2_p31 (SEQ ID NOS:4787 and 4835); siTIMP2_p36 (SEQ ID NOS:4790 and 4838); siTIMP2_p42 (SEQ ID NOS:4791 and 4839); siTIMP2_p47 (SEQ ID NOS:4794 and 4842); siTIMP2_p50 (SEQ ID NOS:4797 and 4845); siTIMP2_p56 (SEQ ID NOS:4801 and 4849); siTIMP2_p57 (SEQ ID NOS:4802 and 4850); siTIMP2_p58 (SEQ ID NOS:4803 and 4851); siTIMP2_p60 (SEQ ID NOS:4805 and 4853); siTIMP2_p63 (SEQ ID NOS:4806 and 4854); siTIMP2_p70 (SEQ ID NOS:4808 and 4856); siTIMP2_p73 (SEQ ID NOS:4810 and 4858); siTIMP2_p74 (SEQ ID NOS:4811 and 4859); and siTIMP2_p81 (SEQ ID NOS:4814 and 4862), shown in Table B8, infra.

In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p6 (SEQ ID NOS:4771 and 4819). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p9 (SEQ ID NOS:4774 and 4822). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p15 (SEQ ID NOS:4780 and 4828). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p19 (SEQ ID NOS:4781 and 4829). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p21 (SEQ ID NOS:4782 and 4830). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p22 (SEQ ID NOS:4783 and 4831). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p23 (SEQ ID NOS:4784 and 4832). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p28 (SEQ ID NOS:4786 and 4834). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p31 (SEQ ID NOS:4787 and 4835). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p36 (SEQ ID NOS:4790 and 4838). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p42 (SEQ ID NOS:4791 and 4839). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p47 (SEQ ID NOS:4794 and 4842). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p50 (SEQ ID NOS:4797 and 4845). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p56 (SEQ ID NOS:4801 and 4849). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p57 (SEQ ID NOS:4802 and 4850). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p58 (SEQ ID NOS:4803 and 4851). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p60 (SEQ ID NOS:4805 and 4853). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p63 (SEQ ID NOS:4806 and 4854); siTIMP2_p70 (SEQ ID NOS:4808 and 4856). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p73 (SEQ ID NOS:4810 and 4858). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p74 (SEQ ID NOS:4811 and 4859). In some embodiments the antisense and sense strands of a nucleic acid molecule (e.g., a siNA molecule) as disclosed herein includes the sequence pairs set forth in siTIMP2_p81 (SEQ ID NOS:4814 and 4862).

In some embodiments N1 and N2 form a Watson-Crick base pair. In other embodiments N1 and N2 form a non-Watson-Crick base pair. In some embodiments N1 is a modified riboadenosine or a modified ribouridine.

In certain embodiments N1 is selected from the group consisting of riboadenosine, modified riboadenosine, deoxyriboadenosine, modified deoxyriboadenosine. In other embodiments N1 is selected from the group consisting of ribouridine, deoxyribouridine, modified ribouridine, and modified deoxyribouridine.

In certain embodiments N1 is selected from the group consisting of riboadenosine, modified riboadenosine, deoxyriboadenosine, modified deoxyriboadenosine and N2 is selected from the group consisting of ribouridine, deoxyribouridine, modified ribouridine, and modified deoxyribouridine. In certain embodiments N1 is selected from the group consisting of riboadenosine and modified riboadenosine and N2 is selected from the group consisting of ribouridine and modified ribouridine.

In certain embodiments N2 is selected from the group consisting of riboadenosine, modified riboadenosine, deoxyriboadenosine, modified deoxyriboadenosine and N1 is selected from the group consisting of ribouridine, deoxyribouridine, modified ribouridine, and modified deoxyribouridine. In certain embodiments N1 is selected from the group consisting of ribouridine and modified ribouridine and N2 is selected from the group consisting of riboadenine and modified riboadenine. In certain embodiments N1 is ribouridine and N2 is riboadenine.

In some embodiments of Structure (A2), N1 includes 2′OMe sugar-modified ribouracil or 2′OMe sugar-modified riboadenosine. In certain embodiments of structure (A), N2 includes a 2′OMe sugar modified ribonucleotide or deoxyribonucleotide.

In some embodiments Z and Z′ are absent. In other embodiments one of Z or Z′ is present.

In some embodiments each of N and N′ is an unmodified nucleotide. In some embodiments at least one of N or N′ includes a chemically modified nucleotide or an unconventional moiety. In some embodiments the unconventional moiety is selected from a mirror nucleotide, an abasic ribose moiety and an abasic deoxyribose moiety. In some embodiments the unconventional moiety is a mirror nucleotide, preferably an L-DNA moiety. In some embodiments at least one of N or N′ includes a 2′ OMe sugar-modified ribonucleotide.

In some embodiments the sequence of (N′)y is fully complementary to the sequence of (N)x. In other embodiments the sequence of (N′)y is substantially complementary to the sequence of (N)x.

In some embodiments (N)x includes an antisense sequence that is fully complementary to about 17 to about 39 consecutive nucleotides in a target mRNA. In other embodiments (N)x includes an antisense that is substantially complementary to about 17 to about 39 consecutive nucleotides in a target mRNA. In some embodiments (N)x includes an antisense that is substantially complementary to about 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, to about 39 consecutive nucleotides in a target mRNA. In other embodiments (N)x includes an antisense that is substantially complementary to about 17 to about 23, 18 to about 23, 18 to about 21, or 18 to about 19 consecutive nucleotides in a target mRNA.

In some embodiments of Structure A1 and Structure A2 the compound is blunt ended, for example wherein both Z and Z′ are absent. In an alternative embodiment, at least one of Z or Z′ is present. Z and Z′ independently include one or more covalently linked modified and or unmodified nucleotides, including deoxyribonucleotides and ribonucleotides, or an unconventional moiety for example inverted abasic deoxyribose moiety or abasic ribose moiety; a non-nucleotide C3, C4 or C5 moiety, an amino-6 moiety, a mirror nucleotide and the like. In some embodiments each of Z and Z′ independently includes a C3 moiety or an amino-C6 moiety. In some embodiments Z′ is absent and Z is present and includes a non-nucleotide C3 moiety. In some embodiments Z is absent and Z′ is present and includes a non-nucleotide C3 moiety.

In some preferred embodiments of Structures A1 and Structure A2 an asymmetrical siNA compound molecule has a 3′ terminal non-nucleotide overhang (for example C3-C3 3′-overhang) on one side of a duplex occurring on the antisense strand; and a blunt end on the other side of the molecule. In some preferred embodiments z′ is present and the dsNA molecule has a 5′ terminal non-nucleotide overhang (for example an abasic moiety) on one side of a duplex occurring on the sense strand; and a blunt end on the other side of the molecule.

In some embodiments of Structure A1 and Structure A2 each N consists of an unmodified ribonucleotide. In some embodiments of Structure A1 and Structure A2 each N′ consists of an unmodified nucleotide. In preferred embodiments, at least one of N and N′ is a modified ribonucleotide or an unconventional moiety.

In other embodiments the compound of Structure A1 or Structure A2 includes at least one ribonucleotide modified in the sugar residue. In some embodiments the compound includes a modification at the 2′ position of the sugar residue. In some embodiments the modification in the 2′ position includes the presence of an amino, a fluoro, an alkoxy or an alkyl moiety. In certain embodiments the 2′ modification includes an alkoxy moiety. In preferred embodiments the alkoxy moiety is a methoxy moiety (also known as 2′-O-methyl; 2′OMe; 2′-OCH3). In some embodiments the nucleic acid compound includes 2′OMe sugar modified alternating ribonucleotides in one or both of the antisense and the sense strands. In other embodiments the compound includes 2′OMe sugar modified ribonucleotides in the antisense strand, (N)x or N1-(N)x, only. In certain embodiments the middle ribonucleotide of the antisense strand; e.g. ribonucleotide in position 10 in a 19-mer strand is unmodified. In various embodiments the nucleic acid compound includes at least 5 alternating 2′OMe sugar modified and unmodified ribonucleotides.

In additional embodiments the compound of Structure A1 or Structure A2 includes modified ribonucleotides in alternating positions wherein each ribonucleotide at the 5′ and 3′ termini of (N)x or N1-(N)x are modified in their sugar residues, and each ribonucleotide at the 5′ and 3′ termini of (N′)y or N2-(N)y are unmodified in their sugar residues.

In some embodiments, (N)x or N1-(N)x includes 2′OMe modified ribonucleotides at positions 2, 4, 6, 8, 11, 13, 15, 17 and 19. In other embodiments (N)x (N)x or N1-(N)x includes 2′OMe modified ribonucleotides at positions 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19. In some embodiments (N)x or N1-(N)x includes 2′OMe modified pyrimidines. In some embodiments all the pyrimidine nucleotides in (N)x or N1-(N)x are 2′OMe modified. In some embodiments (N′)y or N2-(N′)y includes 2′OMe modified pyrimidines.

In additional embodiments the compound of Structure A1 or Structure A2 includes modified ribonucleotides in alternating positions wherein each ribonucleotide at the 5′ and 3′ termini of (N)x or N1-(N)x are modified in their sugar residues, and each ribonucleotide at the 5′ and 3′ termini of (N′)y or N2-(N)y are unmodified in their sugar residues.

In some embodiments of Structure A1 and Structure A2, neither of the sense strand nor the antisense strand is phosphorylated at the 3′ and 5′ termini. In other embodiments one or both of the sense strand or the antisense strand are phosphorylated at the 3′ termini.

In some embodiments of Structure A1 and Structure A2 (N)y includes at least one unconventional moiety selected from a mirror nucleotide and a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide phosphate bond also known as 2′-5′ linked or 2′-5′ linkage. In some embodiments the unconventional moiety is a mirror nucleotide. In various embodiments the mirror nucleotide is selected from an L-ribonucleotide (L-RNA) and an L-deoxyribonucleotide (L-DNA). In preferred embodiments the mirror nucleotide is L-DNA.

In some embodiments of Structure A1 (N′)y includes at least one L-DNA moiety. In some embodiments x=y=19 and (N′)y, consists of unmodified ribonucleotides at positions 1-17 and 19 and one L-DNA at the 3′ penultimate position (position 18). In other embodiments x=y=19 and (N′)y consists of unmodified ribonucleotides at position 1-16 and 19 and two consecutive L-DNA at the 3′ penultimate position (positions 17 and 18). In various embodiments the unconventional moiety is a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide phosphate linkage. According to various embodiments (N′)y includes 2, 3, 4, 5, or 6 consecutive ribonucleotides at the 3′ terminus linked by 2′-5′ internucleotide linkages. In one embodiment, four consecutive nucleotides at the 3′ terminus of (N′)y are joined by three 2′-5′ phosphodiester bonds, wherein one or more of the 2′-5′ nucleotides which form the 2′-5′ phosphodiester bonds further includes a 3′-O-methyl (3′OMe) sugar modification. Preferably the 3′ terminal nucleotide of (N′)y includes a 2′OMe sugar modification. In certain embodiments x=y=19 and (N′)y includes two or more consecutive nucleotides at positions 15, 16, 17, 18 and 19 include a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide bond. In various embodiments the nucleotide forming the 2′-5′ internucleotide bond includes a 3′ deoxyribose nucleotide or a 3′ methoxy nucleotide. In some embodiments x=y=19 and (N′)y includes nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond between positions 15-16, 16-17 and 17-18 or between positions 16-17, 17-18 and 18-19. In some embodiments x=y=19 and (N′)y includes nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond between positions 16-17 and 17-18 or between positions 17-18 and 18-19 or between positions 15-16 and 17-18. In other embodiments the pyrimidine ribonucleotides (rU, rC) in (N′)y are substituted with nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond.

In some embodiments of Structure A2, (N)y includes at least one L-DNA moiety. In some embodiments x=y=18 and (N′)y consists of unmodified ribonucleotides at positions 1-16 and 18 and one L-DNA at the 3′ penultimate position (position 17). In other embodiments x=y=18 and (N′)y consists of unmodified ribonucleotides at position 1-15 and 18 and two consecutive L-DNA at the 3′ penultimate position (positions 16 and 17). In various embodiments the unconventional moiety is a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide phosphate linkage. According to various embodiments (N′)y includes 2, 3, 4, 5, or 6 consecutive ribonucleotides at the 3′ terminus linked by 2′-5′ internucleotide linkages. In one embodiment, four consecutive nucleotides at the 3′ terminus of (N′)y are joined by three 2′-5′ phosphodiester bonds, wherein one or more of the 2′-5′ nucleotides which form the 2′-5′ phosphodiester bonds further includes a 3′-O-methyl (3′OMe) sugar modification. Preferably the 3′ terminal nucleotide of (N′)y includes a 2′OMe sugar modification. In certain embodiments x=y=18 and in (N′)y two or more consecutive nucleotides at positions 14, 15, 16, 17, and 18 include a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide bond. In various embodiments the nucleotide forming the 2′-5′ internucleotide bond includes a 3′ deoxyribose nucleotide or a 3′ methoxy nucleotide. In some embodiments x=y=18 and (N′)y includes nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond between positions 15-16, 16-17 and 17-18 or between positions 16-17 and 17-18. In some embodiments x=y=18 and (N′)y includes nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond between positions 14-15, 15-16, 16-17, and 17-18 or between positions 15-16, 16-17, and 17-18 or between positions 16-17 and 17-18 or between positions 17-18 or between positions 15-16 and 17-18. In other embodiments the pyrimidine ribonucleotides (rU, rC) in (N′)y are substituted with nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond.

In some embodiments, x=y=19 and (N′)y comprises five consecutive nucleotides at the 3′ terminus joined by four 2′-5′ linkages, specifically the linkages between the nucleotides position 15-16, 16-17, 17-18 and 18-19.

In some embodiments the internucleotide linkages include phosphodiester bonds. In some embodiments x=y=19 and (N′)y comprises five consecutive nucleotides at the 3′ terminus joined by four 2′-5′ linkages and optionally further includes Z′ and z′ independently selected from an inverted abasic moiety and a C3 alkyl [C3; 1,3-propanediol mono(dihydrogen phosphate)] cap.

In some embodiments x=y=19 and (N′)y comprises an L-DNA position 18; and (N′)y optionally further includes Z′ and z′ independently selected from an inverted abasic moiety and a C3 alkyl [C3; 1,3-propanediol mono(dihydrogen phosphate)] cap.

In some embodiments (N′)y comprises a 3′ terminal phosphate. In some embodiments (N′)y comprises a 3′ terminal hydroxyl.

In some embodiments x=y=19 and (N)x includes 2′OMe sugar modified ribonucleotides at positions 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 or at positions 2, 4, 6, 8, 11, 13, 15, 17, 19. In some embodiments x=y=19 and (N)x includes 2′OMe sugar modified pyrimidines. In some embodiments all pyrimidines in (N)x include the 2′OMe sugar modification.

In some embodiments x=y=18 and N2 is a riboadenine moiety.

In some embodiments in x=y=18, and N2-(N′)y comprises five consecutive nucleotides at the 3′ terminus joined by four 2′-5′ linkages, specifically the linkages between the nucleotides position 15-16, 16-17, 17-18 and 18-19. In some embodiments the linkages include phosphodiester bonds.

In some embodiments x=y=18 and N2-(N′)y comprises five consecutive nucleotides at the 3′ terminus joined by four 2′-5′ linkages and optionally further includes Z′ and z′ independently selected from an inverted abasic moiety and a C3 alkyl [C3; 1,3-propanediol mono(dihydrogen phosphate)] cap.

In some embodiments x=y=18 and N2-(N′)y comprises an L-DNA position 18; and (N′)y optionally further includes Z′ and z′ independently selected from an inverted abasic moiety and a C3 alkyl [C3; 1,3-propanediol mono(dihydrogen phosphate)] cap.

In some embodiments N2-(N′)y comprises a 3′ terminal phosphate. In some embodiments N2-(N′)y comprises a 3′ terminal hydroxyl.

In some embodiments x=y=18 and N1-(N)x includes 2′OMe sugar modified ribonucleotides at positions 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 or at positions 2, 4, 6, 8, 11, 13, 15, 17, 19.

In some embodiments x=y=18 and N1-(N)x includes 2′OMe sugar modified pyrimidines. In some embodiments all pyrimidines in (N)x include the 2′OMe sugar modification. In some embodiments N1-(N)x further comprises an L-DNA at position 6 or 7 (5′>3′). In other embodiments N1-(N)x further comprises a ribonucleotide which generates a 2′5′ internucleotide linkage in between the ribonucleotides at positions 5-6 or 6-7 (5′>3′)

In additional embodiments N1-(N)x further includes Z wherein Z comprises a non-nucleotide overhang. In some embodiments the non-nucleotide overhang is C3-C3 [1,3-propanediol mono(dihydrogen phosphate)]2.

In some embodiments the double stranded molecules disclosed herein, in particular molecules set forth in Tables A3, A4, A7, A8 and B3, B4, B7 and B8, include one or more of the following modifications:

• • a) N in at least one of positions 5, 6, 7, 8, or 9 from the 5′ terminus of the antisense strand is selected from a DNA, TNA, a 2′5′ nucleotide or a mirror nucleotide;
  • b) N′ in at least one of positions 9 or 10 from the 5′ terminus of the sense strand is selected from a TNA, 2′5′ nucleotide and a pseudoUridine;
  • c) N′ in 4, 5, or 6 consecutive positions at the 3′ terminus positions of (N′)y comprises a 2′5′ nucleotide;
  • d) one or more pyrimidine ribonucleotides are 2′ modified in the sense strand, the antisense strand or both the sense strand and the antisense strand.

In some embodiments the double stranded molecules in particular molecules set forth in Tables A3, A4, A7, A8 and B3, B4, B7 and B8 include a combination of the following modifications

• • a) the antisense strand includes a DNA, TNA, a 2′5′ nucleotide or a mirror nucleotide in at least one of positions 5, 6, 7, 8, or 9 from the 5′ terminus;
  • b) the sense strand includes at least one of a TNA, a 2′5′ nucleotide and a pseudoUridine in positions 9 or 10 from the 5′ terminus; and
  • c) one or more pyrimidine ribonucleotides are 2′ modified in the sense strand, the antisense strand or both the sense strand and the antisense strand.

In some embodiments the double stranded molecules in particular molecules set forth in Tables A3, A4, A7, A8 and B3, B4, B7 and B8 include a combination of the following modifications

• • a) the antisense strand includes a DNA, 2′5′ nucleotide or a mirror nucleotide in at least one of positions 5, 6, 7, 8, or 9 from the 5′ terminus;
  • b) the sense strand includes 4, 5, or 6 consecutive 2′5′ nucleotides at the 3′ penultimate or 3′ terminal positions; and
  • c) one or more pyrimidine ribonucleotides are 2′ modified in the sense strand, the antisense strand or both the sense strand and the antisense strand.

In some embodiments of Structure A1 and/or Structure A2 (N)y includes at least one unconventional moiety selected from a mirror nucleotide, a 2′5′ nucleotide and a TNA. In some embodiments the unconventional moiety is a mirror nucleotide. In various embodiments the mirror nucleotide is selected from an L-ribonucleotide (L-RNA) and an L-deoxyribonucleotide (L-DNA). In preferred embodiments the mirror nucleotide is L-DNA. In certain embodiments the sense strand comprises an unconventional moiety in position 9 or 10 (from the 5′ terminus). In preferred embodiments the sense strand includes an unconventional moiety in position 9 (from the 5′ terminus). In some embodiments the sense strand is 19 nucleotides in length and comprises 4, 5, or 6 consecutive unconventional moieties in positions 15, (from the 5′ terminus). In some embodiments the sense strand includes 4 consecutive 2′5′ ribonucleotides in positions 15, 16, 17, and 18. In some embodiments the sense strand includes 5 consecutive 2′5′ ribonucleotides in positions 15, 16, 17, 18 and 19. In various embodiments the sense strand further comprises Z′. In some embodiments Z′ includes a C3OH moiety or a C3Pi moiety.

In some embodiments of Structure A1 and/or Structure A2 (N)y comprises at least one unconventional moiety selected from a mirror nucleotide and a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide phosphate bond. In some embodiments the unconventional moiety is a mirror nucleotide. In various embodiments the mirror nucleotide is selected from an L-ribonucleotide (L-RNA) and an L-deoxyribonucleotide (L-DNA). In preferred embodiments the mirror nucleotide is L-DNA.

In some embodiments of Structure A1 (N′)y comprises at least one L-DNA moiety. In some embodiments x=y=19 and (N′)y consists of unmodified ribonucleotides at positions 1-17 and 19 and one L-DNA at the 3′ penultimate position (position 18). In other embodiments x=y=19 and (N′)y consists of unmodified ribonucleotides at position 1-16 and 19 and two consecutive L-DNA at the 3′ penultimate position (positions 17 and 18). In various embodiments the unconventional moiety is a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide phosphate linkage. According to various embodiments (N′)y comprises 2, 3, 4, 5, or 6 consecutive ribonucleotides at the 3′ terminus linked by 2′-5′ internucleotide linkages. In one embodiment, four consecutive nucleotides at the 3′ terminus of (N′)y are joined by three 2′-5′ phosphodiester bonds. In one embodiment, five consecutive nucleotides at the 3′ terminus of (N′)y are joined by four 2′-5′ phosphodiester bonds. In some embodiments, wherein one or more of the 2′-5′ nucleotides form a 2′-5′ phosphodiester bonds the nucleotide further comprises a 3′-O-methyl (3′OMe) sugar modification. In some embodiments the 3′ terminal nucleotide of (N′)y comprises a 3′OMe sugar modification. In certain embodiments x=y=19 and (N′)y comprises two or more consecutive nucleotides at positions 15, 16, 17, 18 and 19 comprise a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide bond. In various embodiments the nucleotide forming the 2′-5′ internucleotide bond comprises a 3′ deoxyribose nucleotide or a 3′ methoxy nucleotide. In some embodiments x=y=19 and (N′)y comprises nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond between positions 15-16, 16-17 and 17-18 or between positions 16-17, 17-18 and 18-19. In some embodiments x=y=19 and (N′)y comprises nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond between positions 16-17 and 17-18 or between positions 17-18 and 18-19 or between positions 15-16 and 17-18. In other embodiments the pyrimidine ribonucleotides (rU, rC) in (N′)y are substituted with nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond.

In some embodiments of Structure A2 (N)y comprises at least one L-DNA moiety. In some embodiments x=y=18 and N2-(N′)y, consists of unmodified ribonucleotides at positions 1-17 and 19 and one L-DNA at the 3′ penultimate position (position 18). In other embodiments x=y=18 and N2-(N′)y consists of unmodified ribonucleotides at position 1-16 and 19 and two consecutive L-DNA at the 3′ penultimate position (positions 17 and 18). In various embodiments the unconventional moiety is a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide phosphate linkage. According to various embodiments N2-(N′)y comprises 2, 3, 4, 5, or 6 consecutive ribonucleotides at the 3′ terminus linked by 2′-5′ internucleotide linkages. In one embodiment, four consecutive nucleotides at the 3′ terminus of N2-(N′)y are joined by three 2′-5′ phosphodiester bonds, wherein one or more of the 2′-5′ nucleotides which form the 2′-5′ phosphodiester bonds further comprises a 3′-O-methyl (3′OMe) sugar modification. In some embodiments the 3′ terminal nucleotide of N2-(N′)y comprises a 2′OMe sugar modification. In certain embodiments x=y=18 and N2-(N′)y comprises two or more consecutive nucleotides at positions 15, 16, 17, 18 and 19 comprise a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide bond. In various embodiments the nucleotide forming the 2′-5′ internucleotide bond comprises a 3′ deoxyribose nucleotide or a 3′ methoxy nucleotide. In some embodiments x=y=18 and N2-(N′)y comprises nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond between positions 16-17 and 17-18 or between positions 17-18 and 18-19 or between positions 15-16 and 17-18. In other embodiments the pyrimidine ribonucleotides (rU, rC) in (N′)y comprise nucleotides joined to the adjacent nucleotide by a 2′-5′ internucleotide bond.

In further embodiments of Structures A1 and A2 (N′)y comprises 1-8 modified ribonucleotides wherein the modified ribonucleotide is a deoxyribose (DNA) nucleotide. In certain embodiments (N′)y comprises 1, 2, 3, 4, 5, 6, 7, or up to 8 DNA moieties. In further embodiments of Structures A1 and A2 (N′)y includes 1-8 modified ribonucleotides wherein the modified ribonucleotide is a DNA nucleotide. In certain embodiments (N′)y includes 1, 2, 3, 4, 5, 6, 7, or up to 8 DNA moieties.

In some embodiments either Z or Z′ is present and independently includes two non-nucleotide moieties.

In additional embodiments Z and Z′ are present and each independently includes two non-nucleotide moieties.

In some embodiments each of Z and Z′ includes an abasic moiety, for example a deoxyriboabasic moiety (referred to herein as “dAb”) or riboabasic moiety (referred to herein as “rAb”). In some embodiments each of Z and/or Z′ includes two covalently linked abasic moieties and is for example dAb-dAb or rAb-rAb or dAb-rAb or rAb-dAb, wherein each moiety is covalently attached to an adjacent moiety, preferably via a phospho-based bond. In some embodiments the phospho-based bond includes a phosphorothioate, a phosphonoacetate or a phosphodiester bond. In preferred embodiments the phospho-based bond includes a phosphodiester bond.

In some embodiments each of Z and/or Z′ independently includes an alkyl moiety, optionally propane [(CH2)3] moiety (C3) or a derivative thereof including propanol (C3-OH) and phospho derivative of propanediol (“C3-3′Pi”). In some embodiments each of Z and/or Z′ includes two alkyl moieties and in some examples is C3-C3-OH. The 3′ terminus of the antisense strand and/or the 3′ terminus of the sense strand is covalently attached to a C3 moiety via a phospho-based bond and the C3 moiety is covalently conjugated a C3-OH moiety via a phospho-based bond. In some embodiments the phospho-based bonds include a phosphorothioate, a phosphonoacetate or a phosphodiester bond. In preferred embodiments the phospho-based bond includes a phosphodiester bond.

In one specific embodiment of Structure A1 or Structure A2, Z includes C3-C3-OH (a propyl moiety covalently linked to a propanol moiety via a phosphodiester bond). In some embodiments Z includes a propanol moiety covalently attached to the 3′ terminus of the antisense strand via a phosphodiester bond. In some embodiments the C3-C3-OH overhang is covalently attached to the 3′ terminus of (N)x or (N′)y via covalent linkage, for example a phosphodiester linkage. In some embodiments the linkage between a first C3 and a second C3 is a phosphodiester linkage.

In various embodiments the alkyl moiety is a C3 alkyl (“C3”) to C6 alkyl (“C6”) (e.g. C3, C4, C5 or C6) moiety including a terminal hydroxyl, a terminal amino, terminal phosphate group.

In some embodiments the alkyl moiety is a C3 alkyl moiety. In some embodiments the C3 alkyl moiety includes propanol, propylphosphate, propylphosphorothioate or a combination thereof.

The C3 alkyl moiety may be covalently linked to the 3′ terminus of (N′)y and or the 3′ terminus of (N)x via a phosphodiester bond. In some embodiments the alkyl moiety includes propanol, propyl phosphate (trimethyl phosphate) or propyl phosphorothioate (trimethyl phosphorothioate).

In some embodiments each of Z and Z′ is independently selected from propanol, propyl phosphate (trimethyl phosphate), propyl phosphorothioate (trimethyl phosphorothioate), combinations thereof or multiples thereof.

In some embodiments each of Z and Z′ is independently selected from propyl phosphate (trimethyl phosphate), propyl phosphorothioate (trimethyl phosphorothioate), propyl phospho-propanol; propyl phospho-propyl phosphorothioate; propylphospho-propyl phosphate; (propyl phosphate)3, (propyl phosphate)-2-propanol, (propyl phosphate)2-propyl phosphorothioate. Any propane or propanol conjugated moiety can be included in Z or Z′.

In additional embodiments each of Z and/or Z′ includes a combination of an abasic moiety and an unmodified deoxyribonucleotide or ribonucleotide or a combination of a hydrocarbon moiety and an unmodified deoxyribonucleotide or ribonucleotide or a combination of an abasic moiety (deoxyribo or ribo) and a hydrocarbon moiety. In such embodiments, each of Z and/or Z′ includes C3-rAb or C3-dAb wherein each moiety is covalently bond to the adjacent moiety via a phospho-based bond, preferably a phosphodiester, phosphorothioate or phosphonoacetate bond.

In certain embodiments nucleic acid molecules as disclosed herein include a sense oligonucleotide sequence selected from any one of Tables A1-B8.

In some embodiments, provided is a tandem structure and a triple armed structure, also known as RNAstar. Such structures are disclosed in PCT patent publication WO 2007/091269. A tandem oligonucleotide comprises at least two siRNA compounds.

A triple-stranded oligonucleotide may be an oligoribonucleotide having the general structure:

5′	oligo1 (sense)	LINKER A	Oligo2 (sense)	3′
3′	oligo1 (antisense)	LINKER B	Oligo3 (sense)	5′
3′	oligo3 (antisense)	LINKER C	oligo2 (antisense)	5′
	or
5′	oligo1 (sense)	LINKER A	Oligo2 (antisense)	3′
3′	oligo1 (antisense)	LINKER B	Oligo3 (sense)	5′
3′	oligo3 (antisense)	LINKER C	oligo2 (sense)	5′
	or
5′	oligo1 (sense)	LINKER A	oligo3 (antisense)	3′
3′	oligo1 (antisense)	LINKER B	oligo2 (sense)	5′
5′	oligo3 (sense)	LINKER C	oligo2 (antisense)	3′

wherein one or more of linker A, linker B or linker C is present; any combination of two or more oligonucleotides and one or more of linkers A-C is possible, so long as the polarity of the strands and the general structure of the molecule remains. Further, if two or more of linkers A-C are present, they may be identical or different.

In some embodiments a “gapped” RNAstar compound is preferred wherein the compound consists of four ribonucleotide strands forming three siRNA duplexes having the general structure as follows:

wherein each of oligo A, oligo B, oligo C, oligo D, oligo E and oligo F represents at least 19 consecutive ribonucleotides, wherein from 19 to 40 of such consecutive ribonucleotides, in each of oligo A, B, C, D, E and F comprise a strand of a siRNA duplex, wherein each ribonucleotide may be modified or unmodified;wherein strand 1 comprises oligo A which is either a sense portion or an antisense portion of a first siRNA duplex of the compound, strand 2 comprises oligo B which is complementary to at least 19 nucleotides in oligo A, and oligo A and oligo B together form a first siRNA duplex that targets a first target mRNA;wherein strand 1 further comprises oligo C which is either a sense portion or an antisense strand portion of a second siRNA duplex of the compound, strand 3 comprises oligo D which is complementary to at least 19 nucleotides in oligo C and oligo C and oligo D together form a second siRNA duplex that targets a second target mRNA;wherein strand 4 comprises oligo E which is either a sense portion or an antisense strand portion of a third siRNA duplex of the compound, strand 2 further comprises oligo F which is complementary to at least 19 nucleotides in oligo E and oligo E and oligo F together form a third siRNA duplex that targets a third target mRNA; andwherein linker A is a moiety that covalently links oligo A and oligo C; linker B is a moiety that covalently links oligo B and oligo F, and linker A and linker B can be the same or different.

In some embodiments the first, second and third siRNA duplex target the same gene, In other embodiments two of the first, second or third siRNA duplexes target the same mRNA and the third siRNA duplex targets a different mRNA. In some embodiments each of the first, second and third duplex targets a different mRNA.

In another aspect, provided are methods for reducing the expression of TIMP1 and TIMP2 in a cell by introducing into a cell a nucleic acid molecule as provided herein in an amount sufficient to reduce expression of TIMP1 and TIMP2. In one embodiment, the cell is hepatocellular stellate cell. In another embodiment, the cell is a stellate cell in renal or pulmonary tissue. In certain embodiments, the method is performed in vitro, in other embodiments, the method is performed in vivo.

In yet another aspect, provided are methods for treating an individual suffering from a disease associated with TIMP1 and/or TIMP2. The methods include administering to the individual a nucleic acid molecule such as provided herein in an amount sufficient to reduce expression of TIMP1 or TIMP2. In certain embodiments the disease associated with TIMP1 or TIMP2 is a disease selected from the group consisting of liver fibrosis, cirrhosis, pulmonary fibrosis including lung fibrosis (including ILF), any condition causing kidney fibrosis (e.g., CKD including ESRD), peritoneal fibrosis, chronic hepatic damage, fibrillogenesis, fibrotic diseases in other organs, abnormal scarring (keloids) associated with all possible types of skin injury accidental and jatrogenic (operations); scleroderma; cardiofibrosis, fibrosis in the brain; failure of glaucoma filtering operation; and intestinal adhesions. The compounds are useful in treating organ specific indications including those shown in Table I below:

TABLE I
Organ         Indication
Skin          Pathologic scarring as keloid and hypertrophic scar
              Surgical scarring
              Injury scarring
              keloid, or nephrogenic fibrosing dermatopathy
Peritoneum    Peritoneal fibrosis
              Adhesions
              Peritoneal Sclerosis associated with continual ambulatory peritoneal dialysis
              (CAPD)
Liver         Cirrhosis including post-hepatitis C cirrhosis, primary biliary cirrhosis
              Liver fibrosis, e.g. Prevention of Liver Fibrosis in Hepatitis C carriers
              schistomasomiasis
              cholangitis
              Liver cirrhosis due to Hepatitis C post liver transplant or Non-Alcoholic
              Steatohepatitis (NASH)
Pancreas      inter(peri)lobular fibrosis (as in alcoholic chronic pancreatitis), periductal
              fibrosis (as in hereditary pancreatitis), periductal and interlobular fibrosis (as
              in autoimmune pancreatitis), diffuse inter- and intralobular fibrosis (as in
              obstructive chronic pancreatitis)
Kidney        Chronic Kidney Disease (CKD) of any etiology. Treatment of early stage
              CKD (elevated SCr) in diabetic patients (“prevent” further deterioration in
              renal function)
              kidney fibrosis associated with lupus glomeruloschelerosis
              Diabetic Nephropathy
Heart         Congestive heart failure,
              Endomyocardial fibrosis,
              cardiofibrosis
              fibrosis associated with myocardial infarction
Lung          Asthma, Idiopathic pulmonary fibrosis (IPF); Radiation fibrosis, a sequel of
              radiation pneumonitis (e.g. due to cancer treating radiation)
              Interstitial lung fibrosis (ILF)
              Radiation Pneumonitis leading to Pulmonary Fibrosis (e.g. due to cancer
              treating radiation)
Bone marrow   Myeloproliferative disorders: Myelofibrosis (MF), Polycythemia vera (PV),
              Essential thrombocythemia (ET)
              idiopathic myelofibrosis
              drug induced myelofibrosis.
Eye           Anterior segment: Corneal opacification e,g, following inherited dystrophies,
              herpetic keratitis or pterygia; Glaucoma
              Posterior segment fibrosis and traction retinal detachment, a complication of
              advanced diabetic retinopathy (DR); Fibrovascular scarring and gliosis in the
              retina;
              Under the retina fibrosis for example subsequent to subretinal hemorrhage
              associated with neovascular AMD
              Retro-orbital fibrosis, postcataract surgery, proliferative vitreoretinopathy.
              Ocular cicatricial pemphigoid
Intestine     Intestinal fibrosis, Crohn's disease
Vocal cord    Vocal cord scarring, vocal cord mucosal fibrosis, laryngeal fibrosis
Vasculature   Atherosclerosis, postangioplasty arterial restenosis
Brain         Fibrosis associated with brain (cerebral) infarction
Multisystemic Scleroderma systemic sclerosis; multifocal fibrosclerosis; sclerodermatous
              graft-versus-host disease in bone marrow transplant recipients, and
              nephrogenic systemic fibrosis (exposure to gadolinium-based contrast agents
              (GBCAs), 30% of MRIs)
Malignancies  Metastatic and invasive cancer by inhibiting function of activated tumor
of various    associated myofibroblasts
origin

In some embodiments the preferred indications include, Liver cirrhosis due to Hepatitis C post liver transplant; Liver cirrhosis due to Non-Alcoholic Steatohepatitis (NASH); Idiopathic Pulmonary Fibrosis (IPF); Radiation Pneumonitis leading to Pulmonary Fibrosis; Diabetic Nephropathy; Peritoneal Sclerosis associated with continual ambulatory peritoneal dialysis (CAPD) and Ocular cicatricial pemphigoid.

Fibrotic Liver indications include Alcoholic Cirrhosis, Hepatitis B cirrhosis, Hepatitis C cirrhosis, Hepatitis C (Hep C) cirrhosis post orthotopic liver transplant (OLTX), NASH/NAFLD wherein NASH is an extreme form of nonalcoholic fatty liver disease (NAFLD), Primary biliary cirrhosis (PBC), Primary sclerosing cholangitis (PSC), Biliary atresia, alpha1 antitrypsin deficiency (A1AD), Copper storage diseases (Wilson's disease), Fructosemia, Galactosemia, Glycogen storage diseases (especially types III, IV, VI, IX, and X), Iron-overload syndromes (hemochromatosis), Lipid abnormalities (e.g., Gaucher's disease). Peroxisomal disorders (eg, Zellweger syndrome), Tyrosinemia, Congenital hepatic fibrosis, Bacterial Infections (eg, brucellosis), Parasitic (eg, echinococcosis), Budd-Chiari syndrome (hepatic veno-occlusive disease).

Pulmonary Indications indications include Idiopathic Pulmonary Fibrosis, Silicosis, Pneumoconiosis, Bronchopulmonary Dysplasia in newborn following neonatal respiratory distress syndrome, Bleomycin/chemotherapeutic induced lung injury, Brochiolitis Obliterans (BOS) post lung transplant, Chronic obstructive pulmonary disorder (COPD), Cystic Fibrosis, Asthma.

Cardiac indications include Cardiomyopathy, Atherosclerosis (Bergers disease, etc), Endomyocardial fibrosis, Atrial Fibrillation, Scarring post Myocardial Infarction (MI).

Other Thoracic indications include Radiation-induced capsule tissue reactions around textured breast implants and Oral submucosal fibrosis.

Renal indications include Autosomal Dominant Polycystic Kidney Disease (ADPKD), Diabetic nephropathy (diabetic glomerulosclerosis), FSGS (collapsing vs. other histologic variants), IgA Nephropathy (Berger Disease), Lupus Nephritis, Wegner's, Scleroderma, Goodpasture Syndrome, tubulointerstitial fibrosis: drug induced (protective) pencillins, cephalosporins, analgesic nephropathy, Membranoproliferative glomerulonephritis (MPGN), Henoch-Schonlein Purpura, Congenital nephropathies: Medullary Cystic Disease, Nail-Patella Syndrome and Alport Syndrome.

Bone Marrow indications include lympangiolyomyositosis (LAM), Chronic graft vs. host disease, Polycythemia vera, Essential thrombocythemia, Myelofibrosis.

Ocular indications include Retinopathy of Prematurity (RoP), Ocular cicatricial pemphigoid, Lacrimal gland fibrosis, Retinal attachment surgery, Corneal opacity, Herpetic keratitis, Pterygia, Glaucoma, Age-related macular degeneration (AMD/ARMD), Retinal fibrosis associated Diabetes mellitus (DM) retinopathy.

Brain indications include fibrosis associated with brain infarction.

Gynecological indications include Endometriosis add on to hormonal therapy for prevention of scarring, post STD fibrosis/salphingitis.

Systemic indications include Dupuytren's disease, palmar fibromatosis, Peyronie's disease, Ledderhose disease, keloids, multifocal fibrosclerosis, nephrogenic systemic fibrosis, nephrogenic myelofibrosis (anemia).

Injury Associated Fibrotic Diseases include Burn (chemical included) induced skin & soft tissue scarring and contraction, Radiation induce skin & organ scarring post cancer therapeutic radiation treatment, Keloid (skin).

Surgical indications include peritoneal fibrosis post peritoneal dialysis catheter, corneal implant, cochlear implant, other implants, silicone implants in breasts, chronic sinusitis; adhesions, pseudointimal hyperplasia of dialysis grafts.

Other indications include Chronic Pancreatitis.

In some embodiments the methods include administering to the individual a nucleic acid molecule such as provided herein in an amount sufficient to reduce expression of TIMP1. In some embodiments the methods include administering to the individual a nucleic acid molecule such as provided herein in an amount sufficient to reduce expression of TIMP2. In some embodiments the methods include administering to the individual nucleic acid molecules such as provided herein in an amount sufficient to reduce expression of TIMP1. In some embodiments the methods include administering to the individual nucleic acid molecules such as provided herein in an amount sufficient to reduce expression of TIMP2. In some embodiments provided is a nucleic acid disclosed herein for the treatment of a fibrotic disease selected from a disease or disorder set forth in Table I. In another embodiment provided is a nucleic acid molecule for use in therapy. In some embodiments therapy comprises treatment of a fibrotic disease or disorder set forth in Table I. In some embodiments provided is use of a nucleic acid molecule disclosed herein for the preparation of a medicament useful in treating a fibrotic disease or disorder set forth in Table I. In some embodiments the nucleic acid molecule is set forth in Table C, e.g. TIMP1-A, TIMP1-B, TIMP1-C. In some embodiments the nucleic acid molecule is set forth in Table D, e.g. TIMP2-A, TIMP2-B, TIMP2-C, TIMP2-D, TIMP2-E. In some embodiments the sense and antisense sequences of the nucleic acid molecule are selected from the sequence pairs set forth in any one of Table A3, Table A4, Table A7 or Table A8. In some embodiments the sense and antisense sequences of the nucleic acid molecule are selected from the sequence pairs set forth in any one of Table B3, Table B4, Table B7 or Table B8.

In one aspect, provided are pharmaceutical compositions that include a nucleic acid molecule (e.g., an siNA molecule) as described herein in a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical formulation includes, or involves, a delivery system suitable for delivering nucleic acid molecules (e.g., siNA molecules) to an individual such as a patient; for example delivery systems described in more detail below.

In a related aspect, provided are compositions or kits that include a nucleic acid molecule (e.g., an siNA molecule) packaged for use by a patient. The package may be labeled or include a package label or insert that indicates the content of the package and provides certain information regarding how the nucleic acid molecule (e.g., an siNA molecule) should be or can be used by a patient, for example the label may include dosing information and/or indications for use. In certain embodiments the contents of the label will bear a notice in a form prescribed by a government agency, for example the United States Food and Drug Administration (FDA). In certain embodiments, the label may indicate that the nucleic acid molecule (e.g., an siNA molecule) is suitable for use in treating a patient suffering from a disease associated with TIMP1 or TIMP2; for example, the label may indicate that the nucleic acid molecule (e.g., an siNA molecule) is suitable for use in treating fibroids; or for example the label may indicate that the nucleic acid molecule (e.g., an siNA molecule) is suitable for use in treating a disease selected from the group consisting of fibrosis, liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, and fibrillogenesis.

As used herein, the term “tissue inhibitor of metalloproteinases 1” or “TIMP1” are used interchangeably and refer to any tissue inhibitor of metalloproteinases 1 peptide, or polypeptide having any TIMP1 protein activity. Tissue inhibitor of metalloproteinases 1 is a natural inhibitor of matrix metalloproteinases. In certain preferred embodiments, “TIMP1” refers to human TIMP1. Tissue inhibitor of metalloproteinases 1 (or more particularly human TIMP1) may have an amino acid sequence that is the same, or substantially the same, as SEQ ID NO. 3 (FIG. 1C).

As used herein, the term “tissue inhibitor of metalloproteinases 2” or “TIMP2” are used interchangeably and refer to any tissue inhibitor of metalloproteinases 2 peptide, or polypeptide having any TIMP2 protein activity. Tissue inhibitor of metalloproteinases 2 (or more particularly human TIMP2) may have an amino acid sequence that is the same, or substantially the same, as SEQ ID NO. 4 (FIG. 1D).

As used herein the term “nucleotide sequence encoding TIMP1 and TIMP2” means a nucleotide sequence that codes for a TIMP1 and TIMP2 protein or portion thereof. The term “nucleotide sequence encoding TIMP1 and TIMP2” is also meant to include TIMP1 and TIMP2 coding sequences such as TIMP1 and TIMP2 isoforms, mutant TIMP1 and TIMP2 genes, splice variants of TIMP1 and TIMP2 genes, and TIMP1 and TIMP2 gene polymorphisms. A nucleic acid sequence encoding TIMP1 and TIMP2 includes mRNA sequences encoding TIMP1 and TIMP2, which can also be referred to as “TIMP1 and TIMP2 mRNA.” Exemplary sequences of human TIMP1 mRNA and TIMP2 mRNA are set forth as SEQ ID. NO. 1 and SEQ ID NO:2, respectively.

As used herein, the term “nucleic acid molecule” or “nucleic acid” are used interchangeably and refer to an oligonucleotide, nucleotide or polynucleotide. Variations of “nucleic acid molecule” are described in more detail herein. A nucleic acid molecule encompasses both modified nucleic acid molecules and unmodified nucleic acid molecules as described herein. A nucleic acid molecule may include deoxyribonucleotides, ribonucleotides, modified nucleotides or nucleotide analogs in any combination.

As used herein, the term “nucleotide” refers to a chemical moiety having a sugar (or an analog thereof, or a modified sugar), a nucleotide base (or an analog thereof, or a modified base), and a phosphate group (or analog thereof, or a modified phosphate group). A nucleotide encompasses both modified nucleotides or unmodified nucleotides as described herein. As used herein, nucleotides may include deoxyribonucleotides (e.g., unmodified deoxyribonucleotides), ribonucleotides (e.g., unmodified ribonucleotides), and modified nucleotide analogs including, inter alia, locked nucleic acids and unlocked nucleic acids, peptide nucleic acids, L-nucleotides (also referred to as mirror nucleotides), ethylene-bridged nucleic acid (ENA), arabinoside, PACE, nucleotides with a 6 carbon sugar, as well as nucleotide analogs (including abasic nucleotides) often considered to be non-nucleotides. In some embodiments, nucleotides may be modified in the sugar, nucleotide base and/or in the phosphate group with any modification known in the art, such as modifications described herein. A “polynucleotide” or “oligonucleotide” as used herein refer to a chain of linked nucleotides; polynucleotides and oligonucleotides may likewise have modifications in the nucleotide sugar, nucleotide bases and phosphate backbones as are well known in the art and/or are disclosed herein.

As used herein, the term “short interfering nucleic acid”, “siNA”, or “short interfering nucleic acid molecule” refers to any nucleic acid molecule capable of modulating gene expression or viral replication. Preferably siNA inhibits or down regulates gene expression or viral replication. siNA includes without limitation nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically-modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA), and others. As used herein, “short interfering nucleic acid”, “siNA”, or “short interfering nucleic acid molecule” has the meaning described in more detail elsewhere herein.

As used herein, the term “complementary” means that a nucleic acid can form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules disclosed herein, the binding free energy for a nucleic acid molecule with its complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., RNAi activity. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al., 1987, CSH Symp. Quant. Biol. LII pp. 123-133; Frier et al., 1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc. 109:3783-3785). A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule that can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, or 10 nucleotides out of a total of 10 nucleotides in the first oligonucleotide being based paired to a second nucleic acid sequence having 10 nucleotides represents 50%, 60%, 70%, 80%, 90%, and 100% complementary respectively). “Fully complementary” means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. In one embodiment, a nucleic acid molecule disclosed herein includes about 15 to about 35 or more (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 or more) nucleotides that are complementary to one or more target nucleic acid molecules or a portion thereof.

As used herein, the term “sense region” refers to a nucleotide sequence of a siNA molecule complementary (partially or fully) to an antisense region of the siNA molecule. The sense strand of a siNA molecule can include a nucleic acid sequence having homology with a target nucleic acid sequence. As used herein, “sense strand” refers to nucleic acid molecule that includes a sense region and may also include additional nucleotides.

As used herein, the term “antisense region” refers to a nucleotide sequence of a siNA molecule complementary (partially or fully) to a target nucleic acid sequence. The antisense strand of a siNA molecule can optionally include a nucleic acid sequence complementary to a sense region of the siNA molecule. As used herein, “antisense strand” refers to nucleic acid molecule that includes an antisense region and may also include additional nucleotides.

As used herein, the term “RNA” refers to a molecule that includes at least one ribonucleotide residue.

As used herein, the term “duplex region” refers to the region in two complementary or substantially complementary oligonucleotides that form base pairs with one another, either by Watson-Crick base pairing or any other manner that allows for a duplex between oligonucleotide strands that are complementary or substantially complementary. For example, an oligonucleotide strand having 21 nucleotide units can base pair with another oligonucleotide of 21 nucleotide units, yet only 19 bases on each strand are complementary or substantially complementary, such that the “duplex region” consists of 19 base pairs. The remaining base pairs may, for example, exist as 5′ and 3′ overhangs. Further, within the duplex region, 100% complementarity is not required; substantial complementarity is allowable within a duplex region. Substantial complementarity refers to complementarity between the strands such that they are capable of annealing under biological conditions. Techniques to empirically determine if two strands are capable of annealing under biological conditions are well know in the art. Alternatively, two strands can be synthesized and added together under biological conditions to determine if they anneal to one another.

As used herein, the terms “non-pairing nucleotide analog” means a nucleotide analog which includes a non-base pairing moiety including but not limited to: 6 des amino adenosine (Nebularine), 4-Me-indole, 3-nitropyrrole, 5-nitroindole, Ds, Pa, N3-Me ribo U, N3-Me riboT, N3-Me dC, N3-Me-dT, N1-Me-dG, N1-Me-dA, N3-ethyl-dC, N3-Me dC. In some embodiments the non-base pairing nucleotide analog is a ribonucleotide. In other embodiments it is a deoxyribonucleotide.

As used herein, the term, “terminal functional group” includes without limitation a halogen, alcohol, amine, carboxylic, ester, amide, aldehyde, ketone, ether groups.

An “abasic nucleotide” or “abasic nucleotide analog” is as used herein may also be often referred to herein and in the art as a pseudo-nucleotide or an unconventional moiety. While a nucleotide is a monomeric unit of nucleic acid, generally consisting of a ribose or deoxyribose sugar, a phosphate, and a base (adenine, guanine, thymine, or cytosine in DNA; adenine, guanine, uracil, or cytosine in RNA). an abasic or pseudo-nucleotide lacks a base, and thus is not strictly a nucleotide as the term is generally used in the art. Abasic deoxyribose moieties include for example, abasic deoxyribose-3′-phosphate; 1,2-dideoxy-D-ribofuranose-3-phosphate; 1,4-anhydro-2-deoxy-D-ribitol-3-phosphate. Inverted abasic deoxyribose moieties include inverted deoxyriboabasic; 3′,5′ inverted deoxyabasic 5′-phosphate.

The term “capping moiety” (z″) as used herein includes a moiety which can be covalently linked to the 5′ terminus of (N′)y and includes abasic ribose moiety, abasic deoxyribose moiety, modifications abasic ribose and abasic deoxyribose moieties including 2′ O alkyl modifications; inverted abasic ribose and abasic deoxyribose moieties and modifications thereof; C6-imino-Pi; a mirror nucleotide including L-DNA and L-RNA; 5′OMe nucleotide; and nucleotide analogs including 4′,5′-methylene nucleotide; 1-(β-D-erythrofuranosyl)nucleotide; 4′-thio nucleotide, carbocyclic nucleotide; 5′-amino-alkyl phosphate; 1,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 12-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; alpha-nucleotide; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5′-5′-inverted abasic moiety; 1,4-butanediol phosphate; 5′-amino; and bridging or non bridging methylphosphonate and 5′-mercapto moieties.

Certain capping moieties may be abasic ribose or abasic deoxyribose moieties; inverted abasic ribose or abasic deoxyribose moieties; C6-amino-Pi; a mirror nucleotide including L-DNA and L-RNA. The nucleic acid molecules as disclosed herein may be synthesized using one or more inverted nucleotides, for example inverted thymidine or inverted adenine (for example see Takei, et al., 2002. JBC 277(26):23800-06).

The term “unconventional moiety” as used herein refers to non-nucleotide moieties including an abasic moiety, an inverted abasic moiety, a hydrocarbon (alkyl) moiety and derivatives thereof, and further includes a deoxyribonucleotide, a modified deoxyribonucleotide, a mirror nucleotide (L-DNA or L-RNA), a non-base pairing nucleotide analog and a nucleotide joined to an adjacent nucleotide by a 2′-5′ internucleotide phosphate bond; bridged nucleic acids including LNA and ethylene bridged nucleic acids, linkage modified (e.g. PACE) and base modified nucleotides as well as additional moieties explicitly disclosed herein as unconventional moieties.

As used herein, the term “inhibit”, “down-regulate”, or “reduce” with respect to gene expression means the expression of the gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits (e.g., mRNA), or activity of one or more proteins or protein subunits, is reduced below that observed in the absence of an inhibitory factor (such as a nucleic acid molecule, e.g., an siNA, for example having structural features as described herein); for example the expression may be reduced to 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5% or less than that observed in the absence of an inhibitor.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1D show exemplary polynucleotide and polypeptide sequences. FIG. 1A shows mRNA sequence of human TIMP1 (NM_—003254.2 GI:73858576; SEQ ID NO:1). FIG. 1B shows mRNA sequence of TIMP2 (NM_—003255.4 GI:738585774; SEQ ID NO:2). FIG. 1C shows polypeptide sequence of human TIMP1 (NP_—003245.1 GI:4507509; SEQ ID NO:3). FIG. 1D shows polypeptide sequence of human TIMP2 (NP_—003246.1 GI:4507511; SEQ ID NO:4).

FIG. 2 shows knock down efficacy as determined by qPCR of TIMP1-A, TIMP1-B or TIMP1-C siRNAs (Table C) for TIMP1. The siRNA compounds were capable of knocking down the target TIMP1 gene.

FIG. 3 shows knock down efficacy as determined by qPCR TIMP2-A, TIMP2-B, TIMP2-C, TIMP2-D and TIMP2-E siRNAs (Table D). The siRNA compounds were capable of knocking down the target TIMP2 gene.

FIG. 4 shows the results of an in vivo assay testing the efficacy of siTIMP1 and siTIMP2 in treating liver fibrosis. Analysis of the liver fibrosis area was performed using Sirius red staining. The fibrotic area was calculated as the mean of 4 liver sections. The bar graph summarizes the digital quantification of staining for each group.

DETAILED DESCRIPTION OF THE INVENTION

RNA Interference and siNA Nucleic Acid Molecules

RNA interference refers to the process of sequence-specific post-transcriptional gene silencing in animals mediated by short interfering RNAs (siRNAs) (Zamore et al., 2000, Cell, 101, 25-33; Fire et al., 1998, Nature, 391, 806; Hamilton et al., 1999, Science, 286, 950-951; Lin et al., 1999, Nature, 402, 128-129; Sharp, 1999, Genes & Dev., 13:139-141; and Strauss, 1999, Science, 286, 886). The corresponding process in plants (Heifetz et al., International PCT Publication No. WO 99/61631) is often referred to as post-transcriptional gene silencing (PTGS) or RNA silencing. The process of post-transcriptional gene silencing is thought to be an evolutionarily-conserved cellular defense mechanism used to prevent the expression of foreign genes (Fire et al., 1999, Trends Genet., 15, 358). Such protection from foreign gene expression may have evolved in response to the production of double-stranded RNAs (dsRNAs) derived from viral infection or from the random integration of transposon elements into a host genome via a cellular response that specifically destroys homologous single-stranded RNA or viral genomic RNA. The presence of dsRNA in cells triggers the RNAi response through a mechanism that has yet to be fully characterized. This mechanism appears to be different from other known mechanisms involving double stranded RNA-specific ribonucleases, such as the interferon response that results from dsRNA-mediated activation of protein kinase PKR and 2′,5′-oligoadenylate synthetase resulting in non-specific cleavage of mRNA by ribonuclease L (see for example U.S. Pat. Nos. 6,107,094; 5,898,031; Clemens et al., 1997, J. Interferon & Cytokine Res., 17, 503-524; Adah et al., 2001, Curr. Med. Chem., 8, 1189).

The presence of long dsRNAs in cells stimulates the activity of a ribonuclease III enzyme referred to as dicer (Bass, 2000, Cell, 101, 235; Zamore et al., 2000, Cell, 101, 25-33; Hammond et al., 2000, Nature, 404, 293). Dicer is involved in the processing of the dsRNA into short pieces of dsRNA known as short interfering RNAs (siRNAs) (Zamore et al., 2000, Cell, 101, 25-33; Bass, 2000, Cell, 101, 235; Berstein et al., 2001, Nature, 409, 363). Short interfering RNAs derived from dicer activity are typically about 21 to about 23 nucleotides in length and include about 19 base pair duplexes (Zamore et al., 2000, Cell, 101, 25-33; Elbashir et al., 2001, Genes Dev., 15, 188). Dicer has also been implicated in the excision of 21- and 22-nucleotide small temporal RNAs (stRNAs) from precursor RNA of conserved structure that are implicated in translational control (Hutvagner et al., 2001, Science, 293, 834). The RNAi response also features an endonuclease complex, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single-stranded RNA having sequence complementary to the antisense strand of the siRNA duplex. Cleavage of the target RNA takes place in the middle of the region complementary to the antisense strand of the siRNA duplex (Elbashir et al., 2001, Genes Dev., 15, 188).

RNAi has been studied in a variety of systems. Fire et al., 1998, Nature, 391, 806, were the first to observe RNAi in C. elegans. Bahramian and Zarbl, 1999, Molecular and Cellular Biology, 19, 274-283 and Wianny and Goetz, 1999, Nature Cell Biol., 2, 70, describe RNAi mediated by dsRNA in mammalian systems. Hammond et al., 2000, Nature, 404, 293, describe RNAi in Drosophila cells transfected with dsRNA. Elbashir et al., 2001, Nature, 411, 494 and Tuschl et al., International PCT Publication No. WO 01/75164, describe RNAi induced by introduction of duplexes of synthetic 21-nucleotide RNAs in cultured mammalian cells including human embryonic kidney and HeLa cells. Recent work in Drosophila embryonic lysates (Elbashir et al., 2001, EMBO J., 20, 6877 and Tuschl et al., International PCT Publication No. WO 01/75164) has revealed certain requirements for siRNA length, structure, chemical composition, and sequence that are essential to mediate efficient RNAi activity.

Nucleic acid molecules (for example having structural features as disclosed herein) may inhibit or down regulate gene expression or viral replication by mediating RNA interference “RNAi” or gene silencing in a sequence-specific manner; see e.g., Zamore et al., 2000, Cell, 101, 25-33; Bass, 2001, Nature, 411, 428-429; Elbashir et al., 2001, Nature, 411, 494-498; and Kreutzer et al., International PCT Publication No. WO 00/44895; Zernicka-Goetz et al., International PCT Publication No. WO 01/36646; Fire, International PCT Publication No. WO 99/32619; Plaetinck et al., International PCT Publication No. WO 00/01846; Mello and Fire, International PCT Publication No. WO 01/29058; Deschamps-Depaillette, International PCT Publication No. WO 99/07409; and Li et al., International PCT Publication No. WO 00/44914; Allshire, 2002, Science, 297, 1818-1819; Volpe et al., 2002, Science, 297, 1833-1837; Jenuwein, 2002, Science, 297, 2215-2218; and Hall et al., 2002, Science, 297, 2232-2237; Hutvagner and Zamore, 2002, Science, 297, 2056-60; McManus et al., 2002, RNA, 8, 842-850; Reinhart et al., 2002, Gene & Dev., 16, 1616-1626; and Reinhart & Bartel, 2002, Science, 297, 1831).

An siNA nucleic acid molecule can be assembled from two separate polynucleotide strands, where one strand is the sense strand and the other is the antisense strand in which the antisense and sense strands are self-complementary (i.e. each strand includes nucleotide sequence that is complementary to nucleotide sequence in the other strand); such as where the antisense strand and sense strand form a duplex or double stranded structure having any length and structure as described herein for nucleic acid molecules as provided, for example wherein the double stranded region (duplex region) is about 15 to about 49 (e.g., about 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 base pairs); the antisense strand includes nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule (i.e., TIMP1 and TIMP2 mRNA) or a portion thereof and the sense strand includes nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof (e.g., about 17 to about 49 or more nucleotides of the nucleic acid molecules herein are complementary to the target nucleic acid or a portion thereof).

In certain aspects and embodiments a nucleic acid molecule (e.g., a siNA molecule) provided herein may be a “RISC length” molecule or may be a Dicer substrate as described in more detail below.

An siNA nucleic acid molecule may include separate sense and antisense sequences or regions, where the sense and antisense regions are covalently linked by nucleotide or non-nucleotide linkers molecules as is known in the art, or are alternately non-covalently linked by ionic interactions, hydrogen bonding, van der Waals interactions, hydrophobic interactions, and/or stacking interactions. Nucleic acid molecules may include a nucleotide sequence that is complementary to nucleotide sequence of a target gene. Nucleic acid molecules may interact with nucleotide sequence of a target gene in a manner that causes inhibition of expression of the target gene.

Alternatively, an siNA nucleic acid molecule is assembled from a single polynucleotide, where the self-complementary sense and antisense regions of the nucleic acid molecules are linked by means of a nucleic acid based or non-nucleic acid-based linker(s), i.e., the antisense strand and the sense strand are part of one single polynucleotide that having an antisense region and sense region that fold to form a duplex region (for example to form a “hairpin” structure as is well known in the art). Such siNA nucleic acid molecules can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region includes nucleotide sequence that is complementary to nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence (e.g., a sequence of TIMP1 and TIMP2 mRNA). Such siNA nucleic acid molecules can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region includes nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active nucleic acid molecule capable of mediating RNAi.

The following nomenclature is often used in the art to describe lengths and overhangs of siNA molecules and may be used throughout the specification and Examples. Names given to duplexes indicate the length of the oligomers and the presence or absence of overhangs. For example, a “21+2” duplex contains two nucleic acid strands both of which are 21 nucleotides in length, also termed a 21-mer siRNA duplex or a 21-mer nucleic acid and having a 2 nucleotides 3′-overhang. A “21-2” design refers to a 21-mer nucleic acid duplex with a 2 nucleotides 5′-overhang. A 21-0 design is a 21-mer nucleic acid duplex with no overhangs (blunt). A “21+2UU” is a 21-mer duplex with 2-nucleotides 3′-overhang and the terminal 2 nucleotides at the 3′-ends are both U residues (which may result in mismatch with target sequence). The aforementioned nomenclature can be applied to siNA molecules of various lengths of strands, duplexes and overhangs (such as 19-0, 21+2, 27+2, and the like). In an alternative but similar nomenclature, a “ 25/27” is an asymmetric duplex having a 25 base sense strand and a 27 base antisense strand with a 2-nucleotides 3′-overhang. A “ 27/25” is an asymmetric duplex having a 27 base sense strand and a 25 base antisense strand.

Chemical Modifications

In certain aspects and embodiments, nucleic acid molecules (e.g., siNA molecules) as provided herein include one or more modifications (or chemical modifications). In certain embodiments, such modifications include any changes to a nucleic acid molecule or polynucleotide that would make the molecule different than a standard ribonucleotide or RNA molecule (i.e., that includes standard adenine, cytosine, uracil, or guanine moieties); which may be referred to as an “unmodified” ribonucleotide or unmodified ribonucleic acid. Traditional DNA bases and polynucleotides having a 2′-deoxy sugar represented by adenine, cytosine, thymine, or guanine moieties may be referred to as an “unmodified deoxyribonucleotide” or “unmodified deoxyribonucleic acid”; accordingly, the term “unmodified nucleotide” or “unmodified nucleic acid” as used herein refers to an “unmodified ribonucleotide” or “unmodified ribonucleic acid” unless there is a clear indication to the contrary. Such modifications can be in the nucleotide sugar, nucleotide base, nucleotide phosphate group and/or the phosphate backbone of a polynucleotide.

In certain embodiments modifications as disclosed herein may be used to increase RNAi activity of a molecule and/or to increase the in vivo stability of the molecules, particularly the stability in serum, and/or to increase bioavailability of the molecules. Non-limiting examples of modifications include without limitation internucleotide or internucleoside linkages; deoxyribonucleotides or dideoxyribonucleotides at any position and strand of the nucleic acid molecule; nucleic acid (e.g., ribonucleic acid) with a modification at the 2′-position preferably selected from an amino, fluoro, methoxy, alkoxy and alkyl; 2′-deoxyribonucleotides, 2′-O-methyl ribonucleotides, 2′-deoxy-2′-fluoro ribonucleotides, “universal base” nucleotides, “acyclic” nucleotides, 5-C-methyl nucleotides, biotin group, and terminal glyceryl and/or inverted deoxy abasic residue incorporation, sterically hindered molecules, such as fluorescent molecules and the like. Other nucleotides modifiers could include 3′-deoxyadenosine (cordycepin), 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxy-3′-thiacytidine (3TC), 2′,3′-didehydro-2′,3′-dideoxythymidi-ne (d4T) and the monophosphate nucleotides of 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxy-3′-thiacytidine (3TC) and 2′,3′-didehydro-2′,3′-dide-oxythymidine (d4T). Further details on various modifications are described in more detail below.

Modified nucleotides include those having a Northern conformation (e.g., Northern pseudorotation cycle, see for example Saenger, Principles of Nucleic Acid Structure, Springer-Verlag ed., 1984). Non-limiting examples of nucleotides having a northern configuration include locked nucleic acid (LNA) nucleotides (e.g., 2′-O, 4′-C-methylene-(D-ribofuranosyl)nucleotides); 2′-methoxyethoxy (MOE) nucleotides; 2′-methyl-thio-ethyl, 2′-deoxy-2′-fluoro nucleotides, 2′-deoxy-2′-chloro nucleotides, 2′-azido nucleotides, and 2′-O-methyl nucleotides. Locked nucleic acids, or LNA's are described, for example, in Elman et al., 2005; Kurreck et al., 2002; Crinelli et al., 2002; Braasch and Corey, 2001; Bondensgaard et al., 2000; Wahlestedt et al., 2000; and International Patent Publication Nos. WO 00/47599, WO 99/14226, and WO 98/39352 and WO 2004/083430. In one embodiment, an LNA is incorporated at the 5′ terminus of the sense strand.

Chemical modifications also include unlocked nucleic acids, or UNAs, which are non-nucleotide, acyclic analogues, in which the C2′-C3′ bond is not present (although UNAs are not truly nucleotides, they are expressly included in the scope of “modified” nucleotides or modified nucleic acids as contemplated herein). In particular embodiments, nucleic acid molecules with an overhang may be modified to have UNAs at the overhang positions (i.e., 2 nucleotide overhand). In other embodiments, UNAs are included at the 3′- or 5′-ends. A UNA may be located anywhere along a nucleic acid strand, i.e. at position 7. Nucleic acid molecules may contain one or more than UNA. Exemplary UNAs are disclosed in Nucleic Acids Symposium Series No. 52 p. 133-134 (2008). In certain embodiments a nucleic acid molecule (e.g., a siNA molecule) as described herein include one or more UNAs; or one UNA. In some embodiments, a nucleic acid molecule (e.g., a siNA molecule) as described herein that has a 3′-overhang include one or two UNAs in the 3′ overhang. In some embodiments a nucleic acid molecule (e.g., a siNA molecule) as described herein includes a UNA (for example one UNA) in the antisense strand; for example in position 6 or position 7 of the antisense strand. Chemical modifications also include non-pairing nucleotide analogs, for example as disclosed herein. Chemical modifications further include unconventional moieties as disclosed herein.

Chemical modifications also include terminal modifications on the 5′ and/or 3′ part of the oligonucleotides and are also known as capping moieties. Such terminal modifications are selected from a nucleotide, a modified nucleotide, a lipid, a peptide, and a sugar.

Chemical modifications also include six membered “six membered ring nucleotide analogs.” Examples of six-membered ring nucleotide analogs are disclosed in Allart, et al (Nucleosides & Nucleotides, 1998, 17:1523-1526; and Perez-Perez, et al., 1996, Bioorg. and Medicinal Chem Letters 6:1457-1460) Oligonucleotides including 6-membered ring nucleotide analogs including hexitol and altritol nucleotide monomers are disclosed in International patent application publication No. WO 2006/047842.

Chemical modifications also include “mirror” nucleotides which have a reversed chirality as compared to normal naturally occurring nucleotide; that is a mirror nucleotide may be an “L-nucleotide” analogue of naturally occurring D-nucleotide (see U.S. Pat. No. 6,602,858). Mirror nucleotides may further include at least one sugar or base modification and/or a backbone modification, for example, as described herein, such as a phosphorothioate or phosphonate moiety. U.S. Pat. No. 6,602,858 discloses nucleic acid catalysts including at least one L-nucleotide substitution. Mirror nucleotides include for example L-DNA (L-deoxyriboadenosine-3′-phosphate (mirror dA); L-deoxyribocytidine-3′-phosphate (mirror dC); L-deoxyriboguanosine-3′-phosphate (mirror dG); L-deoxyribothymidine-3′-phosphate (mirror image dT)) and L-RNA (L-riboadenosine-3′-phosphate (mirror rA); L-ribocytidine-3′-phosphate (mirror rC); L-riboguanosine-3′-phosphate (mirror rG); L-ribouracil-3′-phosphate (mirror dU).

In some embodiments, modified ribonucleotides include modified deoxyribonucleotides, for example 5′OMe DNA (5-methyl-deoxyriboguanosine-3′-phosphate) which may be useful as a nucleotide in the 5′ terminal position (position number 1); PACE (deoxyriboadenine 3′ phosphonoacetate, deoxyribocytidine 3′ phosphonoacetate, deoxyriboguanosine 3′ phosphonoacetate, deoxyribothymidine 3′ phosphonoacetate.

Modifications may be present in one or more strands of a nucleic acid molecule disclosed herein, e.g., in the sense strand, the antisense strand, or both strands. In certain embodiments, the antisense strand may include modifications and the sense strand my only include unmodified RNA.

Nucleobases

Nucleobases of the nucleic acid disclosed herein may include unmodified ribonucleotides (purines and pyrimidines) such as adenine, guanine, cytosine, uridine. The nucleobases in one or both strands can be modified with natural and synthetic nucleobases such as thymine, xanthine, hypoxanthine, inosine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, any “universal base” nucleotides; 2-propyl and other alkyl derivatives of adenine and guanine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, amino, thiol, thioalkyl, hydroxyl and other 8-substituted adenines and guanines, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine, deazapurines, heterocyclic substituted analogs of purines and pyrimidines, e.g., aminoethyoxy phenoxazine, derivatives of purines and pyrimidines (e.g., 1-alkyl-, 1-alkenyl-, heteroaromatic- and 1-alkynyl derivatives) and tautomers thereof, 8-oxo-N6-methyladenine, 7-diazaxanthine, 5-methylcytosine, 5-methyluracil, 5-(1-propynyl)uracil, 5-(1-propynyl)cytosine and 4,4-ethanocytosine). Other examples of suitable bases include non-purinyl and non-pyrimidinyl bases such as 2-aminopyridine and triazines.

Sugar Moieties

Sugar moieties in nucleic acid disclosed herein may include 2′-hydroxyl-pentofuranosyl sugar moiety without any modification. Alternatively, sugar moieties can be modified such as, 2′-deoxy-pentofuranosyl sugar moiety, D-ribose, hexose, modification at the 2′ position of the pentofuranosyl sugar moiety such as 2′-O-alkyl (including 2′-O-methyl and 2′-O-ethyl), i.e., 2′-alkoxy, 2′-amino, 2′-O-allyl, 2′-S-alkyl, 2′-halogen (including 2′-fluoro, chloro, and bromo), 2′-methoxyethoxy, 2′-O-methoxyethyl, 2′-O-2-methoxyethyl, 2′-allyloxy (—OCH₂CH═CH₂), 2′-propargyl, 2′-propyl, ethynyl, propenyl, CF, cyano, imidazole, carboxylate, thioate, C₁ to C₁₀ lower alkyl, substituted lower alkyl, alkaryl or aralkyl, OCF₃, OCN, O-, S-, or N-alkyl; O-, S, or N-alkenyl; SOCH₃; SO₂CH₃; ONO₂; NO₂, N₃; heterozycloalkyl; heterozycloalkaryl; aminoalkylamino; polyalkylamino or substituted silyl, as, among others, for example as described in European patents EP 0 586 520 B1 or EP 0 618 925 B1.

Alkyl group includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C₁-C₆ for straight chain, C₃-C₆ for branched chain), and more preferably 4 or fewer. Likewise, preferred cycloalkyls may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C₁-C₆ includes alkyl groups containing 1 to 6 carbon atoms. The alkyl group can be substituted alkyl group such as alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Alkoxy group includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.

In some embodiments, the pentafuronosyl ring may be replaced with acyclic derivatives lacking the C2′-C3′-bond of the pentafuronosyl ring. For example, acyclonucleotides may substitute a 2-hydroxyethoxymethyl group for-the 2′-deoxyribofuranosyl sugar normally present in dNMPs.

Halogens include fluorine, bromine, chlorine, iodine.

Backbone

The nucleoside subunits of the nucleic acid disclosed herein may be linked to each other by phosphodiester bond. The phosphodiester bond may be optionally substituted with other linkages. For example, phosphorothioate, thiophosphate-D-ribose entities, triester, thioate, 2′-5′ bridged backbone (may also be referred to as 5′-2′), PACE, 3′-(or -5′)deoxy-3′-(or -5′)thio-phosphorothioate, phosphorodithioate, phosphoroselenates, 3′-(or -5′)deoxy phosphinates, borano phosphates, 3′-(or -5′)deoxy-3′-(or 5′-)amino phosphoramidates, hydrogen phosphonates, phosphonates, borano phosphate esters, phosphoramidates, alkyl or aryl phosphonates and phosphotriester modifications such as alkylphosphotriesters, phosphotriester phosphorus linkages, 5′-ethoxyphosphodiester, P-alkyloxyphosphotriester, methylphosphonate, and nonphosphorus containing linkages for example, carbonate, carbamate, silyl, sulfur, sulfonate, sulfonamide, formacetal, thioformacetyl, oxime, methyleneimino, methylenemethylimino, methylenehydrazo, methylenedimethylhydrazo and methyleneoxymethylimino linkages.

Nucleic acid molecules disclosed herein may include a peptide nucleic acid (PNA) backbone. The PNA backbone is includes repeating N-(2-aminoethyl)-glycine units linked by peptide bonds. The various bases such as purine, pyrimidine, natural and synthetic bases are linked to the backbone by methylene carbonyl bonds.

Terminal Phosphates

Modifications can be made at terminal phosphate groups. Non-limiting examples of different stabilization chemistries can be used, e.g., to stabilize the 3′-end of nucleic acid sequences, including (1) [3-3′]-inverted deoxyribose; (2) deoxyribonucleotide; (3) [5′-3′]-3′-deoxyribonucleotide; (4) [5′-3′]-ribonucleotide; (5) [5′-3′]-3′-O-methyl ribonucleotide; (6) 3′-glyceryl; (7) [3′-5′]-3′-deoxyribonucleotide; (8) [3′-3′]-deoxyribonucleotide; (9) [5′-2′]-deoxyribonucleotide; and (10) [5-3′]-dideoxyribonucleotide. In addition to unmodified backbone chemistries can be combined with one or more different backbone modifications described herein.

Exemplary chemically modified terminal phosphate groups include those shown below:

Conjugates

Modified nucleotides and nucleic acid molecules (e.g., siNA molecules) as provided herein may include conjugates, for example, a conjugate covalently attached to the chemically-modified nucleic acid molecule. Non-limiting examples of conjugates include conjugates and ligands described in Vargeese et al., U.S. Ser. No. 10/427,160. The conjugate may be covalently attached to a nucleic acid molecule (such as an siNA molecule) via a biodegradable linker. The conjugate molecule may be attached at the 3′-end of either the sense strand, the antisense strand, or both strands of the chemically-modified nucleic acid molecule.

The conjugate molecule may be attached at the 5′-end of either the sense strand, the antisense strand, or both strands of the chemically-modified nucleic acid molecule. The conjugate molecule may be attached both the 3′-end and 5′-end of either the sense strand, the antisense strand, or both strands of the chemically-modified nucleic acid molecule, or any combination thereof. In one embodiment, a conjugate molecule may include a molecule that facilitates delivery of a chemically-modified nucleic acid molecule into a biological system, such as a cell. In another embodiment, the conjugate molecule attached to the chemically-modified nucleic acid molecule is a polyethylene glycol, human serum albumin, or a ligand for a cellular receptor that can mediate cellular uptake. Examples of specific conjugate molecules contemplated by herein that can be attached to chemically-modified nucleic acid molecules are described in Vargeese et al., U.S. Ser. No. 10/201,394.

Linkers

A nucleic acid molecule provided herein (e.g., an siNA) molecule may include a nucleotide, non-nucleotide, or mixed nucleotide/non-nucleotide linker that joins the sense region of the nucleic acid to the antisense region of the nucleic acid. A nucleotide linker can be a linker of ≧2 nucleotides in length, for example about 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length. The nucleotide linker can be a nucleic acid aptamer. By “aptamer” or “nucleic acid aptamer” as used herein refers to a nucleic acid molecule that binds specifically to a target molecule wherein the nucleic acid molecule has sequence that includes a sequence recognized by the target molecule in its natural setting. Alternately, an aptamer can be a nucleic acid molecule that binds to a target molecule (such as TIMP1 and TIMP2 mRNA) where the target molecule does not naturally bind to a nucleic acid. For example, the aptamer can be used to bind to a ligand-binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein. This is a non-limiting example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art. See e.g., Gold et al.; 1995, Annu Rev. Biochem., 64, 763; Brody and Gold, 2000, J. Biotechnol., 74, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J. Biotechnol., 74, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628.

A non-nucleotide linker may include an abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, polyhydrocarbon, or other polymeric compounds (e.g. polyethylene glycols such as those having between 2 and 100 ethylene glycol units). Specific examples include those described by Seela and Kaiser, Nucleic Acids Res. 1990, 18:6353 and Nucleic Acids Res. 1987, 15:3113; Cload and Schepartz, J. Am. Chem. Soc. 1991, 113:6324; Richardson and Schepartz, J. Am. Chem. Soc. 1991, 113:5109; Ma et al., Nucleic Acids Res. 1993, 21:2585 and Biochemistry 1993, 32:1751; Durand et al., Nucleic Acids Res. 1990, 18:6353; McCurdy et al., Nucleosides & Nucleotides 1991, 10:287; Jschke et al., Tetrahedron Lett. 1993, 34:301; Ono et al., Biochemistry 1991, 30:9914; Arnold et al., International Publication No. WO 89/02439; Usman et al., International Publication No. WO 95/06731; Dudycz et al., International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc. 1991, 113:4000.

5′ Ends, 3′ Ends and Overhangs

Nucleic acid molecules disclosed herein (e.g., siNA molecules) may be blunt-ended on both sides, have overhangs on both sides or a combination of blunt and overhang ends. Overhangs may occur on either the 5′- or 3′-end of the sense or antisense strand.

5′- and/or 3′-ends of double stranded nucleic acid molecules (e.g., siNA) may be blunt ended or have an overhang. The 5′-end may be blunt ended and the 3′-end has an overhang in either the sense strand or the antisense strand. In other embodiments, the 3′-end may be blunt ended and the 5′-end has an overhang in either the sense strand or the antisense strand. In yet other embodiments, both the 5′- and 3′-end are blunt ended or both the 5′- and 3′-ends have overhangs.

The 5′- and/or 3′-end of one or both strands of the nucleic acid may include a free hydroxyl group. The 5′- and/or 3′-end of any nucleic acid molecule strand may be modified to include a chemical modification. Such modification may stabilize nucleic acid molecules, e.g., the 3′-end may have increased stability due to the presence of the nucleic acid molecule modification. Examples of end modifications (e.g., terminal caps) include, but are not limited to, abasic, deoxy abasic, inverted (deoxy) abasic, glyceryl, dinucleotide, acyclic nucleotide, amino, fluoro, chloro, bromo, CN, CF, methoxy, imidazole, carboxylate, thioate, C₁ to C₁₀ lower alkyl, substituted lower alkyl, alkaryl or aralkyl, OCF₃, OCN, O-, S-, or N-alkyl; O-, S-, or N-alkenyl; SOCH₃; SO₂CH₃; ONO₂; NO₂, N₃; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino or substituted silyl, as, among others, described in European patents EP 586,520 and EP 618,925 and other modifications disclosed herein.

Nucleic acid molecules include those with blunt ends, i.e., ends that do not include any overhanging nucleotides. A nucleic acid molecule can include one or more blunt ends. The blunt ended nucleic acid molecule has a number of base pairs equal to the number of nucleotides present in each strand of the nucleic acid molecule. The nucleic acid molecule can include one blunt end, for example where the 5′-end of the antisense strand and the 3′-end of the sense strand do not have any overhanging nucleotides. Nucleic acid molecule may include one blunt end, for example where the 3′-end of the antisense strand and the 5′-end of the sense strand do not have any overhanging nucleotides. A nucleic acid molecule may include two blunt ends, for example where the 3′-end of the antisense strand and the 5′-end of the sense strand as well as the 5′-end of the antisense strand and 3′-end of the sense strand do not have any overhanging nucleotides. Other nucleotides present in a blunt ended nucleic acid molecule can include, for example, mismatches, bulges, loops, or wobble base pairs to modulate the activity of the nucleic acid molecule to mediate RNA interference.

In certain embodiments of the nucleic acid molecules (e.g., siNA molecules) provided herein, at least one end of the molecule has an overhang of at least one nucleotide (for example 1 to 8 overhang nucleotides). For example, one or both strands of a double stranded nucleic acid molecule disclosed herein may have an overhang at the 5′-end or at the 3′-end or both. An overhang may be present at either or both the sense strand and antisense strand of the nucleic acid molecule. The length of the overhang may be as little as one nucleotide and as long as 1 to 8 or more nucleotides (e.g., 1, 2, 3, 4, 5, 6, 7 or 8 nucleotides; in some preferred embodiments an overhang is 2, 3, 4, 5, 6, 7 or 8 nucleotides; for example an overhang may be 2 nucleotides. The nucleotide(s) forming the overhang may be include deoxyribonucleotide(s), ribonucleotide(s), natural and non-natural nucleobases or any nucleotide modified in the sugar, base or phosphate group such as disclosed herein. A double stranded nucleic acid molecule may have both 5′- and 3′-overhangs. The overhangs at the 5′- and 3′-end may be of different lengths. An overhang may include at least one nucleic acid modification which may be deoxyribonucleotide. One or more deoxyribonucleotides may be at the 5′-terminal. The 3′-end of the respective counter-strand of the nucleic acid molecule may not have an overhang, more preferably not a deoxyribonucleotide overhang. The one or more deoxyribonucleotide may be at the 3′-terminal. The 5′-end of the respective counter-strand of the dsRNA may not have an overhang, more preferably not a deoxyribonucleotide overhang. The overhang in either the 5′- or the 3′-end of a strand may be 1 to 8 (e.g., about 1, 2, 3, 4, 5, 6, 7 or 8) unpaired nucleotides, preferably, the overhang is 2-3 unpaired nucleotides; more preferably 2 unpaired nucleotides. Nucleic acid molecules may include duplex nucleic acid molecules with overhanging ends of about 1 to about 20 (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 1, 15, 16, 17, 18, 19 or 20); preferably 1-8 (e.g., about 1, 2, 3, 4, 5, 6, 7 or 8) nucleotides, for example, about 21-nucleotide duplexes with about 19 base pairs and 3′-terminal mononucleotide, dinucleotide, or trinucleotide overhangs. Nucleic acid molecules herein may include duplex nucleic acid molecules with blunt ends, where both ends are blunt, or alternatively, where one of the ends is blunt. Nucleic acid molecules disclosed herein can include one or more blunt ends, i.e. where a blunt end does not have any overhanging nucleotides. In one embodiment, the blunt ended nucleic acid molecule has a number of base pairs equal to the number of nucleotides present in each strand of the nucleic acid molecule. The nucleic acid molecule may include one blunt end, for example where the 5′-end of the antisense strand and the 3′-end of the sense strand do not have any overhanging nucleotides. The nucleic acid molecule may include one blunt end, for example where the 3′-end of the antisense strand and the 5′-end of the sense strand do not have any overhanging nucleotides. A nucleic acid molecule may include two blunt ends, for example where the 3′-end of the antisense strand and the 5′-end of the sense strand as well as the 5′-end of the antisense strand and 3′-end of the sense strand do not have any overhanging nucleotides. In certain preferred embodiments the nucleic acid compounds are blunt ended. Other nucleotides present in a blunt ended siNA molecule can include, for example, mismatches, bulges, loops, or wobble base pairs to modulate the activity of the nucleic acid molecule to mediate RNA interference.

In many embodiments one or more, or all, of the overhang nucleotides of a nucleic acid molecule (e.g., a siNA molecule) as described herein includes are modified such as described herein; for example one or more, or all, of the nucleotides may be 2′-deoxyribonucleotides.

Amount, Location and Patterns of Modifications.

Nucleic acid molecules (e.g., siNA molecules) disclosed herein may include modified nucleotides as a percentage of the total number of nucleotides present in the nucleic acid molecule. As such, a nucleic acid molecule may include about 5% to about 100% modified nucleotides (e.g., about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% modified nucleotides). The actual percentage of modified nucleotides present in a given nucleic acid molecule will depend on the total number of nucleotides present in the nucleic acid. If the nucleic acid molecule is single stranded, the percent modification can be based upon the total number of nucleotides present in the single stranded nucleic acid molecule. Likewise, if the nucleic acid molecule is double stranded, the percent modification can be based upon the total number of nucleotides present in the sense strand, antisense strand, or both the sense and antisense strands.

Nucleic acid molecules disclosed herein may include unmodified RNA as a percentage of the total nucleotides in the nucleic acid molecule. As such, a nucleic acid molecule may include about 5% to about 100% modified nucleotides (e.g., about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of total nucleotides present in a nucleic acid molecule.

A nucleic acid molecule (e.g., an siNA molecule) may include a sense strand that includes about 1 to about 5, specifically about 1, 2, 3, 4, or 5 phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1, 2, 3, 4, 5, or more) 2′-deoxy, 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or one or more (e.g., about 1, 2, 3, 4, 5, or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3-end, the 5′-end, or both of the 3′- and 5′-ends of the sense strand; and wherein the antisense strand includes about 1 to about 5 or more, specifically about 1, 2, 3, 4, 5, or more phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2′-deoxy, 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of the antisense strand. A nucleic acid molecule may include about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, pyrimidine nucleotides of the sense and/or antisense nucleic acid strand are chemically-modified with 2′-deoxy, 2′-O-methyl and/or 2′-deoxy-2′-fluoro nucleotides, with or without about 1 to about 5 or more, for example about 1, 2, 3, 4, 5, or more phosphorothioate internucleotide linkages and/or a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends, being present in the same or different strand.

A nucleic acid molecule may include about 1 to about 5 or more (specifically about 1, 2, 3, 4, 5 or more) phosphorothioate internucleotide linkages in each strand of the nucleic acid molecule.

A nucleic acid molecule may include 2′-5′ internucleotide linkages, for example at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of one or both nucleic acid sequence strands. In addition, the 2′-5′ internucleotide linkage(s) can be present at various other positions within one or both nucleic acid sequence strands, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more including every internucleotide linkage of a pyrimidine nucleotide in one or both strands of the siNA molecule can include a 2′-5′ internucleotide linkage, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more including every internucleotide linkage of a purine nucleotide in one or both strands of the siNA molecule can include a 2′-5′ internucleotide linkage.

A chemically-modified short interfering nucleic acid (siNA) molecule may include an antisense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the antisense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more or all) purine nucleotides present in the antisense region are 2′-deoxy purine nucleotides (e.g., wherein all purine nucleotides are 2′-deoxy purine nucleotides or alternately a plurality of purine nucleotides are 2′-deoxy purine nucleotides).

A chemically-modified short interfering nucleic acid (siNA) molecule may include an antisense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the antisense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more or all) purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides).

A chemically-modified short interfering nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi) against TIMP1 and TIMP2 inside a cell or reconstituted in vitro system may include a sense region, wherein one or more pyrimidine nucleotides present in the sense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and one or more purine nucleotides present in the sense region are 2′-deoxy purine nucleotides (e.g., wherein all purine nucleotides are 2′-deoxy purine nucleotides or alternately a plurality of purine nucleotides are 2′-deoxy purine nucleotides), and an antisense region, wherein one or more pyrimidine nucleotides present in the antisense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and one or more purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides). The sense region and/or the antisense region can have a terminal cap modification, such as any modification, that is optionally present at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of the sense and/or antisense sequence. The sense and/or antisense region can optionally further include a 3′-terminal nucleotide overhang having about 1 to about 4 (e.g., about 1, 2, 3, or 4) 2′-deoxyribonucleotides. The overhang nucleotides can further include one or more (e.g., about 1, 2, 3, 4 or more) phosphorothioate, phosphonoacetate, and/or thiophosphonoacetate internucleotide linkages. The purine nucleotides in the sense region may alternatively be 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides) and one or more purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides). One or more purine nucleotides in the sense region may alternatively be purine ribonucleotides (e.g., wherein all purine nucleotides are purine ribonucleotides or alternately a plurality of purine nucleotides are purine ribonucleotides) and any purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides). One or more purine nucleotides in the sense region and/or present in the antisense region may alternatively selected from the group consisting of 2′-deoxy nucleotides, locked nucleic acid (LNA) nucleotides, 2′-methoxyethyl nucleotides, 4′-thionucleotides, and 2′-O-methyl nucleotides (e.g., wherein all purine nucleotides are selected from the group consisting of 2′-deoxy nucleotides, locked nucleic acid (LNA) nucleotides, 2′-methoxyethyl nucleotides, 4′-thionucleotides, and 2′-O-methyl nucleotides or alternately a plurality of purine nucleotides are selected from the group consisting of 2′-deoxy nucleotides, locked nucleic acid (LNA) nucleotides, 2′-methoxyethyl nucleotides, 4′-thionucleotides, and 2′-O-methyl nucleotides).

In some embodiments, a nucleic acid molecule (e.g., a siNA molecule) as described herein includes a modified nucleotide (for example one modified nucleotide) in the antisense strand; for example in position 6 or position 7 of the antisense strand.

Modification Patterns and Alternating Modifications

Nucleic acid molecules (e.g., siNA molecules) provided herein may have patterns of modified and unmodified nucleic acids. A pattern of modification of the nucleotides in a contiguous stretch of nucleotides may be a modification contained within a single nucleotide or group of nucleotides that are covalently linked to each other via standard phosphodiester bonds or, at least partially, through phosphorothioate bonds. Accordingly, a “pattern” as contemplated herein, does not necessarily need to involve repeating units, although it may. Examples of modification patterns that may be used in conjunction with the nucleic acid molecules (e.g., siNA molecules) provided herein include those disclosed in Giese, U.S. Pat. No. 7,452,987. For example, nucleic acid molecules (e.g., siNA molecules) provided herein include those having modification patters such as, similar to, or the same as, the patterns shown diagrammatically in FIG. 2 of the Giese U.S. Pat. No. 7,452,987.

A modified nucleotide or group of modified nucleotides may be at the 5′-end or 3′-end of the sense or antisense strand, a flanking nucleotide or group of nucleotides is arrayed on both sides of the modified nucleotide or group, where the flanking nucleotide or group either is unmodified or does not have the same modification of the preceding nucleotide or group of nucleotides. The flanking nucleotide or group of nucleotides may, however, have a different modification. This sequence of modified nucleotide or group of modified nucleotides, respectively, and unmodified or differently modified nucleotide or group of unmodified or differently modified nucleotides may be repeated one or more times.

In some patterns, the 5′-terminal nucleotide of a strand is a modified nucleotide while in other patterns the 5′-terminal nucleotide of a strand is an unmodified nucleotide. In some patterns, the 5′-end of a strand starts with a group of modified nucleotides while in other patterns, the 5′-terminal end is an unmodified group of nucleotides. This pattern may be either on the first stretch or the second stretch of the nucleic acid molecule or on both.

Modified nucleotides of one strand of the nucleic acid molecule may be complementary in position to the modified or unmodified nucleotides or groups of nucleotides of the other strand.

There may be a phase shift between modifications or patterns of modifications on one strand relative to the pattern of modification of the other strand such that the modification groups do not overlap. In one instance, the shift is such that the modified group of nucleotides of the sense strand corresponds to the unmodified group of nucleotides of the antisense strand and vice versa.

There may be a partial shift of the pattern of modification such that the modified groups overlap. The groups of modified nucleotides in any given strand may optionally be the same length, but may be of different lengths. Similarly, groups of unmodified nucleotides in any given strand may optionally be the same length, or of different lengths.

In some patterns, the second (penultimate) nucleotide at the terminus of the strand, is an unmodified nucleotide or the beginning of group of unmodified nucleotides. Preferably, this unmodified nucleotide or unmodified group of nucleotides is located at the 5′-end of the either or both the sense and antisense strands and even more preferably at the terminus of the sense strand. An unmodified nucleotide or unmodified group of nucleotide may be located at the 5′-end of the sense strand. In a preferred embodiment the pattern consists of alternating single modified and unmodified nucleotides.

In some double stranded nucleic acid molecules include a 2′-O-methyl modified nucleotide and a non-modified nucleotide, preferably a nucleotide which is not 2′-O-methyl modified, are incorporated on both strands in an alternating fashion, resulting in a pattern of alternating 2′-O-methyl modified nucleotides and nucleotides that are either unmodified or at least do not include a 2′-O-methyl modification. In certain embodiments, the same sequence of 2′-O-methyl modification and non-modification exists on the second strand; in other embodiments the alternating 2′-O-methyl modified nucleotides are only present in the sense strand and are not present in the antisense strand; and in yet other embodiments the alternating 2′-O-methyl modified nucleotides are only present in the sense strand and are not present in the antisense strand. In certain embodiments, there is a phase shift between the two strands such that the 2′-O-methyl modified nucleotide on the first strand base pairs with a non-modified nucleotide(s) on the second strand and vice versa. This particular arrangement, i.e. base pairing of 2′-O-methyl modified and non-modified nucleotide(s) on both strands is particularly preferred in certain embodiments. In certain embodiments, the pattern of alternating 2′-O-methyl modified nucleotides exists throughout the entire nucleic acid molecule; or the entire duplex region. In other embodiments the pattern of alternating 2′-O-methyl modified nucleotides exists only in a portion of the nucleic acid; or the entire duplex region.

In “phase shift” patterns, it may be preferred if the antisense strand starts with a 2′-O-methyl modified nucleotide at the 5′ end whereby consequently the second nucleotide is non-modified, the third, fifth, seventh and so on nucleotides are thus again 2′-O-methyl modified whereas the second, fourth, sixth, eighth and the like nucleotides are non-modified nucleotides.

Exemplary Modification Locations and Patterns

While exemplary patterns are provided in more detail below, all permutations of patterns with of all possible characteristics of the nucleic acid molecules disclosed herein and those known in the art are contemplated (e.g., characteristics include, but are not limited to, length of sense strand, length of antisense strand, length of duplex region, length of hangover, whether one or both ends of a double stranded nucleic acid molecule is blunt or has an overhang, location of modified nucleic acid, number of modified nucleic acids, types of modifications, whether a double overhang nucleic acid molecule has the same or different number of nucleotides on the overhang of each side, whether a one or more than one type of modification is used in a nucleic acid molecule, and number of contiguous modified/unmodified nucleotides). With respect to all detailed examples provided below, while the duplex region is shown to be 19 nucleotides, the nucleic acid molecules provided herein can have a duplex region ranging from 1 to 49 nucleotides in length as each strand of a duplex region can independently be 17-49 nucleotides in length Exemplary patterns are provided herein.

Nucleic acid molecules may have a blunt end (when n is 0) on both ends that include a single or contiguous set of modified nucleic acids. The modified nucleic acid may be located at any position along either the sense or antisense strand. Nucleic acid molecules may include a group of about 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, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49 contiguous modified nucleotides. Modified nucleic acids may make up 1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 100% of a nucleic acid strand. Modified nucleic acids of the examples immediately below may be in the sense strand only, the antisense strand only, or in both the sense and antisense strand.

General nucleic acid patters are shown below where X=sense strand nucleotide in the duplex region; X_a=5′-overhang nucleotide in the sense strand; X_b=3′-overhang nucleotide in the sense strand; Y=antisense strand nucleotide in the duplex region; Y_a=3′-overhang nucleotide in the antisense strand; Y_b=5′-overhang nucleotide in the antisense strand; and M=a modified nucleotide in the duplex region. Each a and b are independently 0 to 8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7 or 8). Each X, Y, a and b are independently modified or unmodified. The sense and antisense strands can are each independently 17-49 nucleotides in length. The examples provided below have a duplex region of 19 nucleotides; however, nucleic acid molecules disclosed herein can have a duplex region anywhere between 17 and 49 nucleotides and where each strand is independently between 17 and 49 nucleotides in length.

5′ XaXXXXXXXXXXXXXXXXXXXXb
3′ YbYYYYYYYYYYYYYYYYYYYYa

Further exemplary nucleic acid molecule patterns are shown below where X=unmodified sense strand nucleotides; x=an unmodified overhang nucleotide in the sense strand; Y=unmodified antisense strand nucleotides; y=an unmodified overhang nucleotide in the antisense strand; and M=a modified nucleotide. The sense and antisense strands can are each independently 17-49 nucleotides in length. The examples provided below have a duplex region of 19 nucleotides; however, nucleic acid molecules disclosed herein can have a duplex region anywhere between 17 and 49 nucleotides and where each strand is independently between 17 and 49 nucleotides in length.

5′  XXXXXXXXXMXXXXXXXXX
3′  YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYMYYYYYYYYY
5′ XXXXXXXXMMXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYMMYYYYYYYYY
5′ XXXXXXXXXMXXXXXXXXX
3′ YYYYYYYYYMYYYYYYYYY
5′ XXXXXMXXXXXXXXXXXXX
3′ YYYYYYYYYMYYYYYYYYY
5′ MXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYMYYYYYY
5′ XXXXXXXXXXXXXXXXXXM
3′ YYYYYMYYYYYYYYYYYYY
5′ XXXXXXXXXMXXXXXXXX
3′ MYYYYYYYYYYYYYYYYY
5′ XXXXXXXMXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYM
5′ XXXXXXXXXXXXXMXXXX
3′ MYYYYYYYYYYYYYYYYY
5′ MMMMMMMMMMMMMMMMMM
3′ MMMMMMMMMMMMMMMMMM

Nucleic acid molecules may have blunt ends on both ends with alternating modified nucleic acids. The modified nucleic acids may be located at any position along either the sense or antisense strand.

5′ MXMXMXMXMXMXMXMXMXM
3′ YMYMYMYMYMYMYMYMYMY
5′ XMXMXMXMXMXMXMXMXMX
3′ MYMYMYMYMYMYMYMYMYM
5′ MMXMMXMMXMMXMMXMMXM
3′ YMMYMMYMMYMMYMMYMMY
5′ XMMXMMXMMXMMXMMXMMX
3′ MMYMMYMMYMMYMMYMMYM
5′ MMMXMMMXMMMXMMMXMMM
3′ YMMMYMMMYMMMYMMMYMM
5′ XMMMXMMMXMMMXMMMXMM
3′ MMMYMMMYMMMYMMMYMMM

Nucleic acid molecules with a blunt 5′-end and 3′-end overhang end with a single modified nucleic acid.

Nucleic acid molecules with a 5′-end overhang and a blunt 3′-end with a single modified nucleic acid.

Nucleic acid molecules with overhangs on both ends and all overhangs are modified nucleic acids. In the pattern immediately below, M is n number of modified nucleic acids, where n is an integer from 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7 and 8).

5′ XXXXXXXXXXXXXXXXXXXM
3′ MYYYYYYYYYYYYYYYYYYY

Nucleic acid molecules with overhangs on both ends and some overhang nucleotides are modified nucleotides. In the patterns immediately below, M is n number of modified nucleotides, x is n number of unmodified overhang nucleotides in the sense strand, y is n number of unmodified overhang nucleotides in the antisense strand, where each n is independently an integer from 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7 and 8), and where each overhang is maximum of 20 nucleotides; preferably a maximum of 8 nucleotides (modified and/or unmodified).

5′ XXXXXXXXXXXXXXXXXXXM
3′ yYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMx
3′ yYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMxM
3′ yYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMxMx
3′ yYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMxMxM
3′ yYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMxMxMx
3′ yYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMxMxMxM
3′ yYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMxMxMxMx
3′ yYYYYYYYYYYYYYYYYYYY
5′ MXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYy
5′ xMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYy
5′ MxMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYy
5′ xMxMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYy
5′ MxMxMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYy
5′ xMxMxMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYy
5′ MxMxMxMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYy
5′ xMxMxMxMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYy
5′ xXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYM
5′ xXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYMy
5′ xXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYMyM
5′ xXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYMyMy
5′ xXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYMyMyM
5′ xXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYMyMyMy
5′ xXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYMyMyMyM
5′ xXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYYMyMyMyMy
5′ XXXXXXXXXXXXXXXXXXXx
3′ MYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXx
3′ yMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXx
3′ MyMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXx
3′ yMyMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXx
3′ MyMyMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXx
3′ yMyMyMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXx
3′ MyMyMyMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXx
3′ yMyMyMyMYYYYYYYYYYYYYYYYYYY

Modified nucleotides at the 3′ end of the sense region.

5′ XXXXXXXXXXXXXXXXXXXM
3′ YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMM
3′ YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMMM
3′ YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMMMM
3′ YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMMMMM
3′ YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMMMMMM
3′ YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMMMMMMMM
3′ YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMMMMMMMM
3′ YYYYYYYYYYYYYYYYYYY

Overhang at the 5′ end of the sense region.

5′ MXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYY
5′ MMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYY
5′ MMMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYY
5′ MMMMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYY
5′ MMMMMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYY
5′ MMMMMMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYY
5′ MMMMMMMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYY
5′ MMMMMMMMXXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYY

Overhang at the 3′ end of the antisense region.

5′ XXXXXXXXXXXXXXXXXXX
3′ MYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ MMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ MMMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ MMMMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ MMMMMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ MMMMMMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ MMMMMMMYYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ MMMMMMMMYYYYYYYYYYYYYYYYYYY

Modified nucleotide(s) within the sense region

5′ XXXXXXXXXMXXXXXXXXX
3′ YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ YYYYYYYYYMYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXXMM
3′ YYYYYYYYYYYYYYYYYYY
5′ XXXXXXXXXXXXXXXXXXX
3′ MMYYYYYYYYYYYYYYYYYYY

Exemplary nucleic acid molecules are provided below with the equivalent general structure in line with the symbols used above. The following duplexes are in accordance with the pattern:

5′ XXXXXXXXXXXXXXXXXXXMM
3′ MMYYYYYYYYYYYYYYYYYYY

TIMP1-A siRNA to human, mouse, rat and rhesus TIMP1 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3′-ends of the sense and antisense strands.

5′ CCACCUUAUACCAGCGUUATT 3′
3′ TTGGUGGAAUAUGGUCGCAAU 5′

TIMP1-B siRNA to human and rhesus TIMP1 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3′-ends of the sense and antisense strands.

5′ CACUGUUGGCUGUGAGGAATT 3′
3′ TTGUGACAACCGACACUCCUU 5′

TIMP1-C siRNA to human, mouse, rat and rhesus TIMP1 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3′-ends of the sense and antisense strands.

5′ GGAAUAUCUCAUUGCAGGATT 3′
3′ TTCCUUAUAGAGUAACGUCCU 5′

TIMP2-A siRNA to human TIMP2 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3′-ends of the sense and antisense strands.

5′ UGCAGAUGUAGUGAUCAGGTT 3′
3′ TTACGUCUACAUCACUAGUCC 5′

TIMP2-B siRNA to human, rhesus and rabbit TIMP2 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3′-ends of the sense and antisense strands.

5′ GAGGAUCCAGUAUGAGAUCTT 3′
3′ TTCUCCUAGGUCAUACUCUAG 5′

TIMP2-C siRNA to human, mouse, rat, cow, dog and pig TIMP2 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3′-ends of the sense and antisense strands.

5′ GCAGAUAAAGAUGUUCAAATT 3′
3′ TTCGUCUAUUUCUACAAGUUU 5′

TIMP2-D siRNA to human TIMP2 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3′-ends of the sense and antisense strands.

5′ UAUCUCAUUGCAGGAAAGGTT 3′
3′ TTAUAGAGUAACGUCCUUUCC 5′

TIMP2-E siRNA to human TIMP2 having a 19 nucleotide (i.e., 19mer) duplex region and modified 2 nucleotide (i.e., deoxynucleotide) overhangs at the 3′-ends of the sense and antisense strands.

5′ GCACAGUGUUUCCCUGUUUTT 3′
3′ TTCGUGUCACAAAGGGACAAA 5′

Nicks and Gaps in Nucleic Acid Strands

Nucleic acid molecules (e.g., siNA molecules) provided herein may have a strand, preferably the sense strand, that is nicked or gapped. As such, nucleic acid molecules may have three or more strand, for example, such as a meroduplex RNA (mdRNA) disclosed in International Patent Application No. PCT/US07/081,836. Nucleic acid molecules with a nicked or gapped strand may be between about 1-49 nucleotides, or may be RISC length (e.g., about 15 to 25 nucleotides) or Dicer substrate length (e.g., about 25 to 30 nucleotides) such as disclosed herein.

Nucleic acid molecules with three or more strands include, for example, an ‘A’ (antisense) strand, ‘S1’ (second) strand, and ‘S2’ (third) strand in which the ‘S1’ and ‘S2’ strands are complementary to and form base pairs with non-overlapping regions of the ‘A’ strand (e.g., an mdRNA can have the form of A:S1S2). The S1, S2, or more strands together form what is substantially similar to a sense strand to the ‘A’ antisense strand. The double-stranded region formed by the annealing of the ‘S1’ and ‘A’ strands is distinct from and non-overlapping with the double-stranded region formed by the annealing of the ‘S2’ and ‘A’ strands. An nucleic acid molecule (e.g., an siNA molecule) may be a “gapped” molecule, meaning a “gap” ranging from 0 nucleotides up to about 10 nucleotides (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides). Preferably, the sense strand is gapped. In some embodiments, the A:S1 duplex is separated from the A:S2 duplex by a gap resulting from at least one unpaired nucleotide (up to about 10 unpaired nucleotides) in the ‘A’ strand that is positioned between the A:S1 duplex and the A:S2 duplex and that is distinct from any one or more unpaired nucleotide at the 3′-end of one or more of the ‘A’, ‘S1’, or ‘S2 strands. The A:S1 duplex may be separated from the A:B2 duplex by a gap of zero nucleotides (i.e., a nick in which only a phosphodiester bond between two nucleotides is broken or missing in the polynucleotide molecule) between the A:S1 duplex and the A:S2 duplex-which can also be referred to as nicked dsRNA (ndsRNA). For example, A:S1S2 may be include a dsRNA having at least two double-stranded regions that combined total about 14 base pairs to about 40 base pairs and the double-stranded regions are separated by a gap of about 0 to about 10 nucleotides, optionally having blunt ends, or A:S1S2 may include a dsRNA having at least two double-stranded regions separated by a gap of up to 10 nucleotides wherein at least one of the double-stranded regions includes between about 5 base pairs and 13 base pairs.

Dicer Substrates

In certain embodiments, the nucleic acid molecules (e.g., siNA molecules) provided herein may be a precursor “Dicer substrate” molecule, e.g., double stranded nucleic acid, processed in vivo to produce an active nucleic acid molecules, for example as described in Rossi, US Patent App. No. 20050244858. In certain conditions and situations, it has been found that these relatively longer dsRNA siNA species, e.g., of from about 25 to about 30 nucleotides, can give unexpectedly effective results in terms of potency and duration of action. Without wishing to be bound by any particular theory, it is thought that the longer dsRNA species serve as a substrate for the enzyme Dicer in the cytoplasm of a cell. In addition to cleaving double stranded nucleic acid into shorter segments, Dicer may facilitate the incorporation of a single-stranded cleavage product derived from the cleaved dsRNA into the RNA-induced silencing complex (RISC complex) that is responsible for the destruction of the cytoplasmic RNA derived from the target gene.

Dicer substrates may have certain properties which enhance its processing by Dicer. Dicer substrates are of a length sufficient such that it is processed by Dicer to produce an active nucleic acid molecule and may further include one or more of the following properties: (i) the dsRNA is asymmetric, e.g., has a 3′ overhang on the first strand (antisense strand) and (ii) the dsRNA has a modified 3′ end on the antisense strand (sense strand) to direct orientation of Dicer binding and processing of the dsRNA to an active siRNA. In certain embodiments, the longest strand in the Dicer substrate may be 24-30 nucleotides.

Dicer substrates may be symmetric or asymmetric. The Dicer substrate may have a sense strand includes 22-28 nucleotides and the antisense strand may include 24-30 nucleotides; thus, in some embodiments the resulting Dicer substrate may have an overhang on the 3′ end of the antisense strand. Dicer substrate may have a sense strand 25 nucleotides in length, and the antisense strand having 27 nucleotides in length with a 2 base 3′-overhang. The overhang may be 1-3 nucleotides, for example 2 nucleotides. The sense strand may also have a 5′ phosphate.

An asymmetric Dicer substrate may further contain two deoxyribonucleotides at the 3′-end of the sense strand in place of two of the ribonucleotides. Some exemplary Dicer substrates lengths and structures are 21+0, 21+2, 21−2, 22+0, 22+1, 22−1, 23+0, 23+2, 23−2, 24+0, 24+2, 24−2, 25+0, 25+2, 25−2, 26+0, 26+2, 26−2, 27+0, 27+2, and 27−2.

The sense strand of a Dicer substrate may be between about 22 to about 30 (e.g., about 22, 23, 24, 25, 26, 27, 28, 29 or 30); about 22 to about 28; about 24 to about 30; about 25 to about 30; about 26 to about 30; about 26 and 29; or about 27 to about 28 nucleotides in length. In certain preferred embodiments Dicer substrates contain sense and antisense strands, that are at least about 25 nucleotides in length and no longer than about 30 nucleotides; between about 26 and 29 nucleotides; or 27 nucleotides in length. The sense and antisense strands may be the same length (blunt ended), different lengths (have overhangs), or a combination. The sense and antisense strands may exist on the same polynucleotide or on different polynucleotides. A Dicer substrate may have a duplex region of about 19, 20, 21, 22, 23, 24, 25 or 27 nucleotides.

Like other siNA molecules provided herein, the antisense strand of a Dicer substrate may have any sequence that anneals to the antisense strand under biological conditions, such as within the cytoplasm of a eukaryotic cell.

Dicer substrates may have any modifications to the nucleotide base, sugar or phosphate backbone as known in the art and/or as described herein for other nucleic acid molecules (such as siNA molecules). In certain embodiments, Dicer substrates may have a sense strand is modified for Dicer processing by suitable modifiers located at the 3′ end of the sense strand, i.e., the dsRNA is designed to direct orientation of Dicer binding and processing. Suitable modifiers include nucleotides such as deoxyribonucleotides, dideoxyribonucleotides, acyclonucleotides and the like and sterically hindered molecules, such as fluorescent molecules and the like. Acyclonucleotides substitute a 2-hydroxyethoxymethyl group for-the 2′-deoxyribofuranosyl sugar normally present in dNMPs. Other nucleotides modifiers that could be used in Dicer substrate siNA molecules include 3′-deoxyadenosine (cordycepin), 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxy-3′-thiacytidine (3TC), 2′,3′-didehydro-2′,3′-dideoxythymidi-ne (d4T) and the monophosphate nucleotides of 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxy-3′-thiacytidine (3TC) and 2′,3′-didehydro-2′,3′-dide-oxythymidine (d4T). In one embodiment, deoxyribonucleotides are used as the modifiers. When nucleotide modifiers are utilized, they may replace ribonucleotides (e.g., 1-3 nucleotide modifiers, or 2 nucleotide modifiers are substituted for the ribonucleotides on the 3′ end of the sense strand) such that the length of the Dicer substrate does not change. When sterically hindered molecules are utilized, they may be attached to the ribonucleotide at the 3′ end of the antisense strand. Thus, in certain embodiments the length of the strand does not change with the incorporation of the modifiers. In certain embodiments, two DNA bases in the dsRNA are substituted to direct the orientation of Dicer processing of the antisense strand. In a further embodiment of, two terminal DNA bases are substituted for two ribonucleotides on the 3′-end of the sense strand forming a blunt end of the duplex on the 3′ end of the sense strand and the 5′ end of the antisense strand, and a two-nucleotide RNA overhang is located on the 3′-end of the antisense strand. This is an asymmetric composition with DNA on the blunt end and RNA bases on the overhanging end.

In certain embodiments modifications are included in the Dicer substrate such that the modification does not prevent the nucleic acid molecule from serving as a substrate for Dicer. In one embodiment, one or more modifications are made that enhance Dicer processing of the Dicer substrate. One or more modifications may be made that result in more effective RNAi generation. One or more modifications may be made that support a greater RNAi effect. One or more modifications are made that result in greater potency per each Dicer substrate to be delivered to the cell. Modifications may be incorporated in the 3′-terminal region, the 5′-terminal region, in both the 3′-terminal and 5′-terminal region or at various positions within the sequence. Any number and combination of modifications can be incorporated into the Dicer substrate so long as the modification does not prevent the nucleic acid molecule from serving as a substrate for Dicer. Where multiple modifications are present, they may be the same or different. Modifications to bases, sugar moieties, the phosphate backbone, and their combinations are contemplated. Either 5′-terminus can be phosphorylated.

Examples of Dicer substrate phosphate backbone modifications include phosphonates, including methylphosphonate, phosphorothioate, and phosphotriester modifications such as alkylphosphotriesters, and the like. Examples of Dicer substrate sugar moiety modifications include 2′-alkyl pyrimidine, such as 2′-O-methyl, 2′-fluoro, amino, and deoxy modifications and the like (see, e.g., Amarzguioui et al., 2003). Examples of Dicer substrate base group modifications include abasic sugars, 2-O-alkyl modified pyrimidines, 4-thiouracil, 5-bromouracil, 5-iodouracil, and 5-(3-aminoallyl)-uracil and the like. Locked nucleic acids, or LNA's, could also be incorporated.

The sense strand may be modified for Dicer processing by suitable modifiers located at the 3′ end of the sense strand, i.e., the Dicer substrate is designed to direct orientation of Dicer binding and processing. Suitable modifiers include nucleotides such as deoxyribonucleotides, dideoxyribonucleotides, acyclonucleotides and the like and sterically hindered molecules, such as fluorescent molecules and the like. Acyclonucleotides substitute a 2-hydroxyethoxymethyl group for-the 2′-deoxyribofuranosyl sugar normally present in dNMPs. Other nucleotides modifiers could include 3′-deoxyadenosine (cordycepin), 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxy-3′-thiacytidine (3TC), 2′,3′-didehydro-2′,3′-dideoxythymidi-ne (d4T) and the monophosphate nucleotides of 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxy-3′-thiacytidine (3TC) and 2′,3′-didehydro-2′,3′-dide-oxythymidine (d4T). In one embodiment, deoxyribonucleotides are used as the modifiers. When nucleotide modifiers are utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers are substituted for the ribonucleotides on the 3′ end of the sense strand. When sterically hindered molecules are utilized, they are attached to the ribonucleotide at the 3′ end of the antisense strand. Thus, the length of the strand does not change with the incorporation of the modifiers. In another embodiment, substituting two DNA bases in the Dicer substrate to direct the orientation of Dicer processing of the antisense strand is contemplated. In a further embodiment of the present invention, two terminal DNA bases are substituted for two ribonucleotides on the 3′-end of the sense strand forming a blunt end of the duplex on the 3′ end of the sense strand and the 5′ end of the antisense strand, and a two-nucleotide RNA overhang is located on the 3′-end of the antisense strand. This is an asymmetric composition with DNA on the blunt end and RNA bases on the overhanging end.

The antisense strand may be modified for Dicer processing by suitable modifiers located at the 3′ end of the antisense strand, i.e., the dsRNA is designed to direct orientation of Dicer binding and processing. Suitable modifiers include nucleotides such as deoxyribonucleotides, dideoxyribonucleotides, acyclonucleotides and the like and sterically hindered molecules, such as fluorescent molecules and the like. Acyclonucleotides substitute a 2-hydroxyethoxymethyl group for the 2′-deoxyribofuranosyl sugar normally present in dNMPs. Other nucleotide modifiers could include 3′-deoxyadenosine (cordycepin), 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxy-3′-thiacytidine (3TC), 2′,3′-didehydro-2′,3′-dideoxythymidi-ne (d4T) and the monophosphate nucleotides of 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxy-3′-thiacytidine (3TC) and 2′,3′-didehydro-2′,3′-dide-oxythymidine (d4T). In one embodiment, deoxyribonucleotides are used as the modifiers. When nucleotide modifiers are utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers are substituted for the ribonucleotides on the 3′ end of the antisense strand. When sterically hindered molecules are utilized, they are attached to the ribonucleotide at the 3′ end of the antisense strand. Thus, the length of the strand does not change with the incorporation of the modifiers. In another embodiment, the two DNA bases in the dsRNA may be substituted to direct the orientation of Dicer processing. In a further embodiment, two terminal DNA bases are located on the 3′ end of the antisense strand in place of two ribonucleotides forming a blunt end of the duplex on the 5′ end of the sense strand and the 3′ end of the antisense strand, and a two-nucleotide RNA overhang is located on the 3′-end of the sense strand. This is an asymmetric composition with DNA on the blunt end and RNA bases on the overhanging end.

Dicer substrates with a sense and an antisense strand can be linked by a third structure. The third structure will not block Dicer activity on the Dicer substrate and will not interfere with the directed destruction of the RNA transcribed from the target gene. The third structure may be a chemical linking group. Suitable chemical linking groups are known in the art and can be used. Alternatively, the third structure may be an oligonucleotide that links the two oligonucleotides of the dsRNA is a manner such that a hairpin structure is produced upon annealing of the two oligonucleotides making up the Dicer substrate. The hairpin structure preferably does not block Dicer activity on the Dicer substrate or interfere with the directed destruction of the RNA transcribed from the target gene.

The sense and antisense strands of the Dicer substrate are not required to be completely complementary. They only need to be substantially complementary to anneal under biological conditions and to provide a substrate for Dicer that produces an siRNA sufficiently complementary to the target sequence.

Dicer substrate can have certain properties that enhance its processing by Dicer. The Dicer substrate can have a length sufficient such that it is processed by Dicer to produce an active nucleic acid molecules (e.g., siRNA) and may have one or more of the following properties: (i) the Dicer substrate is asymmetric, e.g., has a 3′ overhang on the first strand (antisense strand) and (ii) the Dicer substrate has a modified 3′ end on the second strand (sense strand) to direct orientation of Dicer binding and processing of the Dicer substrate to an active siRNA. The Dicer substrate can be asymmetric such that the sense strand includes 22-28 nucleotides and the antisense strand includes 24-30 nucleotides. Thus, the resulting Dicer substrate has an overhang on the 3′ end of the antisense strand. The overhang is 1-3 nucleotides, for example 2 nucleotides. The sense strand may also have a 5′ phosphate.

A Dicer substrate may have an overhang on the 3′ end of the antisense strand and the sense strand is modified for Dicer processing. The 5′ end of the sense strand may have a phosphate. The sense and antisense strands may anneal under biological conditions, such as the conditions found in the cytoplasm of a cell. A region of one of the strands, particularly the antisense strand, of the Dicer substrate may have a sequence length of at least 19 nucleotides, wherein these nucleotides are in the 21-nucleotide region adjacent to the 3′ end of the antisense strand and are sufficiently complementary to a nucleotide sequence of the RNA produced from the target gene. A Dicer substrate may also have one or more of the following additional properties: (a) the antisense strand has a right shift from a corresponding 21-mer (i.e., the antisense strand includes nucleotides on the right side of the molecule when compared to the corresponding 21-mer), (b) the strands may not be completely complementary, i.e., the strands may contain simple mismatch pairings and (c) base modifications such as locked nucleic acid(s) may be included in the 5′ end of the sense strand.

An antisense strand of a Dicer substrate nucleic acid molecule may be modified to include 1-9 ribonucleotides on the 5′-end to give a length of 22-28 nucleotides. When the antisense strand has a length of 21 nucleotides, then 1-7 ribonucleotides, or 2-5 ribonucleotides and or 4 ribonucleotides may be added on the 3′-end. The added ribonucleotides may have any sequence. Although the added ribonucleotides may be complementary to the target gene sequence, full complementarity between the target sequence and the antisense strands is not required. That is, the resultant antisense strand is sufficiently complementary with the target sequence. A sense strand may then have 24-30 nucleotides. The sense strand may be substantially complementary with the antisense strand to anneal to the antisense strand under biological conditions. In one embodiment, the antisense strand may be synthesized to contain a modified 3′-end to direct Dicer processing. The sense strand may have a 3′ overhang. The antisense strand may be synthesized to contain a modified 3′-end for Dicer binding and processing and the sense strand has a 3′ overhang.

TIMP1 and TIMP2

Exemplary nucleic acid sequence of target tissue inhibitors of metalloproteinase-1 and -2 (human TIMP1 and TIMP2) cDNA is disclosed in GenBank accession numbers: NM_—003454 and NM_—003455 and the corresponding mRNA sequence, for example as listed as SEQ ID NO: 1 and SEQ ID NO:2. One of ordinary skill in the art would understand that a given sequence may change over time and to incorporate any changes needed in the nucleic acid molecules herein accordingly.

Expression of TIMP1 and TIMP2 was shown to be increased in fibrotic liver from rats with hepatic fibrosis (Nie, et al 2004. World J. Gastroenterol. 10:86-90). TIMP1 and TIMP2 are potential targets for the treatment of fibrosis.

Methods and Compositions for Inhibiting TIMP1 and TIMP2

Provided are compositions and methods for inhibition of TIMP1 and TIMP2 expression by using small nucleic acid molecules, such as short interfering nucleic acid (siNA), interfering RNA (RNAi), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating or that mediate RNA interference against TIMP1 and TIMP2 gene expression. The composition and methods disclosed herein are also useful in treating various fibrosis such as liver fibrosis, lung fibrosis, kidney fibrosis and fibrotic conditions shown in Table I, supra.

Nucleic acid molecule(s) and/or methods as disclosed herein may be used to down regulate the expression of gene(s) that encode RNA referred to, by example, Genbank Accession NM_—003254.2 and NM_—004255.4.

Compositions, methods and kits provided herein may include one or more nucleic acid molecules (e.g., siNA) and methods that independently or in combination modulate (e.g., downregulate) the expression of TIMP1 and or TIMP2 protein and/or genes encoding TIMP1 and TIMP2 proteins, proteins and/or genes encoding TIMP1 and TIMP2 associated with the maintenance and/or development of diseases, conditions or disorders associated with TIMP1 and TIMP2, such as liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, and fibrillogenesis (e.g., genes encoding sequences comprising those sequences referred to by GenBank Accession Nos. NM-003254 and NM_—003255), or a TIMP1 and TIMP2 gene family member where the genes or gene family sequences share sequence homology. The description of the various aspects and embodiments is provided with reference to exemplary genes TIMP1 and TIMP2. However, the various aspects and embodiments are also directed to other related TIMP1 and TIMP2 genes, such as homolog genes and transcript variants, and polymorphisms (e.g., single nucleotide polymorphism, (SNPs)) associated with certain TIMP1 and TIMP2 genes. As such, the various aspects and embodiments are also directed to other genes that are involved in TIMP1 and TIMP2 mediated pathways of signal transduction or gene expression that are involved, for example, in the maintenance or development of diseases, traits, or conditions described herein. These additional genes can be analyzed for target sites using the methods described for the TIMP1 and TIMP2 gene herein. Thus, the modulation of other genes and the effects of such modulation of the other genes can be performed, determined, and measured as described herein.

In one embodiment, compositions and methods provided herein include a double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a TIMP1 and TIMP2 gene (e.g., human TIMP1 and TIMP2 exemplified by SEQ ID NO:1 and SEQ ID NO:2, respectively), where the nucleic acid molecule includes about 15 to about 49 base pairs.

In one embodiment, a nucleic acid disclosed may be used to inhibit the expression of the TIMP1 and TIMP2 gene or a TIMP1 and TIMP2 gene family where the genes or gene family sequences share sequence homology. Such homologous sequences can be identified as is known in the art, for example using sequence alignments. Nucleic acid molecules can be designed to target such homologous sequences, for example using perfectly complementary sequences or by incorporating non-canonical base pairs, for example mismatches and/or wobble base pairs, that can provide additional target sequences. In instances where mismatches are identified, non-canonical base pairs (for example, mismatches and/or wobble bases) can be used to generate nucleic acid molecules that target more than one gene sequence. In a non-limiting example, non-canonical base pairs such as UU and CC base pairs are used to generate nucleic acid molecules that are capable of targeting sequences for differing TIMP1 and TIMP2 targets that share sequence homology. As such, one advantage of using siNAs disclosed herein is that a single nucleic acid can be designed to include nucleic acid sequence that is complementary to the nucleotide sequence that is conserved between the homologous genes. In this approach, a single nucleic acid can be used to inhibit expression of more than one gene instead of using more than one nucleic acid molecule to target the different genes.

Nucleic acid molecules may be used to target conserved sequences corresponding to a gene family or gene families such as TIMP1 and TIMP2 family genes. As such, nucleic acid molecules targeting multiple TIMP1 and TIMP2 targets can provide increased therapeutic effect. In addition, nucleic acid can be used to characterize pathways of gene function in a variety of applications. For example, nucleic acid molecules can be used to inhibit the activity of target gene(s) in a pathway to determine the function of uncharacterized gene(s) in gene function analysis, mRNA function analysis, or translational analysis. The nucleic acid molecules can be used to determine potential target gene pathways involved in various diseases and conditions toward pharmaceutical development. The nucleic acid molecules can be used to understand pathways of gene expression involved in, for example fibroses such as liver, kidney or pulmonary fibrosis, and/or inflammatory and proliferative traits, diseases, disorders, and/or conditions.

In one embodiment, the compositions and methods provided herein include a nucleic acid molecule having RNAi activity against TIMP1 RNA, where the nucleic acid molecule includes a sequence complementary to any RNA having TIMP1 encoding sequence. In another embodiment, a nucleic acid molecule may have RNAi activity against TIMP1 RNA, where the nucleic acid molecule includes a sequence complementary to an RNA having variant TIMP1 encoding sequence, for example other mutant TIMP1 genes known in the art to be associated with the maintenance and/or development of fibrosis. In another embodiment, a nucleic acid molecule disclosed herein includes a nucleotide sequence that can interact with nucleotide sequence of a TIMP1 gene and thereby mediate silencing of TIMP1 gene expression, for example, wherein the nucleic acid molecule mediates regulation of TIMP1 gene expression by cellular processes that modulate the chromatin structure or methylation patterns of the TIMP1 gene and prevent transcription of the TIMP1 gene.

In another embodiment the compositions and methods provided herein include a nucleic acid molecule having RNAi activity against TIMP2 RNA, where the nucleic acid molecule includes a sequence complementary to any RNA having TIMP2 encoding sequence, such as those sequences having GenBank Accession No. NM_—003455. Nucleic acid molecules may have RNAi activity against TIMP2 RNA, where the nucleic acid molecule includes a sequence complementary to an RNA having variant TIMP2 encoding sequence, for example other mutant TIMP2 genes known in the art to be associated with the maintenance and/or development of fibrosis. Nucleic acid molecules disclosed herein include a nucleotide sequence that can interact with nucleotide sequence of a TIMP2 gene and thereby mediate silencing of TIMP1 gene expression, e.g., where the nucleic acid molecule mediates regulation of TIMP2 gene expression by cellular processes that modulate the chromatin structure or methylation patterns of the TIMP2 gene and prevent transcription of the TIMP2 gene.

Methods of Treatment

In one embodiment, nucleic acid molecules may be used to down regulate or inhibit the expression of TIMP1 and/or TIMP1 proteins arising from TIMP1 and/or TIMP1 haplotype polymorphisms that are associated with a disease or condition, (e.g., fibrosis). Analysis of TIMP1 and/or TIMP1 genes, or TIMP1 and/or TIMP1 protein or RNA levels can be used to identify subjects with such polymorphisms or those subjects who are at risk of developing traits, conditions, or diseases described herein. These subjects are amenable to treatment, for example, treatment with nucleic acid molecules disclosed herein and any other composition useful in treating diseases related to TIMP1 and/or TIMP1 gene expression. As such, analysis of TIMP1 and/or TIMP1 protein or RNA levels can be used to determine treatment type and the course of therapy in treating a subject. Monitoring of TIMP1 and/or TIMP1 protein or RNA levels can be used to predict treatment outcome and to determine the efficacy of compounds and compositions that modulate the level and/or activity of certain TIMP1 and/or TIMP1 proteins associated with a trait, condition, or disease.

In one embodiment, nucleic acid molecules may be used to down regulate or inhibit the expression of TIMP2 and/or TIMP2 proteins arising from TIMP2 and/or TIMP2 haplotype polymorphisms that are associated with a disease or condition, (e.g., fibrosis). Analysis of TIMP2 and/or TIMP2 genes, or TIMP2 and/or TIMP2 protein or RNA levels can be used to identify subjects with such polymorphisms or those subjects who are at risk of developing traits, conditions, or diseases described herein. These subjects are amenable to treatment, for example, treatment with nucleic acid molecules disclosed herein and any other composition useful in treating diseases related to TIMP2 and/or TIMP2 gene expression. As such, analysis of TIMP2 and/or TIMP2 protein or RNA levels can be used to determine treatment type and the course of therapy in treating a subject. Monitoring of TIMP2 and/or TIMP2 protein or RNA levels can be used to predict treatment outcome and to determine the efficacy of compounds and compositions that modulate the level and/or activity of certain TIMP2 and/or TIMP2 proteins associated with a trait, condition, or disease.

Provided are compositions and methods for inhibition of TIMP1 and TIMP2 expression by using small nucleic acid molecules as provided herein, such as short interfering nucleic acid (siNA), interfering RNA (RNAi), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating or that mediate RNA interference against TIMP1 and TIMP2 gene expression. The composition and methods disclosed herein are also useful in treating various fibrosis such as liver fibrosis, lung fibrosis, and kidney fibrosis.

The nucleic acid molecules disclosed herein individually, or in combination or in conjunction with other drugs, can be use for preventing or treating diseases, traits, conditions and/or disorders associated with TIMP1 and TIMP2, such as liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, and fibrillogenesis.

The nucleic acid molecules disclosed herein are able to inhibit the expression of TIMP1 or TIMP2 in a sequence specific manner. The nucleic acid molecules may include a sense strand and an antisense strand which include contiguous nucleotides that are at least partially complementary (antisense) to a TIMP1 or TIMP2 mRNA.

In some embodiments, dsRNA specific for TIMP1 or TIMP2 can be used in conjunction with other dsRNA specific for other molecular chaperones that assist in the folding of newly synthesized proteins such as, calnexin, calreticulin, BiP (Bergeron et al. Trends Biochem. Sci. 1994; 19:124-128; Herbert et al. 1995; Cold Spring Harb. Symp. Quant. Biol. 60:405-415)

Fibrosis can be treated by RNA interference using nucleic acid molecules as disclosed herein. Exemplary fibrosis include liver fibrosis, peritoneal fibrosis, lung fibrosis, kidney fibrosis, vocal cord fibrosis, intestinal fibrosis. The nucleic acid molecules disclosed herein may inhibit the expression of TIMP1 or TIMP2 in a sequence specific manner.

Treatment of fibrosis can be monitored by determining the level of extracellular collagen using suitable techniques known in the art such as, using anti-collagen I antibodies. Treatment can also be monitored by determining the level of TIMP1 or TIMP2 mRNA or the level of TIMP1 or TIMP2 protein in the cells of the affected tissue. Treatment can also be monitored by non-invasive scanning of the affected organ or tissue such as by computer assisted tomography scan, magnetic resonance elastography scans.

A method for treating or preventing TIMP1 associated disease or condition in a subject or organism may include contacting the subject or organism with a nucleic acid molecule as provided herein under conditions suitable to modulate the expression of the TIMP1 gene in the subject or organism.

A method for treating or preventing TIMP2 associated disease or condition in a subject or organism may include contacting the subject or organism with a nucleic acid molecule as provided herein under conditions suitable to modulate the expression of the TIMP2 gene in the subject or organism.

A method for treating or preventing fibrosis in a subject or organism may include contacting the subject or organism with a nucleic acid molecule under conditions suitable to modulate the expression of the TIMP1 and/or TIMP2 gene in the subject or organism.

A method for treating or preventing one or more fibroses selected from the group consisting of liver fibrosis, kidney fibrosis, and pulmonary fibrosis in a subject or organism may include contacting the subject or organism with a nucleic acid molecule under conditions suitable to modulate the expression of the TIMP1 and/or TIMP2 gene in the subject or organism.

Fibrotic Diseases

Fibrotic diseases are generally characterized by the excess deposition of a fibrous material within the extracellular matrix, which contributes to abnormal changes in tissue architecture and interferes with normal organ function.

All tissues damaged by trauma respond by the initiation of a wound-healing program. Fibrosis, a type of disorder characterized by excessive scarring, occurs when the normal self-limiting process of wound healing response is disturbed, and causes excessive production and deposition of collagen. As a result, normal organ tissue is replaced with scar tissue, which eventually leads to the functional failure of the organ.

Fibrosis may be initiated by diverse causes and in various organs. Liver cirrhosis, pulmonary fibrosis, sarcoidosis, keloids and kidney fibrosis are all chronic conditions associated with progressive fibrosis, thereby causing a continuous loss of normal tissue function.

Acute fibrosis (usually with a sudden and severe onset and of short duration) occurs as a common response to various forms of trauma including accidental injuries (particularly injuries to the spine and central nervous system), infections, surgery, ischemic illness (e.g. cardiac scarring following heart attack), burns, environmental pollutants, alcohol and other types of toxins, acute respiratory distress syndrome, radiation and chemotherapy treatments).

Fibrosis, a fibrosis related pathology or a pathology related to aberrant crosslinking of cellular proteins may all be treated by the siRNAs disclosed herein. Fibrotic diseases or diseases in which fibrosis is evident (fibrosis related pathology) include both acute and chronic forms of fibrosis of organs, including all etiological variants of the following: pulmonary fibrosis, including interstitial lung disease and fibrotic lung disease, liver fibrosis, cardiac fibrosis including myocardial fibrosis, kidney fibrosis including chronic renal failure, skin fibrosis including scleroderma, keloids and hypertrophic scars; myelofibrosis (bone marrow fibrosis); fibrosis in the brain associated with brain infarction; all types of ocular scarring including proliferative vitreoretinopathy (PVR) and scarring resulting from surgery to treat cataract or glaucoma; inflammatory bowel disease of variable etiology, macular degeneration, Grave's ophthalmopathy, drug induced ergotism, keloid scars, scleroderma, psoriasis, glioblastoma in Li-Fraumeni syndrome, sporadic glioblastoma, myleoid leukemia, acute myelogenous leukemia, myelodysplastic syndrome, myeloproferative syndrome, gynecological cancer, Kaposi's sarcoma, Hansen's disease, fibrosis associated with brain infarction and collagenous colitis.

In various embodiments, the compounds (nucleic acid molecules) as disclosed herein may be used to treat fibrotic diseases, for example as disclosed herein, as well as many other diseases and conditions apart from fibrotic diseases, for example such as disclosed herein. Other conditions to be treated include fibrotic diseases in other organs—kidney fibrosis for any reason (CKD including ESRD); lung fibrosis (including ILF); myelofibrosis, abnormal scarring (keloids) associated with all possible types of skin injury accidental and jatrogenic (operations); scleroderma; cardiofibrosis, failure of glaucoma filtering operation; intestinal adhesions.

Ocular Surgery and Fibrotic Complications

Contracture of scar tissue resulting from eye surgery may often occur. Glaucoma surgery to create new drainage channels often fails due to scarring and contraction of tissues and the generated drainage system may be blocked requiring additional surgical intervention. Current anti-scarring regimens (Mitomycin C or 5FU) are limited due to the complications involved (e.g. blindness) e.g. see Cordeiro M F, et al., Human anti-transforming growth factor-beta2 antibody: a new glaucoma anti-scarring agent Invest Ophthalmol Vis Sci. 1999 September; 40(10):2225-34. There may also be contraction of scar tissue formed after corneal trauma or corneal surgery, for example laser or surgical treatment for myopia or refractive error in which contraction of tissues may lead to inaccurate results. Scar tissue may be formed on/in the vitreous humor or the retina, for example, and may eventually causes blindness in some diabetics, and may be formed after detachment surgery, called proliferative vitreoretinopathy (PVR). PVR is the most common complication following retinal detachment and is associated with a retinal hole or break. PVR refers to the growth of cellular membranes within the vitreous cavity and on the front and back surfaces of the retina containing retinal pigment epithelial (RPE) cells. These membranes, which are essentially scar tissues, exert traction on the retina and may result in recurrences of retinal detachment, even after an initially successful retinal detachment procedure.

Scar tissue may be formed in the orbit or on eye and eyelid muscles after squint, orbital or eyelid surgery, or thyroid eye disease, and where scarring of the conjunctiva occurs as may happen after glaucoma surgery or in cicatricial disease, inflammatory disease, for example, pemphigoid, or infective disease, for example, trachoma. A further eye problem associated with the contraction of collagen-including tissues is the opacification and contracture of the lens capsule after cataract extraction. Important role for MMPs has been recognized in ocular diseases including wound healing, dry eye, sterile corneal ulceration, recurrent epithelial erosion, corneal neovascularization, pterygium, conjuctivochalasis, glaucoma, PVR, and ocular fibrosis.

Liver Fibrosis

Liver fibrosis (LF) is a generally irreversible consequence of hepatic damage of several etiologies. In the Western world, the main etiologic categories are: alcoholic liver disease (30-50%), viral hepatitis (30%), biliary disease (5-10%), primary hemochromatosis (5%), and drug-related and cryptogenic cirrhosis of, unknown etiology, (10-15%). Wilson's disease, α₁-antitrypsin deficiency and other rare diseases also have liver fibrosis as one of the symptoms. Liver cirrhosis, the end stage of liver fibrosis, frequently requires liver transplantation and is among the top ten causes of death in the Western world.

Kidney Fibrosis and Related Conditions.

Chronic Renal Failure (CRF)

Chronic renal failure is a gradual and progressive loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes. CRF is slowly progressive. It most often results from any disease that causes gradual loss of kidney function, and fibrosis is the main pathology that produces CRF.

Diabetic Nephropathy

Diabetic nephropathy, hallmarks of which are glomerulosclerosis and tubulointerstitial fibrosis, is the single most prevalent cause of end-stage renal disease in the modern world, and diabetic patients constitute the largest population on dialysis. Such therapy is costly and far from optimal. Transplantation offers a better outcome but suffers from a severe shortage of donors.

Chronic Kidney Disease

Chronic kidney disease (CKD) is a worldwide public health problem and is recognized as a common condition that is associated with an increased risk of cardiovascular disease and chronic renal failure (CRF).

The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) defines chronic kidney disease as either kidney damage or a decreased kidney glomerular filtration rate (GFR) for three or more months. Other markers of CKD are also known and used for diagnosis. In general, the destruction of renal mass with irreversible sclerosis and loss of nephrons leads to a progressive decline in GFR. Recently, the K/DOQI published a classification of the stages of CKD, as follows:

• • Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2)
  • Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2)
  • Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2)
  • Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2)
  • Stage 5: Kidney failure (GFR<15 mL/min/1.73 m2 or dialysis)

In stages 1 and 2 CKD, GFR alone does not confirm the diagnosis. Other markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities in imaging tests, may be relied upon.

Pathophysiology of CKD

Approximately 1 million nephrons are present in each kidney, each contributing to the total GFR. Irrespective of the etiology of renal injury, with progressive destruction of nephrons, the kidney is able to maintain GFR by hyperfiltration and compensatory hypertrophy of the remaining healthy nephrons. This nephron adaptability allows for continued normal clearance of plasma solutes so that substances such as urea and creatinine start to show significant increases in plasma levels only after total GFR has decreased to 50%, when the renal reserve has been exhausted. The plasma creatinine value will approximately double with a 50% reduction in GFR. Therefore, a doubling in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient actually represents a loss of 50% of functioning nephron mass.

The residual nephron hyperfiltration and hypertrophy, although beneficial for the reasons noted, is thought to represent a major cause of progressive renal dysfunction. This is believed to occur because of increased glomerular capillary pressure, which damages the capillaries and leads initially to focal and segmental glomerulosclerosis and eventually to global glomerulosclerosis. This hypothesis has been based on studies of five-sixths nephrectomized rats, which develop lesions that are identical to those observed in humans with CKD.

The two most common causes of chronic kidney disease are diabetes and hypertension. Other factors include acute insults from nephrotoxins, including contrasting agents, or decreased perfusion; Proteinuria; Increased renal ammoniagenesis with interstitial injury; Hyperlipidemia; Hyperphosphatemia with calcium phosphate deposition; Decreased levels of nitrous oxide and smoking

In the United States, the incidence and prevalence of CKD is rising, with poor outcomes and high cost to the health system. Kidney disease is the ninth leading cause of death in the US. The high rate of mortality has led the US Surgeon General's mandate for America's citizenry, Healthy People 2010, to contain a chapter focused on CKD. The objectives of this chapter are to articulate goals and to provide strategies to reduce the incidence, morbidity, mortality, and health costs of chronic kidney disease in the United States.

The incidence rates of end-stage renal disease (ESRD) have also increased steadily internationally since 1989. The United States has the highest incident rate of ESRD, followed by Japan. Japan has the highest prevalence per million population, followed by the US.

The mortality rates associated with hemodialysis are striking and indicate that the life expectancy of patients entering into hemodialysis is markedly shortened. At every age, patients with ESRD on dialysis have significantly increased mortality when compared with nondialysis patients and individuals without kidney disease. At age 60 years, a healthy person can expect to live for more than 20 years, whereas the life expectancy of a 60-year-old patient starting hemodialysis is closer to 4 years (Aurora and Verelli, May 21, 2009. Chronic Renal Failure: Treatment & Medication. Emedicine. http://emedicine.medscape.com/article/238798-treatment).

Pulmonary Fibrosis

Interstitial pulmonary fibrosis (IPF) is scarring of the lung caused by a variety of inhaled agents including mineral particles, organic dusts, and oxidant gases, or by unknown reasons (idiopathic lung fibrosis). The disease afflicts millions of individuals worldwide, and there are no effective therapeutic approaches. A major reason for the lack of useful treatments is that few of the molecular mechanisms of disease have been defined sufficiently to design appropriate targets for therapy (Lasky J A., Brody A R. (2000), “Interstitial fibrosis and growth factors”, Environ Health Perspect.; 108 Suppl 4:751-62).

Cardiac Fibrosis

Heart failure is unique among the major cardiovascular disorders in that it alone is increasing in prevalence while there has been a striking decrease in other conditions. Some of this can be attributed to the aging of the populations of the United States and Europe. The ability to salvage patients with myocardial damage is also a major factor, as these patients may develop progression of left ventricular dysfunction due to deleterious remodelling of the heart.

The normal myocardium is composed of a variety of cells, cardiac myocytes and noncardiomyocytes, which include endothelial and vascular smooth muscle cells and fibroblasts.

Structural remodeling of the ventricular wall is a key determinant of clinical outcome in heart disease. Such remodeling involves the production and destruction of extracellular matrix proteins, cell proliferation and migration, and apoptotic and necrotic cell death. Cardiac fibroblasts are crucially involved in these processes, producing growth factors and cytokines that act as autocrine and paracrine factors, as well as extracellular matrix proteins and proteinases. Recent studies have shown that the interactions between cardiac fibroblasts and cardiomyocytes are essential for the progression of cardiac remodeling of which the net effect is deterioration in cardiac function and the onset of heart failure (Manabe I, et al., (2002), “Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy”, Circ Res. 13; 91(12):1103-13).

Burns and Scars

A particular problem which may arise, particularly in fibrotic disease, is contraction of tissues, for example contraction of scars. Contraction of tissues including extracellular matrix components, especially of collagen-including tissues, may occur in connection with many different pathological conditions and with surgical or cosmetic procedures. Contracture, for example, of scars, may cause physical problems, which may lead to the need for medical treatment, or it may cause problems of a purely cosmetic nature. Collagen is the major component of scar and other contracted tissue and as such is the most important structural component to consider. Nevertheless, scar and other contracted tissue also includes other structural components, especially other extracellular matrix components, for example, elastin, which may also contribute to contraction of the tissue.

Contraction of collagen-including tissue, which may also include other extracellular matrix components, frequently occurs in the healing of burns. The burns may be chemical, thermal or radiation burns and may be of the eye, the surface of the skin or the skin and the underlying tissues. It may also be the case that there are burns on internal tissues, for example, caused by radiation treatment. Contraction of burnt tissues is often a problem and may lead to physical and/or cosmetic problems, for example, loss of movement and/or disfigurement.

Skin grafts may be applied for a variety of reasons and may often undergo contraction after application. As with the healing of burnt tissues the contraction may lead to both physical and cosmetic problems. It is a particularly serious problem where many skin grafts are needed as, for example, in a serious burns case.

Contraction is also a problem in production of artificial skin. To make a true artificial skin it is necessary to have an epidermis made of epithelial cells (keratinocytes) and a dermis made of collagen populated with fibroblasts. It is important to have both types of cells because they signal and stimulate each other using growth factors. The collagen component of the artificial skin often contracts to less than one tenth of its original area when populated by fibroblasts.

Cicatricial contraction, contraction due to shrinkage of the fibrous tissue of a scar, is common. In some cases the scar may become a vicious cicatrix, a scar in which the contraction causes serious deformity. A patient's stomach may be effectively separated into two separate chambers in an hour-glass contracture by the contraction of scar tissue formed when a stomach ulcer heals. Obstruction of passages and ducts, cicatricial stenosis, may occur due to the contraction of scar tissue. Contraction of blood vessels may be due to primary obstruction or surgical trauma, for example, after surgery or angioplasty. Stenosis of other hollow visci, for examples, ureters, may also occur. Problems may occur where any form of scarring takes place, whether resulting from accidental wounds or from surgery. Conditions of the skin and tendons which involve contraction of collagen-including tissues include post-trauma conditions resulting from surgery or accidents, for example, hand or foot tendon injuries, post-graft conditions and pathological conditions, such as scleroderma, Dupuytren's contracture and epidermolysis bullosa. Scarring and contraction of tissues in the eye may occur in various conditions, for example, the sequelae of retinal detachment or diabetic eye disease (as mentioned above). Contraction of the sockets found in the skull for the eyeballs and associated structures, including extra-ocular muscles and eyelids, may occur if there is trauma or inflammatory damage. The tissues contract within the sockets causing a variety of problems including double vision and an unsightly appearance.

Other indications include Vocal cord fibrosis, Intestinal fibrosis and Fibrosis associated with brain infarction.

For further information on different types of fibrosis see: Molina V, et al., (2002), “Fibrotic diseases”, Harefuah, 141(11): 973-8, 1009; Yu L, et al., (2002), “Therapeutic strategies to halt renal fibrosis”, Curr Opin Pharmacol. 2(2):177-81; Keane W F and Lyle P A. (2003), “Recent advances in management of type 2 diabetes and nephropathy: lessons from the RENAAL study”, Am J Kidney Dis. 41(3 Suppl 2): S22-5; Bohle A, et al., (1989), “The pathogenesis of chronic renal failure”, Pathol Res Pract. 185(4):421-40; Kikkawa R, et al., (1997), “Mechanism of the progression of diabetic nephropathy to renal failure”, Kidney Int Suppl. 62:S39-40; Bataller R, and Brenner D A. (2001), “Hepatic stellate cells as a target for the treatment of liver fibrosis”, Semin Liver Dis. 21(3):437-51; Gross T J and Hunninghake G W, (2001) “Idiopathic pulmonary fibrosis”, N Engl J Med. 345(7):517-25; Frohlich E D. (2001) “Fibrosis and ischemia: the real risks in hypertensive heart disease”, Am J Hypertens; 14(6 Pt 2):194S-199S; Friedman S L. (2003), “Liver fibrosis—from bench to bedside”, J Hepatol. 38 Suppl 1:S38-53; Albanis E, et al., (2003), “Treatment of hepatic fibrosis: almost there”, Curr Gastroenterol Rep. 5(1):48-56; (Weber K T. (2000), “Fibrosis and hypertensive heart disease”, Curr Opin Cardiol. 15(4):264-72).

Delivery of Nucleic Acid Molecules and Pharmaceutical Formulations

Nucleic acid molecules may be adapted for use to prevent or treat fibrotic (e.g., liver, kidney, peritoneal, and pulmonary) diseases, traits, conditions and/or disorders, and/or any other trait, disease, disorder or condition that is related to or will respond to the levels of TIMP1 and TIMP2 in a cell or tissue. A nucleic acid molecule may include a delivery vehicle, including liposomes, for administration to a subject, carriers and diluents and their salts, and/or can be present in pharmaceutically acceptable formulations.

Nucleic acid molecules of the present invention may be delivered to the target tissue by direct application of the naked molecules prepared with a carrier or a diluent.

The terms “naked nucleic acid” or “naked dsRNA” or “naked siRNA” refers to nucleic acid molecules that are free from any delivery vehicle that acts to assist, promote or facilitate entry into the cell, including viral sequences, viral particles, liposome formulations, lipofectin or precipitating agents and the like. For example, dsRNA in PBS is “naked dsRNA”.

Nucleic acid molecules disclosed herein may be delivered or administered directly with a carrier or diluent but not any delivery vehicle that acts to assist, promote or facilitate entry to the cell, including viral vectors, viral particles, liposome formulations, lipofectin or precipitating agents and the like.

Nucleic acid molecules may be delivered or administered to a subject by direct application of the nucleic acid molecules with a carrier or diluent or any other delivery vehicle that acts to assist, promote or facilitate entry into a cell, including viral sequences, viral particular, liposome formulations, lipofectin or precipitating agents and the like. Polypeptides that facilitate introduction of nucleic acid into a desired subject such as those described in US. Application Publication No. 20070155658 (e.g., a melamine derivative such as 2,4,6-Triguanidino Traizine and 2,4,6-Tramidosarcocyl Melamine, a polyarginine polypeptide, and a polypeptide including alternating glutamine and asparagine residues).

Methods for the delivery of nucleic acid molecules are described in Akhtar et al., Trends Cell Bio., 2: 139 (1992); Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, (1995), Maurer et al., Mol. Membr. Biol., 16: 129-140 (1999); Hofland and Huang, Handb. Exp. Pharmacol., 137: 165-192 (1999); and Lee et al., ACS Symp. Ser., 752: 184-192 (2000); U.S. Pat. Nos. 6,395,713; 6,235,310; 5,225,182; 5,169,383; 5,167,616; 4,959217; 4,925,678; 4,487,603; and 4,486,194 and Sullivan et al., PCT WO 94/02595; PCT WO 00/03683 and PCT WO 02/08754; and U.S. Patent Application Publication No. 2003077829. These protocols can be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules can be administered to cells by a variety of methods known to those of skill in the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as biodegradable polymers, hydrogels, cyclodextrins (see e.g., Gonzalez et al., Bioconjugate Chem., 10: 1068-1074 (1999); Wang et al., International PCT publication Nos. WO 03/47518 and WO 03/46185), poly(lactic-co-glycolic)acid (PLGA) and PLCA microspheres (see for example U.S. Pat. No. 6,447,796 and U.S. Application Publication No. 2002130430), biodegradable nanocapsules, and bioadhesive microspheres, or by proteinaceous vectors (O'Hare and Normand, International PCT Publication No. WO 00/53722). Alternatively, the nucleic acid/vehicle combination is locally delivered by direct injection or by use of an infusion pump. Direct injection of the nucleic acid molecules as disclosed herein, whether subcutaneous, intramuscular, or intradermal, can take place using standard needle and syringe methodologies, or by needle-free technologies such as those described in Conry et al., Clin. Cancer Res., 5: 2330-2337 (1999) and Barry et al., International PCT Publication No. WO 99/31262. The molecules of as described herein can be used as pharmaceutical agents. Pharmaceutical agents may prevent, modulate the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a subject.

Nucleic acid molecules may be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues. The nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through direct dermal application, transdermal application, or injection, with or without their incorporation in biopolymers.

Delivery systems include surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al. Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al., Chem. Pharm. Bull. 1995, 43, 1005-1011).

Nucleic acid molecules may be formulated or complexed with polyethylenimine (e.g., linear or branched PEI) and/or polyethylenimine derivatives, including for example polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine (PEI-PEG-GAL) or polyethyleneimine-polyethyleneglycol-tri-N-acetylgalactosamine (PEI-PEG-triGAL) derivatives, grafted PEIs such as galactose PEI, cholesterol PEI, antibody derivatized PEI, and polyethylene glycol PEI (PEG-PEI) derivatives thereof (see for example Ogris et al., 2001, AAPA PharmSci, 3, 1-11; Furgeson et al., 2003, Bioconjugate Chem., 14, 840-847; Kunath et al., 2002, Pharmaceutical Research, 19, 810-817; Choi et al., 2001, Bull. Korean Chem. Soc., 22, 46-52; Bettinger et al., 1999, Bioconjugate Chem., 10, 558-561; Peterson et al., 2002, Bioconjugate Chem., 13, 845-854; Erbacher et al., 1999, Journal of Gene Medicine Preprint, 1, 1-18; Godbey et al., 1999., PNAS USA, 96, 5177-5181; Godbey et al., 1999, Journal of Controlled Release, 60, 149-160; Diebold et al., 1999, Journal of Biological Chemistry, 274, 19087-19094; Thomas and Klibanov, 2002, PNAS USA, 99, 14640-14645; Sagara, U.S. Pat. No. 6,586,524 and United States Patent Application Publication No. 20030077829.

Nucleic acid molecules may be complexed with membrane disruptive agents such as those described in U.S. Patent Application Publication No. 20010007666. The membrane disruptive agent or agents and the nucleic acid molecule may also be complexed with a cationic lipid or helper lipid molecule, such as those lipids described in U.S. Pat. No. 6,235,310.

The nucleic acid molecules may be administered via pulmonary delivery, such as by inhalation of an aerosol or spray dried formulation administered by an inhalation device or nebulizer, providing rapid local uptake of the nucleic acid molecules into relevant pulmonary tissues. Solid particulate compositions containing respirable dry particles of micronized nucleic acid compositions can be prepared by grinding dried or lyophilized nucleic acid compositions, and then passing the micronized composition through, for example, a 400 mesh screen to break up or separate out large agglomerates. A solid particulate composition comprising the nucleic acid compositions of contemplated herein can optionally contain a dispersant which serves to facilitate the formation of an aerosol as well as other therapeutic compounds. A suitable dispersant is lactose, which can be blended with the nucleic acid compound in any suitable ratio, such as a 1 to 1 ratio by weight.

Aerosols of liquid particles may include a nucleic acid molecules disclosed herein and can be produced by any suitable means, such as with a nebulizer (see e.g., U.S. Pat. No. 4,501,729). Nebulizers are commercially available devices which transform solutions or suspensions of an active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air or oxygen, through a narrow venturi orifice or by means of ultrasonic agitation. Suitable formulations for use in nebulizers include the active ingredient in a liquid carrier in an amount of up to 40% w/w preferably less than 20% w/w of the formulation. The carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, e.g., sodium chloride or other suitable salts. Optional additives include preservatives if the formulation is not prepared sterile, e.g., methyl hydroxybenzoate, anti-oxidants, flavorings, volatile oils, buffering agents and emulsifiers and other formulation surfactants. The aerosols of solid particles including the active composition and surfactant can likewise be produced with any solid particulate aerosol generator. Aerosol generators for administering solid particulate therapeutics to a subject produce particles which are respirable, as explained above, and generate a volume of aerosol containing a predetermined metered dose of a therapeutic composition at a rate suitable for human administration. One illustrative type of solid particulate aerosol generator is an insufflator. Suitable formulations for administration by insufflation include finely comminuted powders which can be delivered by means of an insufflator. In the insufflator, the powder, e.g., a metered dose thereof effective to carry out the treatments described herein, is contained in capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically includes from 0.1 to 100 w/w of the formulation. A second type of illustrative aerosol generator includes a metered dose inhaler. Metered dose inhalers are pressurized aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquefied propellant. During use these devices discharge the formulation through a valve adapted to deliver a metered volume to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation can additionally contain one or more co-solvents, for example, ethanol, emulsifiers and other formulation surfactants, such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavoring agents. Other methods for pulmonary delivery are described in, e.g., US Patent Application No. 20040037780, and U.S. Pat. Nos. 6,592,904; 6,582,728; 6,565,885. PCT Patent Publiction No. WO2008/132723 discloses aerosol delivery of oligonucleotides in general, and of siRNA in particular, to the respiratory system.

Nucleic acid molecules may be administered to the central nervous system (CNS) or peripheral nervous system (PNS). Experiments have demonstrated the efficient in vivo uptake of nucleic acids by neurons. See e.g., Sommer et al., 1998, Antisense Nuc. Acid Drug Dev., 8, 75; Epa et al., 2000, Antisense Nuc. Acid Drug Dev., 10, 469; Broaddus et al., 1998, J. Neurosurg., 88(4), 734; Karle et al., 1997, Eur. J. Pharmocol., 340(2/3), 153; Bannai et al., 1998, Brain Research, 784(1,2), 304; Rajakumar et al., 1997, Synapse, 26(3), 199; Wu-pong et al., 1999, BioPharm, 12(1), 32; Bannai et al., 1998, Brain Res. Protoc., 3(1), 83; and Simantov et al., 1996, Neuroscience, 74(1), 39. Nucleic acid molecules are therefore amenable to delivery to and uptake by cells in the CNS and/or PNS.

Delivery of nucleic acid molecules to the CNS is provided by a variety of different strategies. Traditional approaches to CNS delivery that can be used include, but are not limited to, intrathecal and intracerebroventricular administration, implantation of catheters and pumps, direct injection or perfusion at the site of injury or lesion, injection into the brain arterial system, or by chemical or osmotic opening of the blood-brain barrier. Other approaches can include the use of various transport and carrier systems, for example though the use of conjugates and biodegradable polymers. Furthermore, gene therapy approaches, e.g., as described in Kaplitt et al., U.S. Pat. No. 6,180,613 and Davidson, WO 04/013280, can be used to express nucleic acid molecules in the CNS.

Delivery systems may include, for example, aqueous and nonaqueous gels, creams, multiple emulsions, microemulsions, liposomes, ointments, aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon bases and powders, and can contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids), and hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone). In one embodiment, the pharmaceutically acceptable carrier is a liposome or a transdermal enhancer. Examples of liposomes which can be used include the following: (1) CellFectin, 1:1.5 (M/M) liposome formulation of the cationic lipid N,NI,NII,NIII-tetramethyl-N,NI,NII,NIII-tetrapalmit-y-spermine and dioleoyl phosphatidylethanolamine (DOPE) (GIBCO BRL); (2) Cytofectin GSV, 2:1 (M/M) liposome formulation of a cationic lipid and DOPE (Glen Research); (3) DOTAP(N-[1-(2,3-dioleoyloxy)-N,N,N-tri-methyl-ammoniummethylsulfate) (Boehringer Manheim); and (4) Lipofectamine, 3:1 (M/M) liposome formulation of the polycationic lipid DOSPA, the neutral lipid DOPE (GIBCO BRL) and Di-Alkylated Amino Acid (DiLA2).

Delivery systems may include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other vehicles (e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid).

Nucleic acid molecules may be formulated or complexed with polyethylenimine (e.g., linear or branched PEI) and/or polyethylenimine derivatives, including for example grafted PEIs such as galactose PEI, cholesterol PEI, antibody derivatized PEI, and polyethylene glycol PEI (PEG-PEI) derivatives thereof (see for example Ogris et al., 2001, AAPA PharmSci, 3, 1-11; Furgeson et al., 2003, Bioconjugate Chem., 14, 840-847; Kunath et al., 2002, Pharmaceutical Research, 19, 810-817; Choi et al., 2001, Bull. Korean Chem. Soc., 22, 46-52; Bettinger et al., 1999, Bioconjugate Chem., 10, 558-561; Peterson et al., 2002, Bioconjugate Chem., 13, 845-854; Erbacher et al., 1999, Journal of Gene Medicine Preprint, 1, 1-18; Godbey et al., 1999., PNAS USA, 96, 5177-5181; Godbey et al., 1999, Journal of Controlled Release, 60, 149-160; Diebold et al., 1999, Journal of Biological Chemistry, 274, 19087-19094; Thomas and Klibanov, 2002, PNAS USA, 99, 14640-14645; and Sagara, U.S. Pat. No. 6,586,524.

Nucleic acid molecules may include a bioconjugate, for example a nucleic acid conjugate as described in Vargeese et al., U.S. Ser. No. 10/427,160; U.S. Pat. No. 6,528,631; U.S. Pat. No. 6,335,434; U.S. Pat. No. 6,235,886; U.S. Pat. No. 6,153,737; U.S. Pat. No. 5,214,136; U.S. Pat. No. 5,138,045.

Compositions, methods and kits disclosed herein may include an expression vector that includes a nucleic acid sequence encoding at least one nucleic acid molecule as provided herein in a manner that allows expression of the nucleic acid molecule. Methods of introducing nucleic acid molecules or one or more vectors capable of expressing the strands of dsRNA into the environment of the cell will depend on the type of cell and the make up of its environment. The nucleic acid molecule or the vector construct may be directly introduced into the cell (i.e., intracellularly); or introduced extracellularly into a cavity, interstitial space, into the circulation of an organism, introduced orally, or may be introduced by bathing an organism or a cell in a solution containing dsRNA. The cell is preferably a mammalian cell; more preferably a human cell. The nucleic acid molecule of the expression vector can include a sense region and an antisense region. The antisense region can include a sequence complementary to a RNA or DNA sequence encoding TIMP1 and TIMP2 and the sense region can include a sequence complementary to the antisense region. The nucleic acid molecule can include two distinct strands having complementary sense and antisense regions. The nucleic acid molecule can include a single strand having complementary sense and antisense regions.

Nucleic acid molecules that interact with target RNA molecules and down-regulate gene encoding target RNA molecules (e.g., target RNA molecules referred to by Genbank Accession numbers herein) may be expressed from transcription units inserted into DNA or RNA vectors. Recombinant vectors can be DNA plasmids or viral vectors. Nucleic acid molecule expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. The recombinant vectors capable of expressing the nucleic acid molecules can be delivered as described herein, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of nucleic acid molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the nucleic acid molecules bind and down-regulate gene function or expression via RNA interference (RNAi). Delivery of nucleic acid molecule expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from a subject followed by reintroduction into the subject, or by any other means that would allow for introduction into the desired target cell.

Expression vectors may include a nucleic acid sequence encoding at least one nucleic acid molecule disclosed herein, in a manner which allows expression of the nucleic acid molecule. For example, the vector may contain sequence(s) encoding both strands of a nucleic acid molecule that include a duplex. The vector can also contain sequence(s) encoding a single nucleic acid molecule that is self-complementary and thus forms a nucleic acid molecule. Non-limiting examples of such expression vectors are described in Paul et al., 2002, Nature Biotechnology, 19, 505; Miyagishi and Taira, 2002, Nature Biotechnology, 19, 497; Lee et al., 2002, Nature Biotechnology, 19, 500; and Novina et al., 2002, Nature Medicine, advance online publication doi:10.1038/nm725. Expression vectors may also be included in a mammalian (e.g., human) cell.

An expression vector may include a nucleic acid sequence encoding two or more nucleic acid molecules, which can be the same or different. Expression vectors may include a sequence for a nucleic acid molecule complementary to a nucleic acid molecule referred to by a Genbank Accession number NM_—003254 (TIMP1) or NM_—003255 (TIMP2).

An expression vector may encode one or both strands of a nucleic acid duplex, or a single self-complementary strand that self hybridizes into a nucleic acid duplex. The nucleic acid sequences encoding nucleic acid molecules can be operably linked in a manner that allows expression of the nucleic acid molecule (see for example Paul et al., 2002, Nature Biotechnology, 19, 505; Miyagishi and Taira, 2002, Nature Biotechnology, 19, 497; Lee et al., 2002, Nature Biotechnology, 19, 500; and Novina et al., 2002, Nature Medicine, advance online publication doi:10.1038/nm725).

An expression vector may include one or more of the following: a) a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g., eukaryotic pol I, II or III termination region); c) an intron and d) a nucleic acid sequence encoding at least one of the nucleic acid molecules, wherein said sequence is operably linked to the initiation region and the termination region in a manner that allows expression and/or delivery of the nucleic acid molecule. The vector can optionally include an open reading frame (ORF) for a protein operably linked on the 5′ side or the 3′-side of the sequence encoding the nucleic acid molecule; and/or an intron (intervening sequences).

Transcription of the nucleic acid molecule sequences can be driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters are expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl. Acad. Sci. USA, 87, 6743-7; Gao and Huang 1993, Nucleic Acids Res., 21, 2867-72; Lieber et al., 1993, Methods Enzymol., 217, 47-66; Zhou et al., 1990, Mol. Cell. Biol., 10, 4529-37). Several investigators have demonstrated that nucleic acid molecules expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992, Antisense Res. Dev., 2, 3-15; Ojwang et al., 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Yu et al., 1993, Proc. Natl. Acad. Sci. USA, 90, 6340-4; L'Huillier et al., 1992, EMBO J., 11, 4411-8; Lisziewicz et al., 1993, Proc. Natl. Acad. Sci. U.S.A, 90, 8000-4; Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Sullenger & Cech, 1993, Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as siNA in cells (Thompson et al., supra; Couture and Stinchcomb, 1996, supra; Noonberg et al., 1994, Nucleic Acid Res., 22, 2830; Noonberg et al., U.S. Pat. No. 5,624,803; Good et al., 1997, Gene Ther., 4, 45; Beigelman et al., International PCT Publication No. WO 96/18736. The above nucleic acid transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (see Couture and Stinchcomb, 1996 supra).

Nucleic acid molecule may be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc. Natl. Acad. Sci., USA 83, 399; Scanlon et al., 1991, Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al., 1992, Antisense Res. Dev., 2, 3-15; Dropulic et al., 1992, J. Virol., 66, 1432-41; Weerasinghe et al., 1991, J. Virol., 65, 5531-4; Ojwang et al., 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Sarver et al., 1990 Science, 247, 1222-1225; Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Good et al., 1997, Gene Therapy, 4, 45. Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a enzymatic nucleic acid (Draper et al., PCT WO 93/23569, and Sullivan et al., PCT WO 94/02595; Ohkawa et al., 1992, Nucleic Acids Symp. Ser., 27, 15-6; Taira et al., 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al., 1993, Nucleic Acids Res., 21, 3249-55; Chowrira et al., 1994, J. Biol. Chem., 269, 25856.

A viral construct packaged into a viral particle would accomplish both efficient introduction of an expression construct into the cell and transcription of dsRNA construct encoded by the expression construct.

Methods for oral introduction include direct mixing of RNA with food of the organism, as well as engineered approaches in which a species that is used as food is engineered to express an RNA, then fed to the organism to be affected. Physical methods may be employed to introduce a nucleic acid molecule solution into the cell. Physical methods of introducing nucleic acids include injection of a solution containing the nucleic acid molecule, bombardment by particles covered by the nucleic acid molecule, soaking the cell or organism in a solution of the RNA, or electroporation of cell membranes in the presence of the nucleic acid molecule.

Other methods known in the art for introducing nucleic acids to cells may be used, such as lipid-mediated carrier transport, chemical mediated transport, such as calcium phosphate, and the like. Thus the nucleic acid molecules may be introduced along with components that perform one or more of the following activities: enhance RNA uptake by the cell, promote annealing of the duplex strands, stabilize the annealed strands, or other-wise increase inhibition of the target gene.

The nucleic acid molecules or the vector construct can be introduced into the cell using suitable formulations. One formulation comprises a lipid formulation such as in Lipofectamine™ 2000 (Invitrogen, CA, USA. Lipid formulations can also be administered to animals such as by intravenous, intramuscular, or intraperitoneal injection, or orally or by inhalation or other methods as are known in the art. When the formulation is suitable for administration into animals such as mammals and more specifically humans, the formulation is also pharmaceutically acceptable. Pharmaceutically acceptable formulations for administering oligonucleotides are known and can be used. In some instances, it may be preferable to formulate dsRNA in a buffer or saline solution and directly inject the formulated dsRNA into cells, as in studies with oocytes. The direct injection of dsRNA duplexes may also be done. For suitable methods of introducing dsRNA see U.S. published patent application No. 2004/0203145, 20070265220 which are incorporated herein by reference.

Polymeric nanocapsules or microcapsules facilitate transport and release of the encapsulated or bound dsRNA into the cell. They include polymeric and monomeric materials, especially including polybutylcyanoacrylate. A summary of materials and fabrication methods has been published (see Kreuter, 1991). The polymeric materials which are formed from monomeric and/or oligomeric precursors in the polymerization/nanoparticle generation step, are per se known from the prior art, as are the molecular weights and molecular weight distribution of the polymeric material which a person skilled in the field of manufacturing nanoparticles may suitably select in accordance with the usual skill.

Nucleic acid moles may be formulated as a microemulsion. A microemulsion is a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution. Typically microemulsions are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a 4th component, generally an intermediate chain-length alcohol to form a transparent system.

Surfactants that may be used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non-ionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310), tetraglycerol monooleate (MO310), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleate (SO750), decaglycerol decaoleate (DA0750), alone or in combination with cosurfactants. The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and 1-butanol, serves to increase the interfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules.

Water Soluble Crosslinked Polymers

Delivery formulations can include water soluble degradable crosslinked polymers that include one or more degradable crosslinking lipid moiety, one or more PEI moiety, and/or one or more mPEG (methyl ether derivative of PEG (methoxypoly (ethylene glycol)).

Degradable lipid moieties preferably include compounds having the following structural motif:

In the above formula, ester linkages are biodegradable groups, R represents a relatively hydrophobic “lipo” group, and the structural motif shown occurs m times where m is in the range of about 1 to about 30. For example, in certain embodiments R is selected from the group consisting of C₂-C₅₀ alkyl, C₂-C₅₀ heteroalkyl, C₂-C₅₀ alkenyl, C₂-C₅₀ heteroalkenyl, C₅-C₅₀ aryl; C₂-C₅₀ heteroaryl; C₂-C₅₀ alkynyl, C₂-C₅₀ heteroalkynyl, C₂-C₅₀ carboxyalkenyl, and C₂-C₅₀ carboxyheteroalkenyl. In preferred embodiments, R is a saturated or unsaturated alkyl having 4 to 30 carbons, more preferably 8 to 24 carbons or a sterol, preferably a cholesteryl moiety. In preferred embodiments, R is oleic, lauric, myristic, palmitic margaric, stearic, arachidic, behenic, or lignoceric. In a most preferred embodiment, R is oleic.

The N in formula (B) may have an electron pair or a bond to a hydrogen atom. When N has an electron pair, the recurring unit may be cationic at low pH.

The degradable crosslinking lipid moiety may be reacted with a polyethyleneimine (PEI) as shown in Scheme A below:

In formula (A), R has the same meanings as described above. The PEI may contain recurring units of formula (B) in which x is an integer in the range of about 1 to about 100 and y is an integer in the range of about 1 to about 100.

The reaction illustrated in Scheme A may be carried out by intermixing the PEI and the diacrylate (I) in a mutual solvent such as ethanol, methanol or dichloromethane with stirring, preferably at room temperature for several hours, then evaporating the solvent to recover the resulting polymer. While not wishing to be bound to any particular theory, it is believed that the reaction between the PEI and diacrylate (I) involves a Michael reaction between one or more amines of the PEI with double bond(s) of the diacrylate (see J. March, Advanced Organic Chemistry 3rd Ed., pp. 711-712 (1985)). The diacrylate shown in Scheme A may be prepared in the manner as described in U.S. application Ser. No. 11/216,986 (US Publication No. 2006/0258751).

The molecular weight of the PEI is preferably in the range of about 200 to 25,000 Daltons more preferably 400 to 5,000 Daltons, yet more preferably 600 to 2000 Daltons. PEI may be either branched or linear.

The molar ratio of PEI to diacrylate is preferably in the range of about 1:2 to about 1:20. The weight average molecular weight of the cationic lipopolymer may be in the range of about 500 Daltons to about 1,000,000 Daltons preferably in the range of about 2,000 Daltons to about 200,000 Daltons. Molecular weights may be determined by size exclusion chromatography using PEG standards or by agarose gel electrophoresis.

The cationic lipopolymer is preferably degradable, more preferably biodegradable, e.g., degradable by a mechanism selected from the group consisting of hydrolysis, enzyme cleavage, reduction, photo-cleavage, and sonication. While not wishing to be bound to any particular theory, but it is believed that degradation of the cationic lipopolymer of formula (II) within the cell proceeds by enzymatic cleavage and/or hydrolysis of the ester linkages.

Synthesis may be carried out by reacting the degradable lipid moiety with the PEI moiety as described above. Then the mPEG (methyl ether derivative of PEG (methoxypoly (ethylene glycol)), is added to form the degradable crosslinked polymer. In preferred embodiments, the reaction is carried out at room temperature. The reaction products may be isolated by any means known in the art including chromatographic techniques. In a preferred embodiment, the reaction product may be removed by precipitation followed by centrifugation.

Dosages

The useful dosage to be administered and the particular mode of administration will vary depending upon such factors as the cell type, or for in vivo use, the age, weight and the particular animal and region thereof to be treated, the particular nucleic acid and delivery method used, the therapeutic or diagnostic use contemplated, and the form of the formulation, for example, suspension, emulsion, micelle or liposome, as will be readily apparent to those skilled in the art. Typically, dosage is administered at lower levels and increased until the desired effect is achieved.

When lipids are used to deliver the nucleic acid, the amount of lipid compound that is administered can vary and generally depends upon the amount of nucleic acid being administered. For example, the weight ratio of lipid compound to nucleic acid is preferably from about 1:1 to about 30:1, with a weight ratio of about 5:1 to about 10:1 being more preferred.

A suitable dosage unit of nucleic acid molecules may be in the range of 0.001 to 0.25 milligrams per kilogram body weight of the recipient per day, or in the range of 0.01 to 20 micrograms per kilogram body weight per day, or in the range of 0.01 to 10 micrograms per kilogram body weight per day, or in the range of 0.10 to 5 micrograms per kilogram body weight per day, or in the range of 0.1 to 2.5 micrograms per kilogram body weight per day.

Suitable amounts of nucleic acid molecules may be introduced and these amounts can be empirically determined using standard methods. Effective concentrations of individual nucleic acid molecule species in the environment of a cell may be about 1 femtomolar, about 50 femtomolar, 100 femtomolar, 1 picomolar, 1.5 picomolar, 2.5 picomolar, 5 picomolar, 10 picomolar, 25 picomolar, 50 picomolar, 100 picomolar, 500 picomolar, 1 nanomolar, 2.5 nanomolar, 5 nanomolar, 10 nanomolar, 25 nanomolar, 50 nanomolar, 100 nanomolar, 500 nanomolar, 1 micromolar, 2.5 micromolar, 5 micromolar, 10 micromolar, 100 micromolar or more.

Dosage may be from 0.01 μg to 1 g per kg of body weight (e.g., 0.1 μg, 0.25 μg, 0.5 μg, 0.75 μg, 1 μg, 2.5 μg, 5 μg, 10 μg, 25 μg, 50 μg, 100 μg, 250 μg, 500 μg, 1 mg, 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg per kg).

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per subject per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient.

It is understood that the specific dose level for any particular subject depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

Pharmaceutical compositions that include the nucleic acid molecule disclosed herein may be administered once daily, qid, tid, bid, QD, or at any interval and for any duration that is medically appropriate. However, the therapeutic agent may also be dosed in dosage units containing two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In that case, the nucleic acid molecules contained in each sub-dose may be correspondingly smaller in order to achieve the total daily dosage unit. The dosage unit can also be compounded for a single dose over several days, e.g., using a conventional sustained release formulation which provides sustained and consistent release of the dsRNA over a several day period. Sustained release formulations are well known in the art. The dosage unit may contain a corresponding multiple of the daily dose. The composition can be compounded in such a way that the sum of the multiple units of a nucleic acid together contain a sufficient dose.

Pharmaceutical Compositions, Kits, and Containers

Also provided are compositions, kits, containers and formulations that include a nucleic acid molecule (e.g., an siNA molecule) as provided herein for reducing expression of TIMP1 and TIMP2 for administering or distributing the nucleic acid molecule to a patient. A kit may include at least one container and at least one label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass, metal or plastic. The container can hold amino acid sequence(s), small molecule(s), nucleic acid sequence(s), cell population(s) and/or antibody(s). In one embodiment, the container holds a polynucleotide for use in examining the mRNA expression profile of a cell, together with reagents used for this purpose. In another embodiment a container includes an antibody, binding fragment thereof or specific binding protein for use in evaluating TIMP1 and TIMP2 protein expression cells and tissues, or for relevant laboratory, prognostic, diagnostic, prophylactic and therapeutic purposes; indications and/or directions for such uses can be included on or with such container, as can reagents and other compositions or tools used for these purposes. Kits may further include associated indications and/or directions; reagents and other compositions or tools used for such purpose can also be included.

The container can alternatively hold a composition that is effective for treating, diagnosis, prognosing or prophylaxing a condition and can have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The active agents in the composition can be a nucleic acid molecule capable of specifically binding TIMP1 and TIMP2 and/or modulating the function of TIMP1 and TIMP2.

A kit may further include a second container that includes a pharmaceutically-acceptable buffer, such as phosphate-buffered saline, Ringer's solution and/or dextrose solution. It can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, stirrers, needles, syringes, and/or package inserts with indications and/or instructions for use.

The units dosage ampoules or multidose containers, in which the nucleic acid molecules are packaged prior to use, may include an hermetically sealed container enclosing an amount of polynucleotide or solution containing a polynucleotide suitable for a pharmaceutically effective dose thereof, or multiples of an effective dose. The polynucleotide is packaged as a sterile formulation, and the hermetically sealed container is designed to preserve sterility of the formulation until use.

The container in which the polynucleotide including a sequence encoding a cellular immune response element or fragment thereof may include a package that is labeled, and the label may bear a notice in the form prescribed by a governmental agency, for example the Food and Drug Administration, which notice is reflective of approval by the agency under Federal law, of the manufacture, use, or sale of the polynucleotide material therein for human administration.

Federal law requires that the use of pharmaceutical compositions in the therapy of humans be approved by an agency of the Federal government. In the United States, enforcement is the responsibility of the Food and Drug Administration, which issues appropriate regulations for securing such approval, detailed in 21 U.S.C. §301-392. Regulation for biologic material, including products made from the tissues of animals is provided under 42 U.S.C. §262. Similar approval is required by most foreign countries. Regulations vary from country to country, but individual procedures are well known to those in the art and the compositions and methods provided herein preferably comply accordingly.

The dosage to be administered depends to a large extent on the condition and size of the subject being treated as well as the frequency of treatment and the route of administration. Regimens for continuing therapy, including dose and frequency may be guided by the initial response and clinical judgment. The parenteral route of injection into the interstitial space of tissues is preferred, although other parenteral routes, such as inhalation of an aerosol formulation, may be required in specific administration, as for example to the mucous membranes of the nose, throat, bronchial tissues or lungs.

As such, provided herein is a pharmaceutical product which may include a polynucleotide including a sequence encoding a cellular immune response element or fragment thereof in solution in a pharmaceutically acceptable injectable carrier and suitable for introduction interstitially into a tissue to cause cells of the tissue to express a cellular immune response element or fragment thereof, a container enclosing the solution, and a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of manufacture, use, or sale of the solution of polynucleotide for human administration.

Indications

The nucleic acid molecules disclosed herein can be used to treat diseases, conditions or disorders associated with TIMP1 and TIMP2, such as liver fibrosis, cirrhosis, pulmonary fibrosis, kidney fibrosis, peritoneal fibrosis, chronic hepatic damage, and fibrillogenesis and any other disease or conditions that are related to or will respond to the levels of TIMP1 and TIMP2 in a cell or tissue. As such, compositions, kits and methods disclosed herein may include packaging a nucleic acid molecule disclosed herein that includes a label or package insert. The label may include indications for use of the nucleic acid molecules such as use for treatment or prevention of liver fibrosis, peritoneal fibrosis, kidney fibrosis and pulmonary fibrosis, and any other disease or conditions that are related to or will respond to the levels of TIMP1 and TIMP2 in a cell or tissue. A label may include an indication for use in reducing expression of TIMP1 and TIMP2. A “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications, other therapeutic products to be combined with the packaged product, and/or warnings concerning the use of such therapeutic products, etc.

Those skilled in the art will recognize that two or more siTIMP1 and or siTIMP2 may be combined or that other anti-fibrosis treatments, drugs and therapies known in the art can be readily combined with the nucleic acid molecules herein (e.g. siNA molecules) and are hence contemplated herein.

The methods and compositions provided herein will now be described in greater detail by reference to the following non-limiting examples.

EXAMPLES

Example 1

siRNA Sequences

siRNA sequences for TIMP-1, TIMP-2, positive control and negative control are listed in Tabls C and D. 100 μM siRNA stock solution was prepared by dissolving in nucrease free water (Ambion). In the “Sequence” columns in Tables C and D, lower case letters represent unmodified ribonucleotides, “T” represents deoxyribothymidine.

TABLE C
				SEQ ID
Target	Name	Orientation	Sequence	NO:	Species	nucleotides
TIMP1	TIMP1-A	S (5′->3′)	ccaccuuauaccagcguuaTT	5	Human,	[355-373]
		AS (3′->5′)	TTgguggaauauggucgcaau	6	mouse, rat,	ORF
					rhesus
TIMP1	TIMP1-B	S (5′->3′)	cacuguuggcugugaggaaTT	7	Human	[620-638]
		AS (3′->5)	TTgugacaaccgacacuccuu	8	rhesus	ORF
TIMP1	TIMP1-C	S (5′->3′)	gcacaguguuucccuguuuTT	9	Human mouse	[640-658]
		AS (3′->5′)	TTcgugucacaaagggacaaa	10	rat rhesus	ORF

TABLE D
				SEQ ID
Target	Name	Orientation	Sequence	NO	Species	nucleotides
TIMP2	TIMP2-A	S (5′->3′)	ugcagauguagugaucaggTT	11	human	[421-439]
		AS (3′->5′)	TTacgucuacaucacuagucc	12		ORF
TIMP2	TIMP2-B	S (5′->3′)	gaggauccaguaugagaucTT	13	human	[502-520]
		AS (3′->5′)	TTcuccuaggucauacucuag	14	rhesus	ORF
					rabbit
TIMP2	TIMP2-C	S (5′->3′)	gcagauaaagauguucaaaTT	15	human	[523-541]
		AS (3′->5′)	TTcgucuauuucuacaaguuu	16	mouse rat	ORF
					cow dog
					pig
TIMP2	TIMP2-D	S (5′->3′)	ggaauaucucauugcaggaTT	17	human	[625-643]
		AS (3′->5′)	TTccuuauagaguaacguccu	18		ORF
TIMP2	TIMP2-E	S (5′->3′)	uaucucauugcaggaaaggTT	19	human	[629-647]
		AS (3′->5′)	TTauagaguaacguccuuucc	20		ORF

Example 2

siRNA Delivery

HT-1080 cell (Japanese Collection of Research Bioresources) was maintained incubated in DMEM (Sigma, Cat#D6546) with 10% fetal bovine serum (FBS; Hyclone, Cat.#SH30070.03) and 1% volume/volume L-Glutamine-penicillin-streptomycin solution (Sigma, Cat.#G1146) and 1% volume/volume L-Glutamine solution (Sigma, Cat.#G7513). Before delivering siRNA, cells were seeded in 6-well plate (Nunc. #140675) at the density of 5×10³ cells per well and incubated at 37° C. with 7.5% CO₂ for 2 days. siRNAs for TIMP1 were transfected to the cells with VA-coupled liposome (VA-liposome) as described by Sato et al. (Sato Y. et al. Nature Biotechnology 2008. Vol. 26, p431) and siRNAs for TIMP2 were delivered with VA-conjugated cationic polymer (VA-polymer), synthesized in-house at the ratio of 5:1 (VA-polymer:siRNA, weight per weight). The final concentration of siRNA was 50 nM. 2-hours after siRNA delivery, cell culture medium was replaced to fresh DMEM with 10% FBS and incubated for 2 overnight at 37° C. with 7.5% CO₂.

Example 3

Gene Knocking Down Assessment of siRNA by RT-PCR

After transfection as described in Example 2, total RNA was isolated with QIAshreader QIAGEN, 79654) and RNeasy Mini Kit (QIAGEN, 74104) by following manufacturer's protocol. 1 μg of the isolated total RNA was used for cDNA preparation with Hicapacity RNA-to-cDNA Master Mix (Applied Biosystems, 4390779) as indicated by manufacturer's protocol. Then, 0.05 μg of cDNA was employed for polymerase chain reaction (PCR) with ExTaq (TaKaRa, RR001B) polymerase by following supplied manual. PCR primers for detection of each gene are listed in excel file. PCR condition was as follows: 94° C. 4 min, then 4° C. 30 sec, 63° C. 30 sec, 72° C. 1 min for 23 cycles, 72° C. 5 min before termination. 15 μl of PCR products for TIMP-1 or TIMP-2 gene and 5 μl for GAPDH gene were identified by agarose gel electrophoresis.

FIG. 2 indicates knock down efficacy of siRNAs for TIMP1 as measured by qPCR. The amount of PCR product from cells transfected with TIMP-1 siRNA, e.g. TIMP1-A (SEQ ID NOS:5 and 6), TIMP1-B (SEQ ID NOS:7 and 8) or TIMP1-C (SEQ ID NOS:9 and 10), was less than that from untreated cells, therefore, those siRNA for TIMP1 gene are capable to knock down the target gene.

FIG. 3 represents knock down efficacy of siRNAs for TIMP2 as measured by qPCR: TIMP2-A (SEQ ID NOS:11 and 12), TIMP2-B (SEQ ID NOS:13 and 14), TIMP2-C (SEQ ID NOS:15 and 16), TIMP2-D (SEQ ID NOS:17 and 18) and TIMP2-E (SEQ ID NOS:19 and 20). TIMP2 siRNA showed target gene knock down and level of gene silencing was dependent on the sequence.

Example 4

Treatment of Liver Cirrhosis in Rats with siTIMP1 and siTIMP2

Liver cirrhosis animal model: Liver cirrhosis was induced in rats using the method described by Sato et al., (Sato Y. et al. Nat Biotech 2008. 26:431). Briefly, liver cirrhosis was induced in 4 week-old male SD rats by injecting them dimethylnitrosoamine (DMN) (Wako Chemicals, Japan) as follows: 0.5% DMN in phosphate-buffered saline (PBS) was administered to rats intraperitoneally at a dose of 2 ml/kg per body weight for 3 consecutive days per week. Specifically, DMN solution was injected on days 0 (start of the experiment), 2, 4, 7, 9, 11, 14, 16, 18, 21, 23, 25, 28, 30, 32, 34 and 36.

siRNA Sequence for TIMP1 (“siTIMP1-A”)

S (5′->3′)	ccaccuuauaccagcguuaTT	(SEQ ID NO: 5)
AS (3′->5′)	TTgguggaauauggucgcaau	(SEQ ID NO: 6)

siRNA Sequence for TIMP2 (“siTIMP2-C”)

S (5′->3′)	gcagauaaagauguucaaaTT	(SEQ ID NO: 15)
AS (3′->5′)	TTcgucuauuucuacaaguuu	(SEQ ID NO: 16)

A 10 μg/μl siRNA stock solution was prepared by dissolving siRNA duplexes (siTIMP1 or siTIMP2) in nuclease free water (Ambion). For treatment of rats, siRNA was formulated with vitamin A-coupled liposome as described by Sato et al (Sato Y. et al. Nature Biotech 2008. Vol. 26, p431). The vitamin A (VA)-liposome-siRNA formulation consisted of 0.33 μmol/ml of VA, 0.33 μmol/ml of liposome (Coatsome EL-01-D, NOF Corporation) and 0.5 μg/μl of siRNA in 5% glucose solution.

Injection Solution for siRNA Delivered at a Concentration of 0.75 mg/Kg

The liposomes were prepared at a concentration of 1 mM by addition of nuclease-free water, and left for 15 min at room temperature before use. To prepare VA-coupled liposomes, 100 nmol of vitamin A (dissolved in DMSO) was mixed with the liposomes (100 nmol) by vortex for 15 seconds at R.T.

The siRNA duplexes (150 μg) were prepared at a concentration of 10 μg/μl by addition of nuclease-free water. A 5% glucose (175 μl) solution was added to the liposomal suspension. (Total volume of 300 μl). The VA-liposome-siRNA solutions were injected to each rat to a final concentration of 0.75 ml/Kg body weight.

Injection solution for siRNA delivered at a concentration of 1.5 mg/Kg

The liposomes were prepared at a concentration of 1 mM by addition of nuclease-free water, and left to stand for 15 min before use. To prepare VA-coupled liposome, 200 nmol of vitamin A (dissolved in DMSO) was mixed with the liposome (200 nmol) by vortex for 15 seconds at R.T.

The siRNA duplexes (300 μg) were prepared at a concentration of 10 μg/μl by addition of nuclease-free water. A 5% glucose (50 μl) solution was added to the liposomal suspension. (Total volume 300 μl). The VA-liposome-siRNA solutions were injected to each rat to a final concentration of 1.5 ml/Kg body weight.

siRNA Treatment

The siRNA treatment was carried out from day 28 for 5 times by intravenous injection. In detail, rats were treated with siRNA on days 28, 30, 32, 34 and 36 post DMN treatment. Rats were sacrificed on day 38 or 39. Two different siRNA species (siTIMP1-A and siTIMP2-C) and 2 different doses (0.75 mg siRNA per kg body weight, 1.5 mg siRNA per kg body weight) were tested. Details of tested groups and number of animals in each group are as follows:

• • 1) Control animals: Liver cirrhosis was induced by DMN injection, and a 5% glucose was administered (n=9)
  • 2) VA-Lip-siTIMP1-A 0.75 mg/Kg (n=9)
  • 3) VA-Lip-siTIMP1-A 1.5 mg/Kg (n=9)
  • 4) VA-Lip-siTIMP2-C 0.75 mg/Kg (n=9)
  • 5) VA-Lip-siTIMP2-C1.5 mg/Kg (n=9)
  • 6) Sham (PBS was injected instead of DMN. 5% Glucose was administered instead of siRNA) (n=5)
  • 7) Untreated control animals (Intact) (n=5)

Evaluation of Therapeutic Efficacy

On day 38, 2 out of 10 animals in “siTIMP2-C” group died and were not analyzed further. However, other animals were survived before the sacrifice. After rats were sacrificed, liver tissues were fixed in 10% formalin. The left lobe of the liver was embedded in paraffin for tissue slide preparation. Tissue slides were stained with Sirius red as well as hematoxylin and eosin (HE). Sirius red staining was employed to visualize collagen-deposited area and determine the level of cirrhosis. HE staining was used for nuclei and cytoplasm as counter-staining Each slide was observed under microscope (BZ-9000, Keyence Corp. Japan) and the percentage of Sirius red-stained area per slide was determined by image analysis software attached to the microscope. At least 4 slides per each liver were prepared for image analysis, and whole area of each slide (slice of liver) was captured by camera and analyzed. Statistic analysis was carried out by t-test analysis. Results are shown in FIG. 4. Liver sections were photographed at ×32 magnification. The fibrotic areas were calculated as the mean of 4 liver sections. The bar graph summarizes the digital quantification of staining for each group. Statistical values are as follows: *=P<0.05, **=P<0.01, ***=P<0.001

FIG. 4 represents the fibrotic area in liver sections. The area of fibrosis in the “diseased rat” (group 1) was higher than “sham” (group 6) or “untreated” (group 7) groups. Therefore, DMN treatment induced collagen deposition in liver, typical of liver fibrosis. The area of fibrosis was significantly reduced by the treatment of siRNA targeting TIMP1 gene (groups 2 and 3), compared with “diseased rat” group, indicating that siRNA to TIMP1 has therapeutic efficacy in treating fibrotic diseases and disorders.

Example 5

Selecting TIMP1 and TIMP2 Nucleic Acid Molecule Sequences

Nucleic acid molecules (e.g., siNA≦25 nucleotides) against TIMP1 and TIMP2 were designed using a proprietary database. Candidate sequences are validated by in vitro knock down assays. Details of the nucleic acids set forth in the Tables are

The Tables (A1, A2, A5, A6, B1, B2, B5, B6) include

• • a. 19-mer and 18-mer siRNAs (sense and corresponding antisense sequences to form duplex siRNA) predicted to be active by a proprietary database and excludes known 19-mer siRNAs;
  • b. siRNAs which target human and at least two additional species (cross species) selected from dog, rat, mouse and rabbit and are predicted to be active;
    • i. inclusion of cross-species siRNA compounds are siRNA with full match to the indicated target (“Sense”) and
    • ii. inclusion of siRNAs with mismatches relative to the target, at positions 1, 19 (5′>3′) or both.

The Tables of “preferred” siRNA (A3, A7, B3, B7) include sense and corresponding antisense sequences that were selected as follows:

• • i. Selection for cross species to human (H) and rat (Rt) and inclusion of sequences with 1 MM (single mismatch (MM)) to rat target in positions other than 1/19 (5′>3′)
  • ii. Addition of predicted active siRNA compounds that don't target rat but target at least two other species selected from dog, mouse and rabbit.
  • iii. Addition of best siRNA targeting human or human+rhesus
  • iv. Exclusion of siRNAs that target miRNA seed sequence
  • v. Exclusion of siRNAs with high G/C content
  • vi. Exclusion of siRNAs targeting multiple SNPs

The Tables labeled as “lowest predicted OT effect” (Tables A4, A8, B4 and B8) relate to siRNA from the “preferred” Tables having best off-target (OT) features including

• • c. Column labeled “Crosses”—Indicates species specificity as follows:
    • i. H/Rt=siRNA targeting at least human and rat
    • ii. H/Rt (Rt cross—with 1MM)=siRNA targeting at least human and rat. Target match to rat is partial and there is one mismatch at a position other than 1 or 19
    • iii. Other (w/o Rt)—siRNA targets human and other species but not rat
    • iv. H+/−Rh=siRNA targeting only human or human and Rhesus but no other species

Column labeled “# in HTS list”—Indicates the siRNA number in the preceding “Preferred” Table (A3, A7, B3, B7).

• • 2. Selection is done in the following manner:
    • i. Mismatches (MM) are identified in positions 2-18 of the guide strand. MM in positions 1 and 19 are NOT considered as mismatches.
    • ii. Exclusion of siRNAs having complete match (0 MM) to other genes
    • iii. Exclusion of siRNAs having 1 MM in position 17 or 18 (of AS strand) to other genes
    • iv. Preference (ranking of predicted OT activity):
      • 1—has 3MM within positions 2-16 of AS (5′>3′).
      • 2—has 2MM to 1-4 gene targets within positions 2-16
      • 3—has 2MM to 5-9 gene targets within (positions 2-16)
      • 4—targets 10-20 genes with 2MM (positions 2-16)

Sequences of sense and antisense oligonucleotides useful in the preparation of siRNA molecules are disclosed in Tables A1, A2, A3, A4, A5, A6, A7, A8, B1, B2, B3, B4, B5, B6, B7, B8 (Tables A1-B8) infra. Best OT refers to least number of matches to off-target genes.

The following abbreviations are used in the Tables A1-B8 (Tables A1, A2, A3, A4, A5, A6, A7 A8, B1, B2, B3, B4, B5, B6, B7 and B8) herein: “other spec or Sp.” refers to cross species identity with other animals: D or Dg-dog, Rt-rat, Rb-rabbit, Rh-rhesus monkey, Pg-Pig, M or Ms-Mouse, Ck-Chicken, Cw-Cow; ORF: open reading frame. 19-mers, and 18+1-mers refer to oligomers of 19 and 18+1 (U at position 1 of Antisense, A at position 19 of sense strand or A at position 1 of Antisense, U at position 19 of sense strand) ribonucleic acids in length, respectively.

TABLE A1
19-mer siTIMP1
		SEQ		SEQ
		ID		ID		human-73858576
No.	Sense (5′>3′)	NO.	Antisense (5′>3′)	NO.	Other Sp	ORF: 193-816
1	GUUUCUCAUUGCUGGAAAA	21	UUUUCCAGCAAUGAGAAAC	129	Rh	[506-524] ORF
2	CACAGUGUUUCCCUGUUUA	22	UAAACAGGGAAACACUGUG	130	Rh, M	[641-659] ORF
3	CUUUCUUCCGGACAAUGAA	23	UUCAUUGUCCGGAAGAAAG	131		[874-892] 3′UTR
4	GCUGAAGCCUGCACAGUGU	24	ACACUGUGCAGGCUUCAGC	132		[834-852] 3′UTR
5	GGAGUUUCUCAUUGCUGGA	25	UCCAGCAAUGAGAAACUCC	133	Rh	[503-521] ORF
6	GCACAGUGUUUCCCUGUUU	26	AAACAGGGAAACACUGUGC	134	Rh, Rt, M	[640-658] ORF
7	CAUCUUUCUUCCGGACAAU	27	AUUGUCCGGAAGAAAGAUG	135		[871-889] 3′UTR
8	GGCUUCACCAAGACCUACA	28	UGUAGGUCUUGGUGAAGCC	136	Rh, Rb	[603-621] ORF
9	GGCACUCAUUGCUUGUGGA	29	UCCACAAGCAAUGAGUGCC	137	Rh	[684-702] ORF
10	CUCCCAUCUUUCUUCCGGA	30	UCCGGAAGAAAGAUGGGAG	138		[867-885] 3′UTR
11	GUGUUUCCCUGUUUAUCCA	31	UGGAUAAACAGGGAAACAC	139	Rh	[645-663] ORF
12	AGUCAACCAGACCACCUUA	32	UAAGGUGGUCUGGUUGACU	140	Rh	[344-362] ORF
13	GCCCGGAGUGGAAGCUGAA	33	UUCAGCUUCCACUCCGGGC	141		[821-839] 3′UTR
14	CCACCUUAUACCAGCGUUA	34	UAACGCUGGUAUAAGGUGG	142	Rh, Rt, M	[355-373] ORF
15	CAUGGAGAGUGUCUGCGGA	35	UCCGCAGACACUCUCCAUG	143	Rh	[455-473] ORF
16	CCAAGAUGUAUAAAGGGUU	36	AACCCUUUAUACAUCUUGG	144	Rh	[388-406] ORF
17	GAGAGUGUCUGCGGAUACU	37	AGUAUCCGCAGACACUCUC	145	Rh	[459-477] ORF
18	AGAUCAAGAUGACCAAGAU	38	AUCUUGGUCAUCUUGAUCU	146	Rh, Dg	[376-394] ORF
19	CUGCAGAGUGGCACUCAUU	39	AAUGAGUGCCACUCUGCAG	147	Rh	[675-693] ORF
20	CCUGGAACAGCCUGAGCUU	40	AAGCUCAGGCUGUUCCAGG	148		[571-589] ORF
21	CACUGUUGGCUGUGAGGAA	41	UUCCUCACAGCCAACAGUG	149	Rh	[620-638] ORF
22	CCAGAAGUCAACCAGACCA	42	UGGUCUGGUUGACUUCUGG	150	Rh, Dg	[339-357] ORF
23	GAUGGACUCUUGCACAUCA	43	UGAUGUGCAAGAGUCCAUC	151		[531-549] ORF
24	AGUUUCUCAUUGCUGGAAA	44	UUUCCAGCAAUGAGAAACU	152	Rh	[505-523] ORF
25	GCUCCUCCAAGGCUCUGAA	45	UUCAGAGCCUUGGAGGAGC	153	Rh	[710-728] ORF
26	ACAGUGUUUCCCUGUUUAU	46	AUAAACAGGGAAACACUGU	154	Rh, M	[642-660] ORF
27	GUCUGCGGAUACUUCCACA	47	UGUGGAAGUAUCCGCAGAC	155	Rh	[465-483] ORF
28	CUGGAACAGCCUGAGCUUA	48	UAAGCUCAGGCUGUUCCAG	156		[572-590] ORF
29	GGGCUGUGCACCUGGCAGU	49	ACUGCCAGGUGCACAGCCC	157	Rh	[774-792] ORF
30	GUGUCUGCGGAUACUUCCA	50	UGGAAGUAUCCGCAGACAC	158	Rh	[463-481] ORF
31	AUGAGAUCAAGAUGACCAA	51	UUGGUCAUCUUGAUCUCAU	159	Rh, Dg	[373-391] ORF
32	GGAAGCUGAAGCCUGCACA	52	UGUGCAGGCUUCAGCUUCC	160		[830-848] 3′UTR
33	GAGUUUCUCAUUGCUGGAA	53	UUCCAGCAAUGAGAAACUC	161	Rh	[504-522] ORF
34	CAGACGGCCUUCUGCAAUU	54	AAUUGCAGAAGGCCGUCUG	162	Rh	[285-303] ORF
35	GCACAUCACUACCUGCAGU	55	ACUGCAGGUAGUGAUGUGC	163		[542-560] ORF
36	GGCAGUCCCUGCGGUCCCA	56	UGGGACCGCAGGGACUGCC	164		[787-805] ORF
37	GAUGUAUAAAGGGUUCCAA	57	UUGGAACCCUUUAUACAUC	165	Rh	[392-410] ORF
38	CUGGCAUCCUGUUGUUGCU	58	AGCAACAACAGGAUGCCAG	166		[217-235] ORF
39	GGACGGACCAGCUCCUCCA	59	UGGAGGAGCUGGUCCGUCC	167	Rh	[700-718] ORF
40	GAGUGGCACUCAUUGCUUG	60	CAAGCAAUGAGUGCCACUC	168	Rh	[680-698] ORF
41	AGAGUGUCUGCGGAUACUU	61	AAGUAUCCGCAGACACUCU	169	Rh	[460-478] ORF
42	ACCAGACCACCUUAUACCA	62	UGGUAUAAGGUGGUCUGGU	170	Rh	[349-367] ORF
43	CACCAAGACCUACACUGUU	63	AACAGUGUAGGUCUUGGUG	171	Rh	[608-626] ORF
44	GGCAUCCUGUUGUUGCUGU	64	ACAGCAACAACAGGAUGCC	172	Rh	[219-237] ORF
45	CCUGAAUCCUGCCCGGAGU	65	ACUCCGGGCAGGAUUCAGG	173		[811-829] ORF + 3′UTR
46	GUCAACCAGACCACCUUAU	66	AUAAGGUGGUCUGGUUGAC	174	Rh	[345-363] ORF
47	GGACACCAGAAGUCAACCA	67	UGGUUGACUUCUGGUGUCC	175	Rh	[334-352] ORF
48	AGCGUUAUGAGAUCAAGAU	68	AUCUUGAUCUCAUAACGCU	176	Rh, Dg, Rt	[367-385] ORF
49	UGCACAGUGUUUCCCUGUU	69	AACAGGGAAACACUGUGCA	177	Rh, Rt, M	[639-657] ORF
50	ACUGCAGAGUGGCACUCAU	70	AUGAGUGCCACUCUGCAGU	178	Rh	[674-692] ORF
51	CCCAUCUUUCUUCCGGACA	71	UGUCCGGAAGAAAGAUGGG	179		[869-887] 3′UTR
52	GUGAGGAAUGCACAGUGUU	72	AACACUGUGCAUUCCUCAC	180	Rh	[631-649] ORF
53	CCUCCAAGGCUCUGAAAAG	73	CUUUUCAGAGCCUUGGAGG	181	Rh	[713-731] ORF
54	CAUCACUACCUGCAGUUUU	74	AAAACUGCAGGUAGUGAUG	182		[545-563] ORF
55	AGCUGAAGCCUGCACAGUG	75	CACUGUGCAGGCUUCAGCU	183		[833-851] 3′UTR
56	GCACAGUGUCCACCCUGUU	76	AACAGGGUGGACACUGUGC	184		[844-862] 3′UTR
57	CCAGCUCCUCCAAGGCUCU	77	AGAGCCUUGGAGGAGCUGG	185	Rh	[707-725] ORF
58	CUGUUGUUGCUGUGGCUGA	78	UCAGCCACAGCAACAACAG	186	Rh	[225-243] ORF
59	UCUUCCGGACAAUGAAAUA	79	UAUUUCAUUGUCCGGAAGA	187		[877-895] 3′UTR
60	GCUCCCUGGAACAGCCUGA	80	UCAGGCUGUUCCAGGGAGC	188		[567-585] ORF
61	AUAAAGGGUUCCAAGCCUU	81	AAGGCUUGGAACCCUUUAU	189		[397-415] ORF
62	GAGUGGAAGCUGAAGCCUG	82	CAGGCUUCAGCUUCCACUC	190	Rh	[826-844] 3′UTR
63	CAAACUGCAGAGUGGCACU	83	AGUGCCACUCUGCAGUUUG	191	Rh	[671-689] ORF
64	CGGCCUUCUGCAAUUCCGA	84	UCGGAAUUGCAGAAGGCCG	192	Rh	[289-307] ORF
65	CUCCUCCAAGGCUCUGAAA	85	UUUCAGAGCCUUGGAGGAG	193	Rh	[711-729] ORF
66	CCUGCAAACUGCAGAGUGG	86	CCACUCUGCAGUUUGCAGG	194	Rh, Dg	[667-685] ORF
67	CACAUCACUACCUGCAGUU	87	AACUGCAGGUAGUGAUGUG	195		[543-561] ORF
68	UGCCCGGAGUGGAAGCUGA	88	UCAGCUUCCACUCCGGGCA	196		[820-838] 3′UTR
69	GCUUCUGGCAUCCUGUUGU	89	ACAACAGGAUGCCAGAAGC	197		[213-231] ORF
70	UUUCUUCCGGACAAUGAAA	90	UUUCAUUGUCCGGAAGAAA	198		[875-893] 3′UTR
71	UGCACAGUGUCCACCCUGU	91	ACAGGGUGGACACUGUGCA	199		[843-861] 3′UTR
72	GACCUACACUGUUGGCUGU	92	ACAGCCAACAGUGUAGGUC	200	Rh	[614-632] ORF
73	CACAGACGGCCUUCUGCAA	93	UUGCAGAAGGCCGUCUGUG	201	Rh	[283-301] ORF
74	AGGGCUUCCAGUCCCGUCA	94	UGACGGGACUGGAAGCCCU	202	Rh	[730-748] ORF
75	CCCAGAUAGCCUGAAUCCU	95	AGGAUUCAGGCUAUCUGGG	203		[802-820] ORF + 3′UTR
76	GUUGUUGCUGUGGCUGAUA	96	UAUCAGCCACAGCAACAAC	204	Rh	[227-245] ORF
77	GUCCCUGCGGUCCCAGAUA	97	UAUCUGGGACCGCAGGGAC	205		[791-809] ORF
78	CUUCCAGUCCCGUCACCUU	98	AAGGUGACGGGACUGGAAG	206	Rh	[734-752] ORF
79	CCUACACUGUUGGCUGUGA	99	UCACAGCCAACAGUGUAGG	207	Rh	[616-634] ORF
80	ACAUCACUACCUGCAGUUU	100	AAACUGCAGGUAGUGAUGU	208		[544-562] ORF
81	UCUUUCUUCCGGACAAUGA	101	UCAUUGUCCGGAAGAAAGA	209		[873-891] 3′UTR
82	CCAGAUAGCCUGAAUCCUG	102	CAGGAUUCAGGCUAUCUGG	210		[803-821] ORF + 3′UTR
83	CAGUGUUUCCCUGUUUAUC	103	GAUAAACAGGGAAACACUG	211	Rh, M	[643-661] ORF
84	CUGGCUUCUGGCAUCCUGU	104	ACAGGAUGCCAGAAGCCAG	212		[210-228] ORF
85	GACGGACCAGCUCCUCCAA	105	UUGGAGGAGCUGGUCCGUC	213	Rh	[701-719] ORF
86	UGUUGUUGCUGUGGCUGAU	106	AUCAGCCACAGCAACAACA	214	Rh	[226-244] ORF
87	GACUCUUGCACAUCACUAC	107	GUAGUGAUGUGCAAGAGUC	215		[535-553] ORF
88	CCCGCCAUGGAGAGUGUCU	108	AGACACUCUCCAUGGCGGG	216	Rh	[450-468] ORF
89	CGAGGAGUUUCUCAUUGCU	109	AGCAAUGAGAAACUCCUCG	217	Rh	[500-518] ORF
90	CACAGGUCCCACAACCGCA	110	UGCGGUUGUGGGACCUGUG	218	Rh	[480-498] ORF
91	ACACCAGAAGUCAACCAGA	111	UCUGGUUGACUUCUGGUGU	219	Rh	[336-354] ORF
92	UGUUCCCACUCCCAUCUUU	112	AAAGAUGGGAGUGGGAACA	220	Rh	[859-877] 3′UTR
93	CCCUGUUCCCACUCCCAUC	113	GAUGGGAGUGGGAACAGGG	221	Rh	[856-874] 3′UTR
94	CACCUUAUACCAGCGUUAU	114	AUAACGCUGGUAUAAGGUG	222	Rh, Rt, M	[356-374] ORF
95	CACCAGAAGUCAACCAGAC	115	GUCUGGUUGACUUCUGGUG	223	Rh	[337-355] ORF
96	UCCUCCAAGGCUCUGAAAA	116	UUUUCAGAGCCUUGGAGGA	224	Rh	[712-730] ORF
97	GAAGCCUGCACAGUGUCCA	117	UGGACACUGUGCAGGCUUC	225		[837-855] 3′UTR
98	CCUGCACAGUGUCCACCCU	118	AGGGUGGACACUGUGCAGG	226		[841-859] 3′UTR
99	CCGCCAUGGAGAGUGUCUG	119	CAGACACUCUCCAUGGCGG	227	Rh	[451-469] ORF
100	UAAAGGGUUCCAAGCCUUA	120	UAAGGCUUGGAACCCUUUA	228		[398-416] ORF
101	CAAGAUGACCAAGAUGUAU	121	AUACAUCUUGGUCAUCUUG	229	Rh	[380-398] ORF
102	GUUUUGUGGCUCCCUGGAA	122	UUCCAGGGAGCCACAAAAC	230		[559-577] ORF
103	GGAGUGGAAGCUGAAGCCU	123	AGGCUUCAGCUUCCACUCC	231	Rh	[825-843] 3′UTR
104	CUGACAUCCGGUUCGUCUA	124	UAGACGAACCGGAUGUCAG	232	Rh	[427-445] ORF
105	GCGUUAUGAGAUCAAGAUG	125	CAUCUUGAUCUCAUAACGC	233	Rh, Dg, Rt	[368-386] ORF
106	CGGACCAGCUCCUCCAAGG	126	CCUUGGAGGAGCUGGUCCG	234	Rh	[703-721] ORF
107	CAGGAUGGACUCUUGCACA	127	UGUGCAAGAGUCCAUCCUG	235		[528-546] ORF
108	CAAGAUGUAUAAAGGGUUC	128	GAACCCUUUAUACAUCUUG	236	Rh	[389-407] ORF

TABLE A2
19-mer Cross-Species siTIMP1
		SEQ		SEQ
		ID		ID		human-73858576
No.	Sense (5′>3′)	NO.	Antisense (5′>3′)	NO.	Other Sp	ORF: 193-816
1	ACCACCUUAUACCAGCGUU	237	AACGCUGGUAUAAGGUGGU	252	Rh, Rt, M	[354-372] ORF
2	ACCGCAGCGAGGAGUUUCU	238	AGAAACUCCUCGCUGCGGU	253	Rh, Rb, Dg, Rt	[493-511] ORF
3	AGACCACCUUAUACCAGCG	239	CGCUGGUAUAAGGUGGUCU	254	Rh, Rt, M	[352-370] ORF
4	GGGCUUCACCAAGACCUAC	240	GUAGGUCUUGGUGAAGCCC	255	Rh, Rb, Dg	[602-620] ORF
5	CAACCGCAGCGAGGAGUUU	241	AAACUCCUCGCUGCGGUUG	256	Rh, Rb, Dg, Rt	[491-509] ORF
6	CAGACCACCUUAUACCAGC	242	GCUGGUAUAAGGUGGUCUG	257	Rh, Rt, M	[351-369] ORF
7	ACCUUAUACCAGCGUUAUG	243	CAUAACGCUGGUAUAAGGU	258	Rh, Rt, M	[357-375] ORF
8	CGUCAUCAGGGCCAAGUUC	244	GAACUUGGCCCUGAUGACG	259	Rh, Rb, Dg	[311-329] ORF
9	AUGCACAGUGUUUCCCUGU	245	ACAGGGAAACACUGUGCAU	260	Rh, Rt, M	[638-656] ORF
10	ACCUGGCAGUCCCUGCGGU	246	ACCGCAGGGACUGCCAGGU	261	Rh, Rb, Dg	[783-801] ORF
11	GACCACCUUAUACCAGCGU	247	ACGCUGGUAUAAGGUGGUC	262	Rh, Rt, M	[353-371] ORF
12	CCGCAGCGAGGAGUUUCUC	248	GAGAAACUCCUCGCUGCGG	263	Rh, Rb, Dg, Rt	[494-512] ORF
13	AACCGCAGCGAGGAGUUUC	249	GAAACUCCUCGCUGCGGUU	264	Rh, Rb, Dg, Rt	[492-510] ORF
14	UUAUGAGAUCAAGAUGACC	250	GGUCAUCUUGAUCUCAUAA	265	Rh, Dg, Rt	[371-389] ORF
15	ACCAGCGUUAUGAGAUCAA	251	UUGAUCUCAUAACGCUGGU	266	Rh, Rt	[364-382] ORF

TABLE A3
Preferred 19-mer siTIMP1
		SEQ		SEQ		human-
		ID		ID		73858576
siTIMP1_pNo.	Sense (5′>3′)	NO.	Antisense (5′>3′)	NO.	length	ORF: 193-816
siTIMP1_p2	GCACAGUGUUUCCCUGUUU	267	AAACAGGGAAACACUGUGC	299	19	[640-658] ORF
siTIMP1_p6	CCACCUUAUACCAGCGUUA	268	UAACGCUGGUAUAAGGUGG	300	19	[355-373] ORF
siTIMP1_p14	UGCACAGUGUUUCCCUGUU	269	AACAGGGAAACACUGUGCA	301	19	[639-657] ORF
siTIMP1_p16	CACCUUAUACCAGCGUUAU	270	AUAACGCUGGUAUAAGGUG	302	19	[356-374] ORF
siTIMP1_p17	GCGUUAUGAGAUCAAGAUG	271	CAUCUUGAUCUCAUAACGC	303	19	[368-386] ORF
siTIMP1_p19	ACCACCUUAUACCAGCGUU	272	AACGCUGGUAUAAGGUGGU	304	19	[354-372] ORF
siTIMP1_p20	ACCGCAGCGAGGAGUUUCU	273	AGAAACUCCUCGCUGCGGU	305	19	[493-511] ORF
siTIMP1_p21	ACCAGCGUUAUGAGAUCAA	274	UUGAUCUCAUAACGCUGGU	306	19	[364-382] ORF
siTIMP1_p23	CAACCGCAGCGAGGAGUUU	275	AAACUCCUCGCUGCGGUUG	307	19	[491-509] ORF
siTIMP1_p24	CAGACCACCUUAUACCAGC	276	GCUGGUAUAAGGUGGUCUG	308	19	[351-369] ORF
siTIMP1_p27	AGAUCAAGAUGACCAAGAU	277	AUCUUGGUCAUCUUGAUCU	309	19	[376-394] ORF
siTIMP1_p29	CCAGAAGUCAACCAGACCA	278	UGGUCUGGUUGACUUCUGG	310	19	[339-357] ORF
siTIMP1_p31	AUGAGAUCAAGAUGACCAA	279	UUGGUCAUCUUGAUCUCAU	311	19	[373-391] ORF
siTIMP1_p33	CCUGCAAACUGCAGAGUGG	280	CCACUCUGCAGUUUGCAGG	312	19	[667-685] ORF
siTIMP1_p38	CACAGUGUUUCCCUGUUUA	281	UAAACAGGGAAACACUGUG	313	19	[641-659] ORF
siTIMP1_p42	ACAGUGUUUCCCUGUUUAU	282	AUAAACAGGGAAACACUGU	314	19	[642-660] ORF
siTIMP1_p43	CAGUGUUUCCCUGUUUAUC	283	GAUAAACAGGGAAACACUG	315	19	[643-661] ORF
siTIMP1_p45	CUUUCUUCCGGACAAUGAA	284	UUCAUUGUCCGGAAGAAAG	316	19	[874-892] 3′UTR
siTIMP1_p49	GUUUCUCAUUGCUGGAAAA	285	UUUUCCAGCAAUGAGAAAC	317	19	[506-524] ORF
siTIMP1_p60	CAUCUUUCUUCCGGACAAU	286	AUUGUCCGGAAGAAAGAUG	318	19	[871-889] 3′UTR
siTIMP1_p71	CUCCCAUCUUUCUUCCGGA	287	UCCGGAAGAAAGAUGGGAG	319	19	[867-885] 3′UTR
siTIMP1_p73	GUGUUUCCCUGUUUAUCCA	288	UGGAUAAACAGGGAAACAC	320	19	[645-663] ORF
siTIMP1_p77	GCCCGGAGUGGAAGCUGAA	289	UUCAGCUUCCACUCCGGGC	321	19	[821-839] 3′UTR
siTIMP1_p78	CAUGGAGAGUGUCUGCGGA	290	UCCGCAGACACUCUCCAUG	322	19	[455-473] ORF
siTIMP1_p79	CCAAGAUGUAUAAAGGGUU	291	AACCCUUUAUACAUCUUGG	323	19	[388-406] ORF
siTIMP1_p85	GAGAGUGUCUGCGGAUACU	292	AGUAUCCGCAGACACUCUC	324	19	[459-477] ORF
siTIMP1_p89	CUGCAGAGUGGCACUCAUU	293	AAUGAGUGCCACUCUGCAG	325	19	[675-693] ORF
siTIMP1_p91	CCUGGAACAGCCUGAGCUU	294	AAGCUCAGGCUGUUCCAGG	326	19	[571-589] ORF
siTIMP1_p96	CACUGUUGGCUGUGAGGAA	295	UUCCUCACAGCCAACAGUG	327	19	[620-638] ORF
siTIMP1_p98	GAUGGACUCUUGCACAUCA	296	UGAUGUGCAAGAGUCCAUC	328	19	[531-549] ORF
siTIMP1_p99	AGUUUCUCAUUGCUGGAAA	297	UUUCCAGCAAUGAGAAACU	329	19	[505-523] ORF
siTIMP1_p108	GUCUGCGGAUACUUCCACA	298	UGUGGAAGUAUCCGCAGAC	330	19	[465-483] ORF

TABLE A4
19-mer siTIMP1 with lowest predicted OT effect
				SEQ		SEQ
No. in TABLE				ID		ID
A3	Cross species	Ranking	Sense (5′>3′)	NO.	Antisense (5′>3′)	NO.
siTIMP1_p2	H/Rt	3	GCACAGUGUUUCCCUGUUU	267	AAACAGGGAAACACUGUGC	299
siTIMP1_p6	H/Rt	2	CCACCUUAUACCAGCGUUA	268	UAACGCUGGUAUAAGGUGG	300
siTIMP1_p14	H/Rt	4	UGCACAGUGUUUCCCUGUU	269	AACAGGGAAACACUGUGCA	301
siTIMP1_p16	H/Rt	1	CACCUUAUACCAGCGUUAU	270	AUAACGCUGGUAUAAGGUG	302
siTIMP1_p17	H/Rt	2	GCGUUAUGAGAUCAAGAUG	271	CAUCUUGAUCUCAUAACGC	303
siTIMP1_p19	H/Rt	2	ACCACCUUAUACCAGCGUU	272	AACGCUGGUAUAAGGUGGU	304
siTIMP1_p20	H/Rt	3	ACCGCAGCGAGGAGUUUCU	273	AGAAACUCCUCGCUGCGGU	305
siTIMP1_p21	H/Rt	3	ACCAGCGUUAUGAGAUCAA	274	UUGAUCUCAUAACGCUGGU	306
siTIMP1_p23	H/Rt	3	CAACCGCAGCGAGGAGUUU	275	AAACUCCUCGCUGCGGUUG	307
siTIMP1_p29	Other (w/o Rt)	3	CCAGAAGUCAACCAGACCA	278	UGGUCUGGUUGACUUCUGG	310
siTIMP1_p33	Other (w/o Rt)	4	CCUGCAAACUGCAGAGUGG	280	CCACUCUGCAGUUUGCAGG	312
siTIMP1_p38	H/Rt (Rt Cross-	3	CACAGUGUUUCCCUGUUUA	281	UAAACAGGGAAACACUGUG	313
	with 1MM)
siTIMP1_p42	Other (w/o Rt)	3	ACAGUGUUUCCCUGUUUAU	282	AUAAACAGGGAAACACUGU	314
siTIMP1_p43	Other (w/o Rt)	3	CAGUGUUUCCCUGUUUAUC	283	GAUAAACAGGGAAACACUG	315
siTIMP1_p45	H +/− Rh	4	CUUUCUUCCGGACAAUGAA	284	UUCAUUGUCCGGAAGAAAG	316
siTIMP1_p60	H +/− Rh	2	CAUCUUUCUUCCGGACAAU	286	AUUGUCCGGAAGAAAGAUG	318
siTIMP1_p71	H +/− Rh	4	CUCCCAUCUUUCUUCCGGA	287	UCCGGAAGAAAGAUGGGAG	319
siTIMP1_p73	H +/− Rh	3	GUGUUUCCCUGUUUAUCCA	288	UGGAUAAACAGGGAAACAC	320
siTIMP1_p78	H +/− Rh	3	CAUGGAGAGUGUCUGCGGA	290	UCCGCAGACACUCUCCAUG	322
siTIMP1_p79	H +/− Rh	3	CCAAGAUGUAUAAAGGGUU	291	AACCCUUUAUACAUCUUGG	323
siTIMP1_p85	H +/− Rh	2	GAGAGUGUCUGCGGAUACU	292	AGUAUCCGCAGACACUCUC	324
siTIMP1_p89	H +/− Rh	3	CUGCAGAGUGGCACUCAUU	293	AAUGAGUGCCACUCUGCAG	325
siTIMP1_p91	H +/− Rh	4	CCUGGAACAGCCUGAGCUU	294	AAGCUCAGGCUGUUCCAGG	326
siTIMP1_p96	H +/− Rh	4	CACUGUUGGCUGUGAGGAA	295	UUCCUCACAGCCAACAGUG	327
siTIMP1_p98	H +/− Rh	3	GAUGGACUCUUGCACAUCA	296	UGAUGUGCAAGAGUCCAUC	328
siTIMP1_p99	H +/− Rh	4	AGUUUCUCAUUGCUGGAAA	297	UUUCCAGCAAUGAGAAACU	329
siTIMP1_p108	H +/− Rh	2	GUCUGCGGAUACUUCCACA	298	UGUGGAAGUAUCCGCAGAC	330

TABLE A5
18-mer siTIMP1
		SEQ		SEQ
		ID		ID		human-73858576
No.	Sense (5′>3′)	NO.	Antisense (5′>3′)	NO.	Other Sp	ORF: 193-816
1	GGAGAGUGUCUGCGGAUA	331	UAUCCGCAGACACUCUCC	582	Rh	[458-475] ORF
2	GCUGAAGCCUGCACAGUG	332	CACUGUGCAGGCUUCAGC	583		[834-851] 3′UTR
3	CAUCUUUCUUCCGGACAA	333	UUGUCCGGAAGAAAGAUG	584		[871-888] 3′UTR
4	CCUCCAAGGCUCUGAAAA	334	UUUUCAGAGCCUUGGAGG	585	Rh	[713-730] ORF
5	CCGCCAUGGAGAGUGUCU	335	AGACACUCUCCAUGGCGG	586	Rh	[451-468] ORF
6	GAGUGUCUGCGGAUACUU	336	AAGUAUCCGCAGACACUC	587	Rh	[461-478] ORF
7	GAGUGGCACUCAUUGCUU	337	AAGCAAUGAGUGCCACUC	588	Rh	[680-697] ORF
8	AGCUGAAGCCUGCACAGU	338	ACUGUGCAGGCUUCAGCU	589		[833-850] 3′UTR
9	AGAUCAAGAUGACCAAGA	339	UCUUGGUCAUCUUGAUCU	590	Rh, Dg	[376-393] ORF
10	GACUCUUGCACAUCACUA	340	UAGUGAUGUGCAAGAGUC	591		[535-552] ORF
11	GAGUGGAAGCUGAAGCCU	341	AGGCUUCAGCUUCCACUC	592	Rh	[826-843] 3′UTR
12	CCUGCAAACUGCAGAGUG	342	CACUCUGCAGUUUGCAGG	593	Rh, Dg	[667-684] ORF
13	CAGUGUUUCCCUGUUUAU	343	AUAAACAGGGAAACACUG	594	Rh, Ms	[643-660] ORF
14	CCCUGUUCCCACUCCCAU	344	AUGGGAGUGGGAACAGGG	595	Rh	[856-873] 3′UTR
15	CCAGAUAGCCUGAAUCCU	345	AGGAUUCAGGCUAUCUGG	596		[803-820] ORF + 3′UTR
16	GGUCCCAGAUAGCCUGAA	346	UUCAGGCUAUCUGGGACC	597		[799-816] ORF
17	GGGCUUCACCAAGACCUA	347	UAGGUCUUGGUGAAGCCC	598	Rh, Rb, Dg	[602-619] ORF
18	GCGGAUACUUCCACAGGU	348	ACCUGUGGAAGUAUCCGC	599	Rh	[469-486] ORF
19	GAGAGUGUCUGCGGAUAC	349	GUAUCCGCAGACACUCUC	600	Rh	[459-476] ORF
20	GCGUUAUGAGAUCAAGAU	350	AUCUUGAUCUCAUAACGC	601	Rh, Dg, Rt	[368-385] ORF
21	GGAACAGCCUGAGCUUAG	351	CUAAGCUCAGGCUGUUCC	602		[574-591] ORF
22	CUGAAAAGGGCUUCCAGU	352	ACUGGAAGCCCUUUUCAG	603	Rh	[724-741] ORF
23	CCAGCGUUAUGAGAUCAA	353	UUGAUCUCAUAACGCUGG	604	Rh, Rt	[365-382] ORF
24	CAACCAGACCACCUUAUA	354	UAUAAGGUGGUCUGGUUG	605	Rh	[347-364] ORF
25	GAGGAAUGCACAGUGUUU	355	AAACACUGUGCAUUCCUC	606	Rh	[633-650] ORF
26	CCAAGAUGUAUAAAGGGU	356	ACCCUUUAUACAUCUUGG	607	Rh	[388-405] ORF
27	CAGACCACCUUAUACCAG	357	CUGGUAUAAGGUGGUCUG	608	Rh, Rt, Ms	[351-368] ORF
28	AGUGGAAGCUGAAGCCUG	358	CAGGCUUCAGCUUCCACU	609	Rh	[827-844] 3′UTR
29	ACAGUGUUUCCCUGUUUA	359	UAAACAGGGAAACACUGU	610	Rh, Ms	[642-659] ORF
30	CGCCAUGGAGAGUGUCUG	360	CAGACACUCUCCAUGGCG	611	Rh	[452-469] ORF
31	CACCAGAAGUCAACCAGA	361	UCUGGUUGACUUCUGGUG	612	Rh	[337-354] ORF
32	CAGAAGUCAACCAGACCA	362	UGGUCUGGUUGACUUCUG	613	Rh	[340-357] ORF
33	CCCACUCCCAUCUUUCUU	363	AAGAAAGAUGGGAGUGGG	614	Rh	[863-880] 3′UTR
34	GCGAGGAGUUUCUCAUUG	364	CAAUGAGAAACUCCUCGC	615	Rh	[499-516] ORF
35	GCUUCACCAAGACCUACA	365	UGUAGGUCUUGGUGAAGC	616	Rh	[604-621] ORF
36	CAUCACUACCUGCAGUUU	366	AAACUGCAGGUAGUGAUG	617		[545-562] ORF
37	AGCGUUAUGAGAUCAAGA	367	UCUUGAUCUCAUAACGCU	618	Rh, Dg, Rt	[367-384] ORF
38	CUGCAGAGUGGCACUCAU	368	AUGAGUGCCACUCUGCAG	619	Rh	[675-692] ORF
39	GAAGCUGAAGCCUGCACA	369	UGUGCAGGCUUCAGCUUC	620		[831-848] 3′UTR
40	AUCACUACCUGCAGUUUU	370	AAAACUGCAGGUAGUGAU	621		[546-563] ORF
41	GCACAGUGUUUCCCUGUU	371	AACAGGGAAACACUGUGC	622	Rh, Rt, Ms	[640-657] ORF
42	CCUGGAACAGCCUGAGCU	372	AGCUCAGGCUGUUCCAGG	623		[571-588] ORF
43	GCAUCCUGUUGUUGCUGU	373	ACAGCAACAACAGGAUGC	624	Rh	[220-237] ORF
44	GUCCCAGAUAGCCUGAAU	374	AUUCAGGCUAUCUGGGAC	625		[800-817] ORF + 3′UTR
45	AGUGUUUCCCUGUUUAUC	375	GAUAAACAGGGAAACACU	626	Rh, Ms	[644-661] ORF
46	GGCUGUGAGGAAUGCACA	376	UGUGCAUUCCUCACAGCC	627	Rh	[627-644] ORF
47	AGACCACCUUAUACCAGC	377	GCUGGUAUAAGGUGGUCU	628	Rh, Rt, Ms	[352-369] ORF
48	GGAUGGACUCUUGCACAU	378	AUGUGCAAGAGUCCAUCC	629		[530-547] ORF
49	CGGACCAGCUCCUCCAAG	379	CUUGGAGGAGCUGGUCCG	630	Rh	[703-720] ORF
50	GGCCUUCUGCAAUUCCGA	380	UCGGAAUUGCAGAAGGCC	631	Rh	[290-307] ORF
51	GGGCUUCCAGUCCCGUCA	381	UGACGGGACUGGAAGCCC	632	Rh	[731-748] ORF
52	GCAGAGUGGCACUCAUUG	382	CAAUGAGUGCCACUCUGC	633	Rh	[677-694] ORF
53	CAGCGAGGAGUUUCUCAU	383	AUGAGAAACUCCUCGCUG	634	Rh, Rb, Rt	[497-514] ORF
54	CAGAUAGCCUGAAUCCUG	384	CAGGAUUCAGGCUAUCUG	635		[804-821] ORF + 3′UTR
55	GCAGCGAGGAGUUUCUCA	385	UGAGAAACUCCUCGCUGC	636	Rh, Rb, Rt	[496-513] ORF
56	CCUGCAGUUUUGUGGCUC	386	GAGCCACAAAACUGCAGG	637		[553-570] ORF
57	GUUAUGAGAUCAAGAUGA	387	UCAUCUUGAUCUCAUAAC	638	Rh, Dg, Rt	[370-387] ORF
58	CAAGAUGUAUAAAGGGUU	388	AACCCUUUAUACAUCUUG	639	Rh	[389-406] ORF
59	CCGGAGUGGAAGCUGAAG	389	CUUCAGCUUCCACUCCGG	640	Rh	[823-840] 3′UTR
60	AGGAGUUUCUCAUUGCUG	390	CAGCAAUGAGAAACUCCU	641	Rh	[502-519] ORF
61	GGCUGUGCACCUGGCAGU	391	ACUGCCAGGUGCACAGCC	642	Rh	[775-792] ORF
62	GUUUCCCUGUUUAUCCAU	392	AUGGAUAAACAGGGAAAC	643	Rh	[647-664] ORF
63	GCAGUUUUGUGGCUCCCU	393	AGGGAGCCACAAAACUGC	644		[556-573] ORF
64	GUCAACCAGACCACCUUA	394	UAAGGUGGUCUGGUUGAC	645	Rh	[345-362] ORF
65	CCAUGGAGAGUGUCUGCG	395	CGCAGACACUCUCCAUGG	646	Rh	[454-471] ORF
66	CUGGCAUCCUGUUGUUGC	396	GCAACAACAGGAUGCCAG	647		[217-234] ORF
67	CAGACGGCCUUCUGCAAU	397	AUUGCAGAAGGCCGUCUG	648	Rh	[285-302] ORF
68	ACUGCAGAGUGGCACUCA	398	UGAGUGCCACUCUGCAGU	649	Rh	[674-691] ORF
69	CGGAGUGGAAGCUGAAGC	399	GCUUCAGCUUCCACUCCG	650	Rh	[824-841] 3′UTR
70	GCCUCGGGAGCCAGGGCU	400	AGCCCUGGCUCCCGAGGC	651	Rh	[761-778] ORF
71	CCAGACCACCUUAUACCA	401	UGGUAUAAGGUGGUCUGG	652	Rh	[350-367] ORF
72	GGCUCUGAAAAGGGCUUC	402	GAAGCCCUUUUCAGAGCC	653	Rh	[720-737] ORF
73	GCUGGAAAACUGCAGGAU	403	AUCCUGCAGUUUUCCAGC	654		[516-533] ORF
74	CCUGAAUCCUGCCCGGAG	404	CUCCGGGCAGGAUUCAGG	655		[811-828] ORF + 3′UTR
75	CUGAAGCCUGCACAGUGU	405	ACACUGUGCAGGCUUCAG	656		[835-852] 3′UTR
76	GGCAUCCUGUUGUUGCUG	406	CAGCAACAACAGGAUGCC	657	Rh	[219-236] ORF
77	CCCUGCAAACUGCAGAGU	407	ACUCUGCAGUUUGCAGGG	658	Rh, Dg	[666-683] ORF
78	CUGGAAAACUGCAGGAUG	408	CAUCCUGCAGUUUUCCAG	659		[517-534] ORF
79	UCUCAUUGCUGGAAAACU	409	AGUUUUCCAGCAAUGAGA	660	Rh	[509-526] ORF
80	GUGGCUCCCUGGAACAGC	410	GCUGUUCCAGGGAGCCAC	661		[564-581] ORF
81	CCAGCUCCUCCAAGGCUC	411	GAGCCUUGGAGGAGCUGG	662	Rh	[707-724] ORF
82	AGACCUACACUGUUGGCU	412	AGCCAACAGUGUAGGUCU	663	Rh	[613-630] ORF
83	GGGACACCAGAAGUCAAC	413	GUUGACUUCUGGUGUCCC	664	Rh	[333-350] ORF
84	GGCUCCCUGGAACAGCCU	414	AGGCUGUUCCAGGGAGCC	665		[566-583] ORF
85	GUUCCCACUCCCAUCUUU	415	AAAGAUGGGAGUGGGAAC	666	Rh	[860-877] 3′UTR
86	CUCUGAAAAGGGCUUCCA	416	UGGAAGCCCUUUUCAGAG	667	Rh	[722-739] ORF
87	GGCUUCUGGCAUCCUGUU	417	AACAGGAUGCCAGAAGCC	668		[212-229] ORF
88	AGGAAUGCACAGUGUUUC	418	GAAACACUGUGCAUUCCU	669	Rh	[634-651] ORF
89	CUUCUGGCAUCCUGUUGU	419	ACAACAGGAUGCCAGAAG	670		[214-231] ORF
90	CAAACUGCAGAGUGGCAC	420	GUGCCACUCUGCAGUUUG	671	Rh	[671-688] ORF
91	AUACCAGCGUUAUGAGAU	421	AUCUCAUAACGCUGGUAU	672	Rh, Rt	[362-379] ORF
92	AGAGUGUCUGCGGAUACU	422	AGUAUCCGCAGACACUCU	673	Rh	[460-477] ORF
93	CACCAAGACCUACACUGU	423	ACAGUGUAGGUCUUGGUG	674	Rh	[608-625] ORF
94	GAUCAAGAUGACCAAGAU	424	AUCUUGGUCAUCUUGAUC	675	Rh, Dg	[377-394] ORF
95	AUGUAUAAAGGGUUCCAA	425	UUGGAACCCUUUAUACAU	676		[393-410] ORF
96	ACCAAGACCUACACUGUU	426	AACAGUGUAGGUCUUGGU	677	Rh	[609-626] ORF
97	CCGUCACCUUGCCUGCCU	427	AGGCAGGCAAGGUGACGG	678	Rh	[743-760] ORF
98	GGGAGCCAGGGCUGUGCA	428	UGCACAGCCCUGGCUCCC	679	Rh	[766-783] ORF
99	UGCACAGUGUUUCCCUGU	429	ACAGGGAAACACUGUGCA	680	Rh, Rt, Ms	[639-656] ORF
100	UGCAGAGUGGCACUCAUU	430	AAUGAGUGCCACUCUGCA	681	Rh	[676-693] ORF
101	GUGAGGAAUGCACAGUGU	431	ACACUGUGCAUUCCUCAC	682	Rh	[631-648] ORF
102	AGCGAGGAGUUUCUCAUU	432	AAUGAGAAACUCCUCGCU	683	Rh	[498-515] ORF
103	GGGCUGUGCACCUGGCAG	433	CUGCCAGGUGCACAGCCC	684	Rh	[774-791] ORF
104	ACUCAUUGCUUGUGGACG	434	CGUCCACAAGCAAUGAGU	685	Rh	[687-704] ORF
105	UGUUGUUGCUGUGGCUGA	435	UCAGCCACAGCAACAACA	686	Rh	[226-243] ORF
106	UGAGGAAUGCACAGUGUU	436	AACACUGUGCAUUCCUCA	687	Rh	[632-649] ORF
107	CCUGGCUUCUGGCAUCCU	437	AGGAUGCCAGAAGCCAGG	688		[209-226] ORF
108	GCACAGUGUCCACCCUGU	438	ACAGGGUGGACACUGUGC	689		[844-861] 3′UTR
109	AAAGGGUUCCAAGCCUUA	439	UAAGGCUUGGAACCCUUU	690		[399-416] ORF
110	GCUUCUGGCAUCCUGUUG	440	CAACAGGAUGCCAGAAGC	691		[213-230] ORF
111	CCAAGACCUACACUGUUG	441	CAACAGUGUAGGUCUUGG	692	Rh	[610-627] ORF
112	AAGGGUUCCAAGCCUUAG	442	CUAAGGCUUGGAACCCUU	693		[400-417] ORF
113	UGCACAGUGUCCACCCUG	443	CAGGGUGGACACUGUGCA	694		[843-860] 3′UTR
114	GACCUACACUGUUGGCUG	444	CAGCCAACAGUGUAGGUC	695	Rh	[614-631] ORF
115	CCCAGAUAGCCUGAAUCC	445	GGAUUCAGGCUAUCUGGG	696		[802-819] ORF + 3′UTR
116	GGGUUCCAAGCCUUAGGG	446	CCCUAAGGCUUGGAACCC	697		[402-419] ORF
117	GGCUUCCAGUCCCGUCAC	447	GUGACGGGACUGGAAGCC	698	Rh	[732-749] ORF
118	AGUGUCUGCGGAUACUUC	448	GAAGUAUCCGCAGACACU	699	Rh	[462-479] ORF
119	UGACCAAGAUGUAUAAAG	449	CUUUAUACAUCUUGGUCA	700	Rh	[385-402] ORF
120	CAGCCUGAGCUUAGCUCA	450	UGAGCUAAGCUCAGGCUG	701		[578-595] ORF
121	CUUCCGGACAAUGAAAUA	451	UAUUUCAUUGUCCGGAAG	702		[878-895] 3′UTR
122	CUGUGAGGAAUGCACAGU	452	ACUGUGCAUUCCUCACAG	703	Rh	[629-646] ORF
123	GCCUGAAUCCUGCCCGGA	453	UCCGGGCAGGAUUCAGGC	704		[810-827] ORF + 3′UTR
124	ACUGCAGGAUGGACUCUU	454	AAGAGUCCAUCCUGCAGU	705		[524-541] ORF
125	GUCCCACAACCGCAGCGA	455	UCGCUGCGGUUGUGGGAC	706	Rh	[485-502] ORF
126	AUCUUUCUUCCGGACAAU	456	AUUGUCCGGAAGAAAGAU	707		[872-889] 3′UTR
127	AUAAAGGGUUCCAAGCCU	457	AGGCUUGGAACCCUUUAU	708		[397-414] ORF
128	UCCCAUCUUUCUUCCGGA	458	UCCGGAAGAAAGAUGGGA	709		[868-885] 3′UTR
129	GAAAAGGGCUUCCAGUCC	459	GGACUGGAAGCCCUUUUC	710	Rh	[726-743] ORF
130	UGGAACAGCCUGAGCUUA	460	UAAGCUCAGGCUGUUCCA	711		[573-590] ORF
131	CACCUUAUACCAGCGUUA	461	UAACGCUGGUAUAAGGUG	712	Rh, Rt, Ms	[356-373] ORF
132	CUGUUGGCUGUGAGGAAU	462	AUUCCUCACAGCCAACAG	713	Rh	[622-639] ORF
133	GCACAUCACUACCUGCAG	463	CUGCAGGUAGUGAUGUGC	714		[542-559] ORF
134	UGCUGUGGCUGAUAGCCC	464	GGGCUAUCAGCCACAGCA	715	Rh	[232-249] ORF
135	CCACUCCCAUCUUUCUUC	465	GAAGAAAGAUGGGAGUGG	716	Rh	[864-881] 3′UTR
136	CUGGCUUCUGGCAUCCUG	466	CAGGAUGCCAGAAGCCAG	717		[210-227] ORF
137	CUUCCACAGGUCCCACAA	467	UUGUGGGACCUGUGGAAG	718	Rh	[476-493] ORF
138	ACCAGCUCCUCCAAGGCU	468	AGCCUUGGAGGAGCUGGU	719	Rh	[706-723] ORF
139	CAAGAUGACCAAGAUGUA	469	UACAUCUUGGUCAUCUUG	720	Rh	[380-397] ORF
140	CCCGCCAUGGAGAGUGUC	470	GACACUCUCCAUGGCGGG	721	Rh	[450-467] ORF
141	CCCGGAGUGGAAGCUGAA	471	UUCAGCUUCCACUCCGGG	722	Rh	[822-839] 3′UTR
142	CGAGGAGUUUCUCAUUGC	472	GCAAUGAGAAACUCCUCG	723	Rh	[500-517] ORF
143	CACAUCACUACCUGCAGU	473	ACUGCAGGUAGUGAUGUG	724		[543-560] ORF
144	CUCCAAGGCUCUGAAAAG	474	CUUUUCAGAGCCUUGGAG	725	Rh	[714-731] ORF
145	UGAGAUCAAGAUGACCAA	475	UUGGUCAUCUUGAUCUCA	726	Rh, Dg	[374-391] ORF
146	GCACUCAUUGCUUGUGGA	476	UCCACAAGCAAUGAGUGC	727	Rh, Rb	[685-702] ORF
147	CAUUGCUUGUGGACGGAC	477	GUCCGUCCACAAGCAAUG	728	Rh	[690-707] ORF
148	GGACCAGCUCCUCCAAGG	478	CCUUGGAGGAGCUGGUCC	729	Rh	[704-721] ORF
149	GCCUGCACAGUGUCCACC	479	GGUGGACACUGUGCAGGC	730		[840-857] 3′UTR
150	UGUAUAAAGGGUUCCAAG	480	CUUGGAACCCUUUAUACA	731		[394-411] ORF
151	CCUGCACAGUGUCCACCC	481	GGGUGGACACUGUGCAGG	732		[841-858] 3′UTR
152	ACCUUAUACCAGCGUUAU	482	AUAACGCUGGUAUAAGGU	733	Rh, Rt, Ms	[357-374] ORF
153	CUUCCAGUCCCGUCACCU	483	AGGUGACGGGACUGGAAG	734	Rh	[734-751] ORF
154	CAGUGUCCACCCUGUUCC	484	GGAACAGGGUGGACACUG	735		[847-864] 3′UTR
155	GGAGUGGAAGCUGAAGCC	485	GGCUUCAGCUUCCACUCC	736	Rh	[825-842] 3′UTR
156	CUUAUACCAGCGUUAUGA	486	UCAUAACGCUGGUAUAAG	737	Rh, Rt	[359-376] ORF
157	CCGCAGCGAGGAGUUUCU	487	AGAAACUCCUCGCUGCGG	738	Rh, Rb, Dg, Rt	[494-511] ORF
158	CAGUUUUGUGGCUCCCUG	488	CAGGGAGCCACAAAACUG	739		[557-574] ORF
159	GUAUAAAGGGUUCCAAGC	489	GCUUGGAACCCUUUAUAC	740		[395-412] ORF
160	AAGCCUGCACAGUGUCCA	490	UGGACACUGUGCAGGCUU	741		[838-855] 3′UTR
161	AGGAUGGACUCUUGCACA	491	UGUGCAAGAGUCCAUCCU	742		[529-546] ORF
162	AUGGAGAGUGUCUGCGGA	492	UCCGCAGACACUCUCCAU	743	Rh	[456-473] ORF
163	GCCUUCUGCAAUUCCGAC	493	GUCGGAAUUGCAGAAGGC	744	Rh	[291-308] ORF
164	CUUCUGCAAUUCCGACCU	494	AGGUCGGAAUUGCAGAAG	745	Rh	[293-310] ORF
165	AGACGGCCUUCUGCAAUU	495	AAUUGCAGAAGGCCGUCU	746	Rh	[286-303] ORF
166	GCAGGAUGGACUCUUGCA	496	UGCAAGAGUCCAUCCUGC	747		[527-544] ORF
167	GCUUGUGGACGGACCAGC	497	GCUGGUCCGUCCACAAGC	748	Rh	[694-711] ORF
168	AGAAGUCAACCAGACCAC	498	GUGGUCUGGUUGACUUCU	749	Rh	[341-358] ORF
169	CUGUGCACCUGGCAGUCC	499	GGACUGCCAGGUGCACAG	750	Rh	[777-794] ORF
170	GAGGAGUUUCUCAUUGCU	500	AGCAAUGAGAAACUCCUC	751	Rh	[501-518] ORF
171	UGUUCCCACUCCCAUCUU	501	AAGAUGGGAGUGGGAACA	752	Rh	[859-876] 3′UTR
172	ACCGCAGCGAGGAGUUUC	502	GAAACUCCUCGCUGCGGU	753	Rh, Rb, Dg, Rt	[493-510] ORF
173	ACCAGAAGUCAACCAGAC	503	GUCUGGUUGACUUCUGGU	754	Rh	[338-355] ORF
174	GCAAUUCCGACCUCGUCA	504	UGACGAGGUCGGAAUUGC	755	Rh	[298-315] ORF
175	CUGCAAACUGCAGAGUGG	505	CCACUCUGCAGUUUGCAG	756	Rh	[668-685] ORF
176	GGAGCCAGGGCUGUGCAC	506	GUGCACAGCCCUGGCUCC	757	Rh	[767-784] ORF
177	CCUUCUGCAAUUCCGACC	507	GGUCGGAAUUGCAGAAGG	758	Rh	[292-309] ORF
178	CUUGCACAUCACUACCUG	508	CAGGUAGUGAUGUGCAAG	759		[539-556] ORF
179	GGAAAACUGCAGGAUGGA	509	UCCAUCCUGCAGUUUUCC	760		[519-536] ORF
180	AAUGCACAGUGUUUCCCU	510	AGGGAAACACUGUGCAUU	761	Rh	[637-654] ORF
181	CCCUGGAACAGCCUGAGC	511	GCUCAGGCUGUUCCAGGG	762		[570-587] ORF
182	GGAUGCCGCUGACAUCCG	512	CGGAUGUCAGCGGCAUCC	763	Rh	[419-436] ORF
183	GGAUACUUCCACAGGUCC	513	GGACCUGUGGAAGUAUCC	764	Rh	[471-488] ORF
184	CACUCAUUGCUUGUGGAC	514	GUCCACAAGCAAUGAGUG	765	Rh, Rb	[686-703] ORF
185	GACACCAGAAGUCAACCA	515	UGGUUGACUUCUGGUGUC	766	Rh	[335-352] ORF
186	CUACACUGUUGGCUGUGA	516	UCACAGCCAACAGUGUAG	767	Rh	[617-634] ORF
187	ACCACCUUAUACCAGCGU	517	ACGCUGGUAUAAGGUGGU	768	Rh, Rt, Ms	[354-371] ORF
188	AGAGUGGCACUCAUUGCU	518	AGCAAUGAGUGCCACUCU	769	Rh	[679-696] ORF
189	GCAAACUGCAGAGUGGCA	519	UGCCACUCUGCAGUUUGC	770	Rh	[670-687] ORF
190	GCCGCUGACAUCCGGUUC	520	GAACCGGAUGUCAGCGGC	771	Rh	[423-440] ORF
191	UGUUUCCCUGUUUAUCCA	521	UGGAUAAACAGGGAAACA	772	Rh	[646-663] ORF
192	AAGUCAACCAGACCACCU	522	AGGUGGUCUGGUUGACUU	773	Rh	[343-360] ORF
193	CCACAACCGCAGCGAGGA	523	UCCUCGCUGCGGUUGUGG	774	Rh	[488-505] ORF
194	GCCUGAGCUUAGCUCAGC	524	GCUGAGCUAAGCUCAGGC	775		[580-597] ORF
195	GUCAUCAGGGCCAAGUUC	525	GAACUUGGCCCUGAUGAC	776	Rh, Dg	[312-329] ORF
196	AACCAGACCACCUUAUAC	526	GUAUAAGGUGGUCUGGUU	777	Rh	[348-365] ORF
197	CUCCCUGGAACAGCCUGA	527	UCAGGCUGUUCCAGGGAG	778		[568-585] ORF
198	CCAAGGCUCUGAAAAGGG	528	CCCUUUUCAGAGCCUUGG	779	Rh	[716-733] ORF
199	CUCAUUGCUGGAAAACUG	529	CAGUUUUCCAGCAAUGAG	780	Rh	[510-527] ORF
200	GUGUCCACCCUGUUCCCA	530	UGGGAACAGGGUGGACAC	781		[849-866] 3′UTR
201	CCUGUUCCCACUCCCAUC	531	GAUGGGAGUGGGAACAGG	782	Rh	[857-874] 3′UTR
202	CACCUUGCCUGCCUGCCU	532	AGGCAGGCAGGCAAGGUG	783	Rh	[747-764] ORF
203	UCACCAAGACCUACACUG	533	CAGUGUAGGUCUUGGUGA	784	Rh	[607-624] ORF
204	GAAUGCACAGUGUUUCCC	534	GGGAAACACUGUGCAUUC	785	Rh	[636-653] ORF
205	AUGGACUCUUGCACAUCA	535	UGAUGUGCAAGAGUCCAU	786		[532-549] ORF
206	UGUGAGGAAUGCACAGUG	536	CACUGUGCAUUCCUCACA	787	Rh	[630-647] ORF
207	GAGCCAGGGCUGUGCACC	537	GGUGCACAGCCCUGGCUC	788	Rh	[768-785] ORF
208	UGCGGUCCCAGAUAGCCU	538	AGGCUAUCUGGGACCGCA	789		[796-813] ORF
209	CUGUUCCCACUCCCAUCU	539	AGAUGGGAGUGGGAACAG	790	Rh	[858-875] 3′UTR
210	UGGCUUCUGGCAUCCUGU	540	ACAGGAUGCCAGAAGCCA	791		[211-228] ORF
211	CGGAUACUUCCACAGGUC	541	GACCUGUGGAAGUAUCCG	792	Rh	[470-487] ORF
212	CACAGUGUCCACCCUGUU	542	AACAGGGUGGACACUGUG	793		[845-862] 3′UTR
213	GGAAUGCACAGUGUUUCC	543	GGAAACACUGUGCAUUCC	794	Rh	[635-652] ORF
214	CCAGGGCUGUGCACCUGG	544	CCAGGUGCACAGCCCUGG	795	Rh	[771-788] ORF
215	CCCUGCGGUCCCAGAUAG	545	CUAUCUGGGACCGCAGGG	796		[793-810] ORF
216	GCCUGCACCUGUGUCCCA	546	UGGGACACAGGUGCAGGC	797	Rb	[258-275] ORF
217	CAGAGUGGCACUCAUUGC	547	GCAAUGAGUGCCACUCUG	798	Rh	[678-695] ORF
218	UGCACAUCACUACCUGCA	548	UGCAGGUAGUGAUGUGCA	799		[541-558] ORF
219	GAAGUCAACCAGACCACC	549	GGUGGUCUGGUUGACUUC	800	Rh	[342-359] ORF
220	UCCCUGCGGUCCCAGAUA	550	UAUCUGGGACCGCAGGGA	801		[792-809] ORF
221	AGUGGCACUCAUUGCUUG	551	CAAGCAAUGAGUGCCACU	802	Rh	[681-698] ORF
222	GUGGCACUCAUUGCUUGU	552	ACAAGCAAUGAGUGCCAC	803	Rh	[682-699] ORF
223	CUGAAUCCUGCCCGGAGU	553	ACUCCGGGCAGGAUUCAG	804		[812-829] ORF + 3′UTR
224	CCUGCACCUGUGUCCCAC	554	GUGGGACACAGGUGCAGG	805	Rb	[259-276] ORF
225	GCCUGCCUCGGGAGCCAG	555	CUGGCUCCCGAGGCAGGC	806	Rh	[757-774] ORF
226	GGGAUGCCGCUGACAUCC	556	GGAUGUCAGCGGCAUCCC	807	Rh	[418-435] ORF
227	GCACCUGGCAGUCCCUGC	557	GCAGGGACUGCCAGGUGC	808	Rh, Dg	[781-798] ORF
228	UCCUGUUGUUGCUGUGGC	558	GCCACAGCAACAACAGGA	809	Rh	[223-240] ORF
229	UGCGGAUACUUCCACAGG	559	CCUGUGGAAGUAUCCGCA	810	Rh	[468-485] ORF
230	GACCAAGAUGUAUAAAGG	560	CCUUUAUACAUCUUGGUC	811	Rh	[386-403] ORF
231	ACUGUUGGCUGUGAGGAA	561	UUCCUCACAGCCAACAGU	812	Rh	[621-638] ORF
232	CAUUGCUGGAAAACUGCA	562	UGCAGUUUUCCAGCAAUG	813	Rh	[512-529] ORF
233	UGAAAAGGGCUUCCAGUC	563	GACUGGAAGCCCUUUUCA	814	Rh	[725-742] ORF
234	CGUCAUCAGGGCCAAGUU	564	AACUUGGCCCUGAUGACG	815	Rh, Rb, Dg	[311-328] ORF
235	ACAACCGCAGCGAGGAGU	565	ACUCCUCGCUGCGGUUGU	816	Rh	[490-507] ORF
236	UGUCCACCCUGUUCCCAC	566	GUGGGAACAGGGUGGACA	817	Rh	[850-867] 3′UTR
237	CCUGGCAGUCCCUGCGGU	567	ACCGCAGGGACUGCCAGG	818		[784-801] ORF
238	UGAAGCCUGCACAGUGUC	568	GACACUGUGCAGGCUUCA	819		[836-853] 3′UTR
239	UCCCAGAUAGCCUGAAUC	569	GAUUCAGGCUAUCUGGGA	820		[801-818] ORF + 3′UTR
240	AGCCUGAGCUUAGCUCAG	570	CUGAGCUAAGCUCAGGCU	821		[579-596] ORF
241	CACUACCUGCAGUUUUGU	571	ACAAAACUGCAGGUAGUG	822		[548-565] ORF
242	CUGCACAGUGUCCACCCU	572	AGGGUGGACACUGUGCAG	823		[842-859] 3′UTR
243	CUCGGGAGCCAGGGCUGU	573	ACAGCCCUGGCUCCCGAG	824	Rh	[763-780] ORF
244	AGCCAGGGCUGUGCACCU	574	AGGUGCACAGCCCUGGCU	825	Rh	[769-786] ORF
245	GCCAUGGAGAGUGUCUGC	575	GCAGACACUCUCCAUGGC	826	Rh	[453-470] ORF
246	AGGGCUGUGCACCUGGCA	576	UGCCAGGUGCACAGCCCU	827	Rh	[773-790] ORF
247	GAGCUUAGCUCAGCGCCG	577	CGGCGCUGAGCUAAGCUC	828	Rh	[584-601] ORF
248	AGGCUCUGAAAAGGGCUU	578	AAGCCCUUUUCAGAGCCU	829	Rh	[719-736] ORF
249	ACAUCACUACCUGCAGUU	579	AACUGCAGGUAGUGAUGU	830		[544-561] ORF
250	AACCGCAGCGAGGAGUUU	580	AAACUCCUCGCUGCGGUU	831	Rh, Rb, Dg, Rt	[492-509] ORF
251	CAGCUCCUCCAAGGCUCU	581	AGAGCCUUGGAGGAGCUG	832	Rh	[708-725] ORF

TABLE A6
18-mer Cross-Species siTIMP1
		SEQ		SEQ
		ID		ID		human-73858576
No.	Sense (5′>3′)	NO.	Antisense (5′>3′)	NO.	Other Sp	ORF: 193-816
1	ACCUGGCAGUCCCUGCGG	833	CCGCAGGGACUGCCAGGU	839	Rh, Rb, Dg	[783-800] ORF
2	CAACCGCAGCGAGGAGUU	834	AACUCCUCGCUGCGGUUG	840	Rh, Rb, Dg, Rt	[491-508] ORF
3	AUGCACAGUGUUUCCCUG	835	CAGGGAAACACUGUGCAU	841	Rh, Rt, Ms	[638-655] ORF
4	GACCACCUUAUACCAGCG	836	CGCUGGUAUAAGGUGGUC	842	Rh, Rt, Ms	[353-370] ORF
5	UUAUGAGAUCAAGAUGAC	837	GUCAUCUUGAUCUCAUAA	843	Rh, Dg, Rt	[371-388] ORF
6	UAUACCAGCGUUAUGAGA	838	UCUCAUAACGCUGGUAUA	844	Rh, Rt	[361-378] ORF

TABLE A7
Preferred 18 + A-mer siTIMP1
		SEQ		SEQ
		ID		ID		human-73858576
siTIMP1_pNo.	Sense (5′>3′)	NO.	Antisense (5′>3′)	NO.	length	ORF: 193-816
siTIMP1_p1	GCGUUAUGAGAUCAAGAUA	845	UAUCUUGAUCUCAUAACGC	926	18 + 1	[368-385] ORF
siTIMP1_p3	CAGACCACCUUAUACCAGA	846	UCUGGUAUAAGGUGGUCUG	927	18 + 1	[351-368] ORF
siTIMP1_p4	GCACAGUGUUUCCCUGUUA	847	UAACAGGGAAACACUGUGC	928	18 + 1	[640-657] ORF
siTIMP1_p5	CAGCGAGGAGUUUCUCAUA	848	UAUGAGAAACUCCUCGCUG	929	18 + 1	[497-514] ORF
siTIMP1_p7	AUACCAGCGUUAUGAGAUA	849	UAUCUCAUAACGCUGGUAU	930	18 + 1	[362-379] ORF
siTIMP1_p8	UGCACAGUGUUUCCCUGUA	850	UACAGGGAAACACUGUGCA	931	18 + 1	[639-656] ORF
siTIMP1_p9	CACCUUAUACCAGCGUUAA	851	UUAACGCUGGUAUAAGGUG	932	18 + 1	[356-373] ORF
siTIMP1_p10	ACCUUAUACCAGCGUUAUA	852	UAUAACGCUGGUAUAAGGU	933	18 + 1	[357-374] ORF
siTIMP1_p11	CUUAUACCAGCGUUAUGAA	853	UUCAUAACGCUGGUAUAAG	934	18 + 1	[359-376] ORF
siTIMP1_p12	CCGCAGCGAGGAGUUUCUA	854	UAGAAACUCCUCGCUGCGG	935	18 + 1	[494-511] ORF
siTIMP1_p13	ACCGCAGCGAGGAGUUUCA	855	UGAAACUCCUCGCUGCGGU	936	18 + 1	[493-510] ORF
siTIMP1_p15	ACCACCUUAUACCAGCGUA	856	UACGCUGGUAUAAGGUGGU	937	18 + 1	[354-371] ORF
siTIMP1_p18	AACCGCAGCGAGGAGUUUA	857	UAAACUCCUCGCUGCGGUU	938	18 + 1	[492-509] ORF
siTIMP1_p22	UAUACCAGCGUUAUGAGAA	858	UUCUCAUAACGCUGGUAUA	939	18 + 1	[361-378] ORF
siTIMP1_p25	AGAUCAAGAUGACCAAGAA	859	UUCUUGGUCAUCUUGAUCU	940	18 + 1	[376-393] ORF
siTIMP1_p26	CCUGCAAACUGCAGAGUGA	860	UCACUCUGCAGUUUGCAGG	941	18 + 1	[667-684] ORF
siTIMP1_p28	CCCUGCAAACUGCAGAGUA	861	UACUCUGCAGUUUGCAGGG	942	18 + 1	[666-683] ORF
siTIMP1_p30	GAUCAAGAUGACCAAGAUA	862	UAUCUUGGUCAUCUUGAUC	943	18 + 1	[377-394] ORF
siTIMP1_p32	GUCAUCAGGGCCAAGUUCA	863	UGAACUUGGCCCUGAUGAC	944	18 + 1	[312-329] ORF
siTIMP1_p34	CCUGCACCUGUGUCCCACA	864	UGUGGGACACAGGUGCAGG	945	18 + 1	[259-276] ORF
siTIMP1_p35	GGGCUUCACCAAGACCUAA	865	UUAGGUCUUGGUGAAGCCC	946	18 + 1	[602-619] ORF
siTIMP1_p36	CGUCAUCAGGGCCAAGUUA	866	UAACUUGGCCCUGAUGACG	947	18 + 1	[311-328] ORF
siTIMP1_p37	CACUCAUUGCUUGUGGACA	867	UGUCCACAAGCAAUGAGUG	948	18 + 1	[686-703] ORF
siTIMP1_p39	CAGUGUUUCCCUGUUUAUA	868	UAUAAACAGGGAAACACUG	949	18 + 1	[643-660] ORF
siTIMP1_p40	ACAGUGUUUCCCUGUUUAA	869	UUAAACAGGGAAACACUGU	950	18 + 1	[642-659] ORF
siTIMP1_p41	AGUGUUUCCCUGUUUAUCA	870	UGAUAAACAGGGAAACACU	951	18 + 1	[644-661] ORF
siTIMP1_p44	CAUCUUUCUUCCGGACAAA	871	UUUGUCCGGAAGAAAGAUG	952	18 + 1	[871-888] 3′UTR
siTIMP1_p46	CCAGAUAGCCUGAAUCCUA	872	UAGGAUUCAGGCUAUCUGG	953	18 + 1	[803-820]
						ORF + 3′UTR
siTIMP1_p47	GGUCCCAGAUAGCCUGAAA	873	UUUCAGGCUAUCUGGGACC	954	18 + 1	[799-816] ORF
siTIMP1_p48	GGAGAGUGUCUGCGGAUAA	874	UUAUCCGCAGACACUCUCC	955	18 + 1	[458-475] ORF
siTIMP1_p50	CCGCCAUGGAGAGUGUCUA	875	UAGACACUCUCCAUGGCGG	956	18 + 1	[458-475] ORF
siTIMP1_p51	GAGUGUCUGCGGAUACUUA	876	UAAGUAUCCGCAGACACUC	957	18 + 1	[458-475] ORF
siTIMP1_p52	GAGUGGCACUCAUUGCUUA	877	UAAGCAAUGAGUGCCACUC	958	18 + 1	[680-697] ORF
siTIMP1_p53	GAGUGGAAGCUGAAGCCUA	878	UAGGCUUCAGCUUCCACUC	959	18 + 1	[826-843] 3′UTR
siTIMP1_p54	CCCUGUUCCCACUCCCAUA	879	UAUGGGAGUGGGAACAGGG	960	18 + 1	[856-873] 3′UTR
siTIMP1_p55	GCGGAUACUUCCACAGGUA	880	UACCUGUGGAAGUAUCCGC	961	18 + 1	[469-486] ORF
siTIMP1_p56	GAGAGUGUCUGCGGAUACA	881	UGUAUCCGCAGACACUCUC	962	18 + 1	[459-476] ORF
siTIMP1_p57	GGAACAGCCUGAGCUUAGA	882	UCUAAGCUCAGGCUGUUCC	963	18 + 1	[574-591] ORF
siTIMP1_p58	CAACCAGACCACCUUAUAA	883	UUAUAAGGUGGUCUGGUUG	964	18 + 1	[347-364] ORF
siTIMP1_p59	GAGGAAUGCACAGUGUUUA	884	UAAACACUGUGCAUUCCUC	965	18 + 1	[633-650] ORF
siTIMP1_p61	CCAAGAUGUAUAAAGGGUA	885	UACCCUUUAUACAUCUUGG	966	18 + 1	[388-405] ORF
siTIMP1_p62	CACCAGAAGUCAACCAGAA	886	UUCUGGUUGACUUCUGGUG	967	18 + 1	[337-354] ORF
siTIMP1_p63	CAGAAGUCAACCAGACCAA	887	UUGGUCUGGUUGACUUCUG	968	18 + 1	[340-357] ORF
siTIMP1_p64	CCCACUCCCAUCUUUCUUA	888	UAAGAAAGAUGGGAGUGGG	969	18 + 1	[863-880] 3′UTR
siTIMP1_p65	GCGAGGAGUUUCUCAUUGA	889	UCAAUGAGAAACUCCUCGC	970	18 + 1	[499-516] ORF
siTIMP1_p66	CUGCAGAGUGGCACUCAUA	890	UAUGAGUGCCACUCUGCAG	971	18 + 1	[675-692] ORF
siTIMP1_p67	GAAGCUGAAGCCUGCACAA	891	UUGUGCAGGCUUCAGCUUC	972	18 + 1	[831-848] 3′UTR
siTIMP1_p68	CCUGGAACAGCCUGAGCUA	892	UAGCUCAGGCUGUUCCAGG	973	18 + 1	[571-588] ORF
siTIMP1_p69	GCAUCCUGUUGUUGCUGUA	893	UACAGCAACAACAGGAUGC	974	18 + 1	[220-237] ORF
siTIMP1_p70	GUCCCAGAUAGCCUGAAUA	894	UAUUCAGGCUAUCUGGGAC	975	18 + 1	[800-817]
						ORF + 3′UTR
siTIMP1_p72	GGCUGUGAGGAAUGCACAA	895	UUGUGCAUUCCUCACAGCC	976	18 + 1	[627-644] ORF
siTIMP1_p74	GGCCUUCUGCAAUUCCGAA	896	UUCGGAAUUGCAGAAGGCC	977	18 + 1	[290-307] ORF
siTIMP1_p75	GCAGAGUGGCACUCAUUGA	897	UCAAUGAGUGCCACUCUGC	978	18 + 1	[677-694] ORF
siTIMP1_p76	CAGAUAGCCUGAAUCCUGA	898	UCAGGAUUCAGGCUAUCUG	979	18 + 1	[804-821]
						ORF + 3′UTR
siTIMP1_p80	CCGGAGUGGAAGCUGAAGA	899	UCUUCAGCUUCCACUCCGG	980	18 + 1	[823-840] 3′UTR
siTIMP1_p81	GGCUGUGCACCUGGCAGUA	900	UACUGCCAGGUGCACAGCC	981	18 + 1	[775-792] ORF
siTIMP1_p82	GUCAACCAGACCACCUUAA	901	UUAAGGUGGUCUGGUUGAC	982	18 + 1	[345-362] ORF
siTIMP1_p83	CCAUGGAGAGUGUCUGCGA	902	UCGCAGACACUCUCCAUGG	983	18 + 1	[454-471] ORF
siTIMP1_p84	CUGGCAUCCUGUUGUUGCA	903	UGCAACAACAGGAUGCCAG	984	18 + 1	[217-234] ORF
siTIMP1_p86	ACUGCAGAGUGGCACUCAA	904	UUGAGUGCCACUCUGCAGU	985	18 + 1	[674-691] ORF
siTIMP1_p87	CGGAGUGGAAGCUGAAGCA	905	UGCUUCAGCUUCCACUCCG	986	18 + 1	[824-841] 3′UTR
siTIMP1_p88	CCAGACCACCUUAUACCAA	906	UUGGUAUAAGGUGGUCUGG	987	18 + 1	[350-367] ORF
siTIMP1_p90	GCUGGAAAACUGCAGGAUA	907	UAUCCUGCAGUUUUCCAGC	988	18 + 1	[516-533] ORF
siTIMP1_p92	CCUGAAUCCUGCCCGGAGA	908	UCUCCGGGCAGGAUUCAGG	989	18 + 1	[811-828]
						ORF + 3′UTR
siTIMP1_p93	CUGAAGCCUGCACAGUGUA	909	UACACUGUGCAGGCUUCAG	990	18 + 1	[835-852] 3′UTR
siTIMP1_p94	CUGGAAAACUGCAGGAUGA	910	UCAUCCUGCAGUUUUCCAG	991	18 + 1	[517-534] ORF
siTIMP1_p95	UCUCAUUGCUGGAAAACUA	911	UAGUUUUCCAGCAAUGAGA	992	18 + 1	[509-526] ORF
siTIMP1_p97	AGACCUACACUGUUGGCUA	912	UAGCCAACAGUGUAGGUCU	993	18 + 1	[613-630] ORF
siTIMP1_p100	GGGACACCAGAAGUCAACA	913	UGUUGACUUCUGGUGUCCC	994	18 + 1	[333-350] ORF
siTIMP1_p101	GGCUCCCUGGAACAGCCUA	914	UAGGCUGUUCCAGGGAGCC	995	18 + 1	[566-583] ORF
siTIMP1_p102	GUUCCCACUCCCAUCUUUA	915	UAAAGAUGGGAGUGGGAAC	996	18 + 1	[860-877] 3′UTR
siTIMP1_p103	GGCUUCUGGCAUCCUGUUA	916	UAACAGGAUGCCAGAAGCC	997	18 + 1	[212-229] ORF
siTIMP1_p104	CUUCUGGCAUCCUGUUGUA	917	UACAACAGGAUGCCAGAAG	998	18 + 1	[214-231] ORF
siTIMP1_p105	AGAGUGUCUGCGGAUACUA	918	UAGUAUCCGCAGACACUCU	999	18 + 1	[460-477] ORF
siTIMP1_p106	CACCAAGACCUACACUGUA	919	UACAGUGUAGGUCUUGGUG	1000	18 + 1	[608-625] ORF
siTIMP1_p109	GGGAGCCAGGGCUGUGCAA	920	UUGCACAGCCCUGGCUCCC	1001	18 + 1	[766-783] ORF
siTIMP1_p110	UGCAGAGUGGCACUCAUUA	921	UAAUGAGUGCCACUCUGCA	1002	18 + 1	[676-693] ORF
siTIMP1_p111	GUGAGGAAUGCACAGUGUA	922	UACACUGUGCAUUCCUCAC	1003	18 + 1	[631-648] ORF
siTIMP1_p112	AGCGAGGAGUUUCUCAUUA	923	UAAUGAGAAACUCCUCGCU	1004	18 + 1	[498-515] ORF
siTIMP1_p113	GGGCUGUGCACCUGGCAGA	924	UCUGCCAGGUGCACAGCCC	1005	18 + 1	[774-791] ORF
siTIMP1_p114	UGUUGUUGCUGUGGCUGAA	925	UUCAGCCACAGCAACAACA	1006	18 + 1	[226-243] ORF

TABLE A8
18 + 1-mer siTIMP1 with lowest predicted Off Target (OT) effect
			SEQ		SEQ
			ID		ID	No. in Table
Cross species	Ranking	Sense (5′ > 3′)	NO.	Antisense (5′ > 3′)	NO.	A7
H/Rt	2	GCGUUAUGAGAUCAAGAUA	845	UAUCUUGAUCUCAUAACGC	926	siTIMP1_p1
H/Rt	3	GCACAGUGUUUCCCUGUUA	847	UAACAGGGAAACACUGUGC	928	siTIMP1_p4
H/Rt	3	CAGCGAGGAGUUUCUCAUA	848	UAUGAGAAACUCCUCGCUG	929	siTIMP1_p5
H/Rt	2	AUACCAGCGUUAUGAGAUA	849	UAUCUCAUAACGCUGGUAU	930	siTIMP1_p7
H/Rt	4	UGCACAGUGUUUCCCUGUA	850	UACAGGGAAACACUGUGCA	931	siTIMP1_p8
H/Rt	1	CACCUUAUACCAGCGUUAA	851	UUAACGCUGGUAUAAGGUG	932	siTIMP1_p9
H/Rt	1	ACCUUAUACCAGCGUUAUA	852	UAUAACGCUGGUAUAAGGU	933	siTIMP1_p10
H/Rt	1	CUUAUACCAGCGUUAUGAA	853	UUCAUAACGCUGGUAUAAG	934	siTIMP1_p11
H/Rt	2	CCGCAGCGAGGAGUUUCUA	854	UAGAAACUCCUCGCUGCGG	935	siTIMP1_p12
H/Rt	3	ACCGCAGCGAGGAGUUUCA	855	UGAAACUCCUCGCUGCGGU	936	siTIMP1_p13
H/Rt	2	ACCACCUUAUACCAGCGUA	856	UACGCUGGUAUAAGGUGGU	937	siTIMP1_p15
H/Rt	2	AACCGCAGCGAGGAGUUUA	857	UAAACUCCUCGCUGCGGUU	938	siTIMP1_p18
H/Rt	2	UAUACCAGCGUUAUGAGAA	858	UUCUCAUAACGCUGGUAUA	939	siTIMP1_p22
Other (w/o Rt)	4	CCUGCAAACUGCAGAGUGA	860	UCACUCUGCAGUUUGCAGG	941	siTIMP1_p26
Other (w/o Rt)	4	CGUCAUCAGGGCCAAGUUA	866	UAACUUGGCCCUGAUGACG	947	siTIMP1_p36
H/Rt (Rt with	1	CACUCAUUGCUUGUGGACA	867	UGUCCACAAGCAAUGAGUG	948	siTIMP1_p37
1MM)
Other (w/o Rt)	3	CAGUGUUUCCCUGUUUAUA	868	UAUAAACAGGGAAACACUG	949	siTIMP1_p39
Other (w/o Rt)	3	ACAGUGUUUCCCUGUUUAA	869	UUAAACAGGGAAACACUGU	950	siTIMP1_p40
Other (w/o Rt)	2	AGUGUUUCCCUGUUUAUCA	870	UGAUAAACAGGGAAACACU	951	siTIMP1_p41
H +/− Rh	2	CAUCUUUCUUCCGGACAAA	871	UUUGUCCGGAAGAAAGAUG	952	siTIMP1_p44
H +/− Rh	3	GGUCCCAGAUAGCCUGAAA	873	UUUCAGGCUAUCUGGGACC	954	siTIMP1_p47
H +/− Rh	2	GGAGAGUGUCUGCGGAUAA	874	UUAUCCGCAGACACUCUCC	955	siTIMP1_p48
H +/− Rh	3	CCGCCAUGGAGAGUGUCUA	875	UAGACACUCUCCAUGGCGG	956	siTIMP1_p50
H +/− Rh	3	GAGUGUCUGCGGAUACUUA	876	UAAGUAUCCGCAGACACUC	957	siTIMP1_p51
H +/− Rh	3	GAGUGGCACUCAUUGCUUA	877	UAAGCAAUGAGUGCCACUC	958	siTIMP1_p52
H +/− Rh	2	GCGGAUACUUCCACAGGUA	880	UACCUGUGGAAGUAUCCGC	961	siTIMP1_p55
H +/− Rh	2	GAGAGUGUCUGCGGAUACA	881	UGUAUCCGCAGACACUCUC	962	siTIMP1_p56
H +/− Rh	3	CAACCAGACCACCUUAUAA	883	UUAUAAGGUGGUCUGGUUG	964	siTIMP1_p58
H +/− Rh	3	CCAAGAUGUAUAAAGGGUA	885	UACCCUUUAUACAUCUUGG	966	siTIMP1_p61
H +/− Rh	4	CCCACUCCCAUCUUUCUUA	888	UAAGAAAGAUGGGAGUGGG	969	siTIMP1_p64
H +/− Rh	3	CUGCAGAGUGGCACUCAUA	890	UAUGAGUGCCACUCUGCAG	971	siTIMP1_p66
H +/− Rh	4	CCUGGAACAGCCUGAGCUA	892	UAGCUCAGGCUGUUCCAGG	973	siTIMP1_p68
H +/− Rh	3	GUCCCAGAUAGCCUGAAUA	894	UAUUCAGGCUAUCUGGGAC	975	siTIMP1_p70
H +/− Rh	4	GCAGAGUGGCACUCAUUGA	897	UCAAUGAGUGCCACUCUGC	978	siTIMP1_p75
H +/− Rh	3	CCAUGGAGAGUGUCUGCGA	903	UCGCAGACACUCUCCAUGG	983	siTIMP1_p83
H +/− Rh	4	ACUGCAGAGUGGCACUCAA	904	UUGAGUGCCACUCUGCAGU	985	siTIMP1_p86
H +/− Rh	2	CCAGACCACCUUAUACCAA	906	UUGGUAUAAGGUGGUCUGG	987	siTIMP1_p88
H +/− Rh	4	CCUGAAUCCUGCCCGGAGA	908	UCUCCGGGCAGGAUUCAGG	989	siTIMP1_p92
H +/− Rh	3	CUGAAGCCUGCACAGUGUA	909	UACACUGUGCAGGCUUCAG	990	siTIMP1_p93
H +/− Rh	4	UCUCAUUGCUGGAAAACUA	911	UAGUUUUCCAGCAAUGAGA	992	siTIMP1_p95
H +/− Rh	2	AGACCUACACUGUUGGCUA	912	UAGCCAACAGUGUAGGUCU	993	siTIMP1_p97
H +/− Rh	4	GUUCCCACUCCCAUCUUUA	915	UAAAGAUGGGAGUGGGAAC	996	siTIMP1_p102
H +/− Rh	4	CUUCUGGCAUCCUGUUGUA	917	UACAACAGGAUGCCAGAAG	998	siTIMP1_p104
H +/− Rh	2	AGAGUGUCUGCGGAUACUA	918	UAGUAUCCGCAGACACUCU	999	siTIMP1_p105
H +/− Rh	3	CACCAAGACCUACACUGUA	919	UACAGUGUAGGUCUUGGUG	1000	siTIMP1_p106
H +/− Rh	2	UGCAGAGUGGCACUCAUUA	921	UAAUGAGUGCCACUCUGCA	1002	siTIMP1_p110
H +/− Rh	4	AGCGAGGAGUUUCUCAUUA	923	UAAUGAGAAACUCCUCGCU	1004	siTIMP1_p112

TIMP2—TIMP Metallopeptidase Inhibitor 2

TABLE B1
siTIMP2 19-mers
	SEQ		SEQ
	ID		ID		human-73858577
Sense (5′ > 3′)	NO:	Antisense (5′ > 3′)	NO:	Other Sp	ORF: 303-965
GGAAGAACUUUCUCGGUAA	1007	UUACCGAGAAAGUUCUUCC	1622	Rh	[2332-2350] 3′UTR
GGUUCUCCAGUUCAAAUUA	1008	UAAUUUGAACUGGAGAACC	1623		[3062-3080] 3′UTR
CUGUGUUUAUGCUGGAAUA	1009	UAUUCCAGCAUAAACACAG	1624		[3495-3513] 3′UTR
CCUGUAUGGUGAUAUCAUA	1010	UAUGAUAUCACCAUACAGG	1625		[2789-2807] 3′UTR
GGCACAUUAUGUAAACAUA	1011	UAUGUUUACAUAAUGUGCC	1626	Rh	[2412-2430] 3′UTR
GGUGAAUUCUCAGAUGAUA	1012	UAUCAUCUGAGAAUUCACC	1627		[2165-2183] 3′UTR
CCAUGUGAUUUCAGUAUAU	1013	AUAUACUGAAAUCACAUGG	1628	Rh	[2718-2736] 3′UTR
CUCUGAGCCUUGUAGAAAU	1014	AUUUCUACAAGGCUCAGAG	1629	Rh	[1606-1624] 3′UTR
GGCUGCGAGUGCAAGAUCA	1015	UGAUCUUGCACUCGCAGCC	1630	Ck, Rb, Rt	[752-770] ORF
AGAGGAAGCCGCUCAAAUA	1016	UAUUUGAGCGGCUUCCUCU	1631		[3214-3232] 3′UTR
CUUUGGUUCUCCAGUUCAA	1017	UUGAACUGGAGAACCAAAG	1632		[3058-3076] 3′UTR
CAGUAUGAGAUCAAGCAGA	1018	UCUGCUUGAUCUCAUACUG	1633	Rh, Rb, Cw, Dg, Ms	[509-527] ORF
CUUGCAAAAUGCUUCCAAA	1019	UUUGGAAGCAUUUUGCAAG	1634		[2471-2489] 3′UTR
CUUGGUAGGUAUUAGACUU	1020	AAGUCUAAUACCUACCAAG	1635		[2906-2924] 3′UTR
CCCUCUGAGCCUUGUAGAA	1021	UUCUACAAGGCUCAGAGGG	1636	Rh	[1604-1622] 3′UTR
GGUAGGUAUUAGACUUGCA	1022	UGCAAGUCUAAUACCUACC	1637		[2909-2927] 3′UTR
GGGUCACAGAGAAGAACAU	1023	AUGUUCUUCUCUGUGACCC	1638	Rh	[831-849] ORF
GAACCUGAGUUGCAGAUAU	1024	AUAUCUGCAACUCAGGUUC	1639	Rh	[2187-2205] 3′UTR
GGAUUGAGUUGCACAGCUU	1025	AAGCUGUGCAACUCAAUCC	1640		[1853-1871] 3′UTR
GGUGAUAUCAUAUGUAACA	1026	UGUUACAUAUGAUAUCACC	1641	Rh	[2796-2814] 3′UTR
CCUGCAAGCAACUCAAAAU	1027	AUUUUGAGUUGCUUGCAGG	1642		[3343-3361] 3′UTR
GGAUAUAGAGUUUAUCUAC	1028	GUAGAUAAACUCUAUAUCC	1643		[553-571] ORF
GAUGCUUUGUAUCAUUCUU	1029	AAGAAUGAUACAAAGCAUC	1644		[3589-3607] 3′UTR
GCAAGCAACUCAAAAUAUU	1030	AAUAUUUUGAGUUGCUUGC	1645		[3346-3364] 3′UTR
CGUCUUUGGUUCUCCAGUU	1031	AACUGGAGAACCAAAGACG	1646		[3055-3073] 3′UTR
CCUUUAUAUUUGAUCCACA	1032	UGUGGAUCAAAUAUAAAGG	1647		[3127-3145] 3′UTR
GUGCUGAGCAGAAAACAAA	1033	UUUGUUUUCUGCUCAGCAC	1648		[3164-3182] 3′UTR
CCAACUUCUGCUUGUAUUU	1034	AAAUACAAGCAGAAGUUGG	1649	Rh	[2207-2225] 3′UTR
CCUAUUAAUCCUCAGAAUU	1035	AAUUCUGAGGAUUAAUAGG	1650	Rh	[1572-1590] 3′UTR
CGGUAAUGAUAAGGAGAAU	1036	AUUCUCCUUAUCAUUACCG	1651		[2345-2363] 3′UTR
CGCUCAAAUACCUUCACAA	1037	UUGUGAAGGUAUUUGAGCG	1652		[3223-3241] 3′UTR
GGGCAGACUGGGAGGGUAU	1038	AUACCCUCCCAGUCUGCCC	1653	Rh	[2619-2637] 3′UTR
UGCUGAGCAGAAAACAAAA	1039	UUUUGUUUUCUGCUCAGCA	1654		[3165-3183] 3′UTR
AGCGGUCAGUGAGAAGGAA	1040	UUCCUUCUCACUGACCGCU	1655		[445-463] ORF
GGUAUUAGACUUGCACUUU	1041	AAAGUGCAAGUCUAAUACC	1656		[2913-2931] 3′UTR
GCUGGAAUAUGAAGUCUGA	1042	UCAGACUUCAUAUUCCAGC	1657	Ms	[3505-3523] 3′UTR
CCUGUGUUGUAAAGAUAAA	1043	UUUAUCUUUACAACACAGG	1658	Rh	[2380-2398] 3′UTR
GGUAAGAUGUCAUAAUGGA	1044	UCCAUUAUGACAUCUUACC	1659	Rh	[2694-2712] 3′UTR
GUGGUUUCCUGAAGCCAGU	1045	ACUGGCUUCAGGAAACCAC	1660		[2295-2313] 3′UTR
GGGUCCAAAUUAAUAUGAU	1046	AUCAUAUUAAUUUGGACCC	1661		[1077-1095] 3′UTR
GGAACACACAAGAGUUGUU	1047	AACAACUCUUGUGUGUUCC	1662		[3539-3557] 3′UTR
AGAUUACCUAGCUAAGAAA	1048	UUUCUUAGCUAGGUAAUCU	1663		[2238-2256] 3′UTR
CUGGGAACACACAAGAGUU	1049	AACUCUUGUGUGUUCCCAG	1664		[3536-3554] 3′UTR
UCCCAUGGGUCCAAAUUAA	1050	UUAAUUUGGACCCAUGGGA	1665		[1071-1089] 3′UTR
GUUCUCCAGUUCAAAUUAU	1051	AUAAUUUGAACUGGAGAAC	1666		[3063-3081] 3′UTR
CCAUGGGUCCAAAUUAAUA	1052	UAUUAAUUUGGACCCAUGG	1667		[1073-1091] 3′UTR
UGGGCGUGGUCUUGCAAAA	1053	UUUUGCAAGACCACGCCCA	1668		[2461-2479] 3′UTR
CGUGCUGAGCAGAAAACAA	1054	UUGUUUUCUGCUCAGCACG	1669		[3163-3181] 3′UTR
CGGUCAGUGAGAAGGAAGU	1055	ACUUCCUUCUCACUGACCG	1670		[447-465] ORF
CGAUAUACAGGCACAUUAU	1056	AUAAUGUGCCUGUAUAUCG	1671		[2403-2421] 3′UTR
GCAUUUUGCAGAAACUUUU	1057	AAAAGUUUCUGCAAAAUGC	1672	Rh	[1334-1352] 3′UTR
GGACCAGUCCAUGUGAUUU	1058	AAAUCACAUGGACUGGUCC	1673	Rh	[2710-2728] 3′UTR
GCUCAAAUACCUUCACAAU	1059	AUUGUGAAGGUAUUUGAGC	1674		[3224-3242] 3′UTR
CACCUUAGCCUGUUCUAUU	1060	AAUAGAACAGGCUAAGGUG	1675	Rh	[2492-2510] 3′UTR
GGAUCUCCCAGCUGGGUUA	1061	UAACCCAGCUGGGAGAUCC	1676		[1296-1314] 3′UTR
GUAUUAGACUUGCACUUUU	1062	AAAAGUGCAAGUCUAAUAC	1677		[2914-2932] 3′UTR
AGAGGAUCCAGUAUGAGAU	1063	AUCUCAUACUGGAUCCUCU	1678	Rh, Rb	[501-519] ORF
GAACCUAUGUGUUCCCUCA	1064	UGAGGGAACACAUAGGUUC	1679		[2274-2292] 3′UTR
CUGAGUUGCAGAUAUACCA	1065	UGGUAUAUCUGCAACUCAG	1680	Rh	[2191-2209] 3′UTR
CUCAAAUACCUUCACAAUA	1066	UAUUGUGAAGGUAUUUGAG	1681		[3225-3243] 3′UTR
UCCUAUUAAUCCUCAGAAU	1067	AUUCUGAGGAUUAAUAGGA	1682	Rh	[1571-1589] 3′UTR
CCAGUUCAAAUUAUUGCAA	1068	UUGCAAUAAUUUGAACUGG	1683		[3068-3086] 3′UTR
UGUUUAUGCUGGAAUAUGA	1069	UCAUAUUCCAGCAUAAACA	1684		[3498-3516] 3′UTR
GCACAGAUCUUGAUGACUU	1070	AAGUCAUCAAGAUCUGUGC	1685	Rh	[2591-2609] 3′UTR
AACCUGAGUUGCAGAUAUA	1071	UAUAUCUGCAACUCAGGUU	1686	Rh	[2188-2206] 3 ′UTR
CUGCAAGCAACUCAAAAUA	1072	UAUUUUGAGUUGCUUGCAG	1687		[3344-3362] 3′UTR
GGCUUUGGUGACACACUCA	1073	UGAGUGUGUCACCAAAGCC	1688		[2086-2104] 3′UTR
GUUGCAAGACUGUGUAGCA	1074	UGCUACACAGUCUUGCAAC	1689	Rh	[1360-1378] 3′UTR
GACAUUUAUGGCAACCCUA	1075	UAGGGUUGCCAUAAAUGUC	1690		[479-497] ORF
GUAUGAGAUCAAGCAGAUA	1076	UAUCUGCUUGAUCUCAUAC	1691	Rh, Rb, Cw, Dg, Rt, Ms	[511-529] ORF
GACUUGCUGCCGUAAUUUA	1077	UAAAUUACGGCAGCAAGUC	1692		[3428-3446] 3′UTR
GAAAGAAGGAAUAUCUCAU	1078	AUGAGAUAUUCCUUCUUUC	1693		[618-636] ORF
GAGGAAAGAAGGAAUAUCU	1079	AGAUAUUCCUUCUUUCCUC	1694	Rt	[615-633] ORF
CGUGGACAAUAAACAGUAU	1080	AUACUGUUUAUUGUCCACG	1695		[3624-3642] 3 ′UTR
GGUGAACCUGAGUUGCAGA	1081	UCUGCAACUCAGGUUCACC	1696	Rh	[2184-2202] 3′UTR
CCUGCAUCAAGAGAAGUGA	1082	UCACUUCUCUUGAUGCAGG	1697	Rt, Ms	[876-894] ORF
AGUCCAUGUGAUUUCAGUA	1083	UACUGAAAUCACAUGGACU	1698	Rh	[2715-2733] 3′UTR
AGUAAAGGAUCUUUGAGUA	1084	UACUCAAAGAUCCUUUACU	1699		[3087-3105] 3′UTR
CCCAGAAGAAGAGCCUGAA	1085	UUCAGGCUCUUCUUCUGGG	1700	Rh, Cw, Ms, Pg	[717-735] ORF
GACAUCAGCUGUAAUCAUU	1086	AAUGAUUACAGCUGAUGUC	1701		[2864-2882] 3′UTR
CCUCAAAGACUGACAGCCA	1087	UGGCUGUCAGUCUUUGAGG	1702	Rh	[1980-1998] 3′UTR
CUCGGUCCGUGGACAAUAA	1088	UUAUUGUCCACGGACCGAG	1703		[3617-3635] 3′UTR
AGGGCAGCCUGGAACCAGU	1089	ACUGGUUCCAGGCUGCCCU	1704		[1525-1543] 3′UTR
CCGUGGACAAUAAACAGUA	1090	UACUGUUUAUUGUCCACGG	1705		[3623-3641] 3′UTR
GAAACGACAUUUAUGGCAA	1091	UUGCCAUAAAUGUCGUUUC	1706		[474-492] ORF
CCUCAGAAUUCCAGUGGGA	1092	UCCCACUGGAAUUCUGAGG	1707	Rh	[1581-1599] 3′UTR
GUCACAGAGAAGAACAUCA	1093	UGAUGUUCUUCUCUGUGAC	1708	Rh	[833-851] ORF
CCAGUGGCUAGUUCUUGAA	1094	UUCAAGAACUAGCCACUGG	1709		[1539-1557] 3′UTR
GGAACCAGUGGCUAGUUCU	1095	AGAACUAGCCACUGGUUCC	1710		[1535-1553] 3′UTR
UCCAUGUGAUUUCAGUAUA	1096	UAUACUGAAAUCACAUGGA	1711	Rh	[2717-2735] 3′UTR
AGGUAUUAGACUUGCACUU	1097	AAGUGCAAGUCUAAUACCU	1712		[2912-2930] 3′UTR
CAUUUGACCCAGAGUGGAA	1098	UUCCACUCUGGGUCAAAUG	1713		[2961-2979] 3′UTR
GCACCUGGAUUGAGUUGCA	1099	UGCAACUCAAUCCAGGUGC	1714		[1847-1865] 3′UTR
AGUUGUUGAAAGUUGACAA	1100	UUGUCAACUUUCAACAACU	1715		[3551-3569] 3′UTR
GUGGCCAACUGCAAAAAAA	1101	UUUUUUUGCAGUUGGCCAC	1716		[984-1002] 3′UTR
CUCAAAGACUGACAGCCAU	1102	AUGGCUGUCAGUCUUUGAG	1717	Rh	[1981-1999] 3′UTR
GCCUCAGCUGAGUCUUUUU	1103	AAAAAGACUCAGCUGAGGC	1718	Rh	[1658-1676] 3′UTR
UGCUUUGUAUCAUUCUUGA	1104	UCAAGAAUGAUACAAAGCA	1719		[3591-3609] 3′UTR
GUUUAAGAAGGCUCUCCAU	1105	AUGGAGAGCCUUCUUAAAC	1720		[3265-3283] 3′UTR
CCAGCUAAGCAUAGUAAGA	1106	UCUUACUAUGCUUAGCUGG	1721		[2030-2048] 3′UTR
GUUGGUAAGAUGUCAUAAU	1107	AUUAUGACAUCUUACCAAC	1722	Rh	[2691-2709] 3′UTR
CACCUGUGUUGUAAAGAUA	1108	UAUCUUUACAACACAGGUG	1723	Rh	[2378-2396] 3′UTR
CAGCCUCAGCUGAGUCUUU	1109	AAAGACUCAGCUGAGGCUG	1724	Rh	[1656-1674] 3′UTR
AUGAGAUCAAGCAGAUAAA	1110	UUUAUCUGCUUGAUCUCAU	1725	Rh, Cw, Dg, Rt, Ms	[513-531] ORF
GUUGCACAGCUUUGCUUUA	1111	UAAAGCAAAGCUGUGCAAC	1726		[1860-1878] 3′UTR
GUGGCUAGUUCUUGAAGGA	1112	UCCUUCAAGAACUAGCCAC	1727		[1542-1560] 3′UTR
GAUUGAGUUGCACAGCUUU	1113	AAAGCUGUGCAACUCAAUC	1728		[1854-1872] 3′UTR
GGAUCUUUGAGUAGGUUCG	1114	CGAACCUACUCAAAGAUCC	1729		[3093-3111] 3′UTR
CGCUGGACGUUGGAGGAAA	1115	UUUCCUCCAACGUCCAGCG	1730	Rt, Ms	[603-621] ORF
CACACACGUUGGUCUUUUA	1116	UAAAAGACCAACGUGUGUG	1731		[3142-3160] 3′UTR
CUCAGUGUGGUUUCCUGAA	1117	UUCAGGAAACCACACUGAG	1732		[2289-2307] 3′UTR
AUGUUAUGUUCUAAGCACA	1118	UGUGCUUAGAACAUAACAU	1733		[3303-3321] 3′UTR
GCCACCUUAGCCUGUUCUA	1119	UAGAACAGGCUAAGGUGGC	1734	Rh	[2490-2508] 3′UTR
AAGAGUUGUUGAAAGUUGA	1120	UCAACUUUCAACAACUCUU	1735		[3548-3566] 3′UTR
CCUGAGAAGGAUAUAGAGU	1121	ACUCUAUAUCCUUCUCAGG	1736		[545-563] ORF
ACCAGUGGCUAGUUCUUGA	1122	UCAAGAACUAGCCACUGGU	1737		[1538-1556] 3′UTR
CAUCCUGCAAGCAACUCAA	1123	UUGAGUUGCUUGCAGGAUG	1738		[3340-3358] 3′UTR
GUAAUGAUAAGGAGAAUCU	1124	AGAUUCUCCUUAUCAUUAC	1739		[2347-2365] 3′UTR
GGAAUAUCUCAUUGCAGGA	1125	UCCUGCAAUGAGAUAUUCC	1740		[625-643] ORF
GGGCGUGGUCUUGCAAAAU	1126	AUUUUGCAAGACCACGCCC	1741		[2462-2480] 3′UTR
CAUCCUGAGGACAGAAAAA	1127	UUUUUCUGUCCUCAGGAUG	1742	Rh	[1921-1939] 3′UTR
UGGACUUGCUGCCGUAAUU	1128	AAUUACGGCAGCAAGUCCA	1743		[3426-3444] 3′UTR
GUGACACACUCACUUCUUU	1129	AAAGAAGUGAGUGUGUCAC	1744		[2093-2111] 3 ′UTR
CUGUUUUAAGAGACAUCUU	1130	AAGAUGUCUCUUAAAACAG	1745	Rh	[2135-2153] 3′UTR
GUUUAUGCUGGAAUAUGAA	1131	UUCAUAUUCCAGCAUAAAC	1746		[3499-3517] 3′UTR
GUCCAUGUGAUUUCAGUAU	1132	AUACUGAAAUCACAUGGAC	1747	Rh	[2716-2734] 3′UTR
AGGAGUUUCUCGACAUCGA	1133	UCGAUGUCGAGAAACUCCU	1748	Ck, Dg	[936-954] ORF
GAAGAACUUUCUCGGUAAU	1134	AUUACCGAGAAAGUUCUUC	1749	Rh	[2333-2351] 3′UTR
GGGUCUGGAGGGAGACGUG	1135	CACGUCUCCCUCCAGACCC	1750		[1130-1148] 3′UTR
GGAAGCCGCUCAAAUACCU	1136	AGGUAUUUGAGCGGCUUCC	1751		[3217-3235] 3′UTR
GGUCCGUGGACAAUAAACA	1137	UGUUUAUUGUCCACGGACC	1752		[3620-3638] 3′UTR
CCCUCCAACCCAUAUAACA	1138	UGUUAUAUGGGUUGGAGGG	1753		[2752-2770] 3′UTR
CCCAUGGGUCCAAAUUAAU	1139	AUUAAUUUGGACCCAUGGG	1754		[1072-1090] 3′UTR
CACACUCACUUCUUUCUCA	1140	UGAGAAAGAAGUGAGUGUG	1755		[2097-2115] 3′UTR
GCAGAAAACAAAACAGGUU	1141	AACCUGUUUUGUUUUCUGC	1756		[3171-3189] 3′UTR
CAUCAAUCCUAUUAAUCCU	1142	AGGAUUAAUAGGAUUGAUG	1757	Rh	[1565-1583] 3′UTR
CACAAUAAAUAGUGGCAAU	1143	AUUGCCACUAUUUAUUGUG	1758		[3237-3255] 3′UTR
GUUGGAGGAAAGAAGGAAU	1144	AUUCCUUCUUUCCUCCAAC	1759	Rt	[611-629] ORF
GGCCUUUAUAUUUGAUCCA	1145	UGGAUCAAAUAUAAAGGCC	1760		[3125-3143] 3′UTR
UGUUCAAAGGGCCUGAGAA	1146	UUCUCAGGCCCUUUGAACA	1761		[534-552] ORF
ACUGGGUCACAGAGAAGAA	1147	UUCUUCUCUGUGACCCAGU	1762	Rh, Rt, Ms	[828-846] ORF
GGUAAUGAUAAGGAGAAUC	1148	GAUUCUCCUUAUCAUUACC	1763		[2346-2364] 3′UTR
CACACAAGAGUUGUUGAAA	1149	UUUCAACAACUCUUGUGUG	1764		[3543-3561] 3′UTR
CUCUGGAUGGACUGGGUCA	1150	UGACCCAGUCCAUCCAGAG	1765	Rh, Rb, Cw, Dg, Rt, Ms,	[818-836] ORF
				Pg
GGAACUAGGGAACCUAUGU	1151	ACAUAGGUUCCCUAGUUCC	1766	Rh	[2265-2283] 3′UTR
CUCGGUAAUGAUAAGGAGA	1152	UCUCCUUAUCAUUACCGAG	1767		[2343-2361] 3′UTR
AGGUGAAUUCUCAGAUGAU	1153	AUCAUCUGAGAAUUCACCU	1768		[2164-2182] 3′UTR
UCGGUAAUGAUAAGGAGAA	1154	UUCUCCUUAUCAUUACCGA	1769		[2344-2362] 3′UTR
GCCAAAGCGGUCAGUGAGA	1155	UCUCACUGACCGCUUUGGC	1770		[440-458] ORF
GAACCAGUGGCUAGUUCUU	1156	AAGAACUAGCCACUGGUUC	1771		[1536-1554] 3′UTR
CCCUUCUCCUUUUAGACAU	1157	AUGUCUAAAAGGAGAAGGG	1772		[1105-1123] 3′UTR
CCACCUUAGCCUGUUCUAU	1158	AUAGAACAGGCUAAGGUGG	1773	Rh	[2491-2509] 3′UTR
CCCUGAGCACCACCCAGAA	1159	UUCUGGGUGGUGCUCAGGG	1774	Rh, Pg	[705-723] ORF
UGCUGUACAGUGACCUAAA	1160	UUUAGGUCACUGUACAGCA	1775		[2672-2690] 3′UTR
CCUUAGCCUGUUCUAUUCA	1161	UGAAUAGAACAGGCUAAGG	1776	Rh	[2494-2512] 3′UTR
GAACUUUCUCGGUAAUGAU	1162	AUCAUUACCGAGAAAGUUC	1777		[2336-2354] 3′UTR
CCUAGGAAGGGAAGGAUUU	1163	AAAUCCUUCCCUUCCUAGG	1778	Rh	[2056-2074] 3′UTR
UCAGUGAGAAGGAAGUGGA	1164	UCCACUUCCUUCUCACUGA	1779		[450-468] ORF
AUAUGAAGUCUGAGACCUU	1165	AAGGUCUCAGACUUCAUAU	1780		[3511-3529] 3′UTR
GGACUCUGGAAACGACAUU	1166	AAUGUCGUUUCCAGAGUCC	1781	Rh	[466-484] ORF
CCUCUGAGCCUUGUAGAAA	1167	UUUCUACAAGGCUCAGAGG	1782	Rh	[1605-1623] 3′UTR
AGUUUAAGAAGGCUCUCCA	1168	UGGAGAGCCUUCUUAAACU	1783		[3264-3282] 3′UTR
AGGGCAGACUGGGAGGGUA	1169	UACCCUCCCAGUCUGCCCU	1784	Rh	[2618-2636] 3′UTR
GUAGAAAUGGGAGCGAGAA	1170	UUCUCGCUCCCAUUUCUAC	1785		[1617-1635] 3′UTR
GGACUUGCUGCCGUAAUUU	1171	AAAUUACGGCAGCAAGUCC	1786		[3427-3445] 3′UTR
AGAACUUUCUCGGUAAUGA	1172	UCAUUACCGAGAAAGUUCU	1787		[2335-2353] 3′UTR
GUAUCAUUCUUGAGCAAUC	1173	GAUUGCUCAAGAAUGAUAC	1788		[3597-3615] 3′UTR
CAGCUAAGCAUAGUAAGAA	1174	UUCUUACUAUGCUUAGCUG	1789		[2031-2049] 3′UTR
GGCCUGUUUUAAGAGACAU	1175	AUGUCUCUUAAAACAGGCC	1790	Rh	[2132-2150] 3′UTR
GACUGGGUCACAGAGAAGA	1176	UCUUCUCUGUGACCCAGUC	1791	Rh, Rt, Ms	[827-845] ORF
CUCUGAUGCUUUGUAUCAU	1177	AUGAUACAAAGCAUCAGAG	1792		[3585-3603] 3′UTR
GUAACAUUUACUCCUGUUU	1178	AAACAGGAGUAAAUGUUAC	1793	Rh	[2809-2827] 3′UTR
UGAGUUGCAGAUAUACCAA	1179	UUGGUAUAUCUGCAACUCA	1794	Rh	[2192-2210] 3′UTR
AUCCCAUGGGUCCAAAUUA	1180	UAAUUUGGACCCAUGGGAU	1795		[1070-1088] 3′UTR
CUCUGGAAACGACAUUUAU	1181	AUAAAUGUCGUUUCCAGAG	1796	Rh	[469-487] ORF
GAUCCAGUAUGAGAUCAAG	1182	CUUGAUCUCAUACUGGAUC	1797	Rh, Rb	[505-523] ORF
AGGUGUGGCCUUUAUAUUU	1183	AAAUAUAAAGGCCACACCU	1798		[3119-3137] 3′UTR
CCCUGUUCGCUUCCUGUAU	1184	AUACAGGAAGCGAACAGGG	1799		[2777-2795] 3′UTR
GGGAGACGUGGGUCCAAGG	1185	CCUUGGACCCACGUCUCCC	1800		[1139-1157] 3′UTR
CAUGGGUCCAAAUUAAUAU	1186	AUAUUAAUUUGGACCCAUG	1801		[1074-1092] 3′UTR
UGGGUCACAGAGAAGAACA	1187	UGUUCUUCUCUGUGACCCA	1802	Rh	[830-848] ORF
CCUCAAGGUCCCUUCCCUA	1188	UAGGGAAGGGACCUUGAGG	1803		[1786-1804] 3′UTR
UGGUUCUCCAGUUCAAAUU	1189	AAUUUGAACUGGAGAACCA	1804		[3061-3079] 3′UTR
GGACCUGGUCAGCACAGAU	1190	AUCUGUGCUGACCAGGUCC	1805	Rh	[2580-2598] 3′UTR
GGAGGGAGACGUGGGUCCA	1191	UGGACCCACGUCUCCCUCC	1806		[1136-1154] 3′UTR
UCUGAUGCUUUGUAUCAUU	1192	AAUGAUACAAAGCAUCAGA	1807		[3586-3604] 3′UTR
GGGACAUGGCCCUUGUUUU	1193	AAAACAAGGGCCAUGUCCC	1808		[1407-1425] 3′UTR
GCCUGGGCGUGGUCUUGCA	1194	UGCAAGACCACGCCCAGGC	1809		[2458-2476] 3′UTR
GGCGUUUUGCAAUGCAGAU	1195	AUCUGCAUUGCAAAACGCC	1810	Cw, Rt, Ms	[409-427] ORF
GAGUAGGUUCGGUCUGAAA	1196	UUUCAGACCGAACCUACUC	1811		[3101-3119] 3′UTR
AGUUCUUCGCCUGCAUCAA	1197	UUGAUGCAGGCGAAGAACU	1812	Rh, Rb, Cw, Dg, Ms	[867-885] ORF
ACAAAGAUUACCUAGCUAA	1198	UUAGCUAGGUAAUCUUUGU	1813		[2234-2252] 3′UTR
GAGGGAGACGUGGGUCCAA	1199	UUGGACCCACGUCUCCCUC	1814		[1137-1155] 3′UTR
CUGUUUCUGCUGAUUGUUU	1200	AAACAAUCAGCAGAAACAG	1815		[2822-2840] 3′UTR
CUGACGAUAUACAGGCACA	1201	UGUGCCUGUAUAUCGUCAG	1816		[2399-2417] 3′UTR
UGUUGAAAGUUGACAAGCA	1202	UGCUUGUCAACUUUCAACA	1817		[3554-3572] 3′UTR
GCCUAGGAAGGGAAGGAUU	1203	AAUCCUUCCCUUCCUAGGC	1818	Rh	[2055-2073] 3′UTR
GGUGACACACUCACUUCUU	1204	AAGAAGUGAGUGUGUCACC	1819		[2092-2110] 3′UTR
GAGCCUUGUAGAAAUGGGA	1205	UCCCAUUUCUACAAGGCUC	1820	Rh	[1610-1628] 3′UTR
CAGAAAACAAAACAGGUUA	1206	UAACCUGUUUUGUUUUCUG	1821		[3172-3190] 3′UTR
CGCAUGUCUCUGAUGCUUU	1207	AAAGCAUCAGAGACAUGCG	1822		[3578-3596] 3′UTR
GACAAAGAUUACCUAGCUA	1208	UAGCUAGGUAAUCUUUGUC	1823		[2233-2251] 3′UTR
CUGUAUGGUGAUAUCAUAU	1209	AUAUGAUAUCACCAUACAG	1824		[2790-2808] 3′UTR
GACUCUGGAAACGACAUUU	1210	AAAUGUCGUUUCCAGAGUC	1825	Rh	[467-485] ORF
GGUUCGGUCUGAAAGGUGU	1211	ACACCUUUCAGACCGAACC	1826		[3106-3124] 3′UTR
AGAUGAUAGGUGAACCUGA	1212	UCAGGUUCACCUAUCAUCU	1827		[2176-2194] 3′UTR
GACACUAUGGCCUGUUUUA	1213	UAAAACAGGCCAUAGUGUC	1828		[2124-2142] 3′UTR
CUGCAAAAAAAGCCUCCAA	1214	UUGGAGGCUUUUUUUGCAG	1829		[992-1010] 3′UTR
CUGUUCUAUUCAGCGGCAA	1215	UUGCCGCUGAAUAGAACAG	1830		[2501-2519] 3′UTR
GUGGGUCCAAGGUCCUCAU	1216	AUGAGGACCUUGGACCCAC	1831		[1146-1164] 3′UTR
GCCUGAGAAGGAUAUAGAG	1217	CUCUAUAUCCUUCUCAGGC	1832		[544-562] ORF
GAAACUUCCUAGGGAACUA	1218	UAGUUCCCUAGGAAGUUUC	1833		[2253-2271] 3′UTR
CGCCAGCUAAGCAUAGUAA	1219	UUACUAUGCUUAGCUGGCG	1834		[2028-2046] 3′UTR
GCCUCUGGAUGGACUGGGU	1220	ACCCAGUCCAUCCAGAGGC	1835	Rh, Rb, Cw, Dg, Rt, Ms	[816-834] ORF
ACGAUAUACAGGCACAUUA	1221	UAAUGUGCCUGUAUAUCGU	1836		[2402-2420] 3′UTR
AGCACCACCCAGAAGAAGA	1222	UCUUCUUCUGGGUGGUGCU	1837	Rh, Pg	[710-728] ORF
CCUCCCUCAAAGACUGACA	1223	UGUCAGUCUUUGAGGGAGG	1838	Rh	[1976-1994] 3′UTR
GGAGCACUGUGUUUAUGCU	1224	AGCAUAAACACAGUGCUCC	1839		[3489-3507] 3′UTR
ACUUGCUGCCGUAAUUUAA	1225	UUAAAUUACGGCAGCAAGU	1840		[3429-3447] 3′UTR
GGUUUCCUGAAGCCAGUGA	1226	UCACUGGCUUCAGGAAACC	1841		[2297-2315] 3′UTR
GGUCAGUGAGAAGGAAGUG	1227	CACUUCCUUCUCACUGACC	1842		[448-466] ORF
GUGACGCCAGCUAAGCAUA	1228	UAUGCUUAGCUGGCGUCAC	1843		[2024-2042] 3′UTR
AUGAUAAGGAGAAUCUCUU	1229	AAGAGAUUCUCCUUAUCAU	1844		[2350-2368] 3′UTR
UAGUGUUCCCUCCCUCAAA	1230	UUUGAGGGAGGGAACACUA	1845		[1968-1986] 3′UTR
GGAGACGUGGGUCCAAGGU	1231	ACCUUGGACCCACGUCUCC	1846		[1140-1158] 3′UTR
CCUGUUCUAUUCAGCGGCA	1232	UGCCGCUGAAUAGAACAGG	1847		[2500-2518] 3′UTR
UCCAGUAUGAGAUCAAGCA	1233	UGCUUGAUCUCAUACUGGA	1848	Rh, Rb	[507-525] ORF
CAAAAUGCUUCCAAAGCCA	1234	UGGCUUUGGAAGCAUUUUG	1849	Rh	[2475-2493] 3′UTR
CACACGCAAUGAAACCGAA	1235	UUCGGUUUCAUUGCGUGUG	1850		[2431-2449] 3′UTR
CUCCAUUUGGCAUCGUUUA	1236	UAAACGAUGCCAAAUGGAG	1851		[3278-3296] 3′UTR
AGCAGGAGUUUCUCGACAU	1237	AUGUCGAGAAACUCCUGCU	1852	Ck, Dg	[933-951] ORF
GUGUGGCCUUUAUAUUUGA	1238	UCAAAUAUAAAGGCCACAC	1853		[3121-3139] 3′UTR
GGGACCUGGUCAGCACAGA	1239	UCUGUGCUGACCAGGUCCC	1854	Rh	[2579-2597] 3′UTR
CCUCAGUGUGGUUUCCUGA	1240	UCAGGAAACCACACUGAGG	1855		[2288-2306] 3′UTR
GACCCAGAGUGGAACGCGU	1241	ACGCGUUCCACUCUGGGUC	1856		[2966-2984] 3′UTR
CCACCUGUGUUGUAAAGAU	1242	AUCUUUACAACACAGGUGG	1857	Rh	[2377-2395] 3′UTR
ACCUGUGUUGUAAAGAUAA	1243	UUAUCUUUACAACACAGGU	1858	Rh	[2379-2397] 3′UTR
GUUUUGCAAUGCAGAUGUA	1244	UACAUCUGCAUUGCAAAAC	1859		[412-430] ORF
AAAAAAGCCUCCAAGGGUU	1245	AACCCUUGGAGGCUUUUUU	1860		[997-1015] 3′UTR
UAAGAAACUUCCUAGGGAA	1246	UUCCCUAGGAAGUUUCUUA	1861		[2250-2268] 3′UTR
GCAUUUGACCCAGAGUGGA	1247	UCCACUCUGGGUCAAAUGC	1862		[2960-2978] 3′UTR
CCCUCAAGGUCCCUUCCCU	1248	AGGGAAGGGACCUUGAGGG	1863		[1785-1803] 3′UTR
AGGAUCCAGUAUGAGAUCA	1249	UGAUCUCAUACUGGAUCCU	1864	Rh, Rb	[503-521] ORF
AAGAUUACCUAGCUAAGAA	1250	UUCUUAGCUAGGUAAUCUU	1865		[2237-2255] 3′UTR
CUAUGUGUUCCCUCAGUGU	1251	ACACUGAGGGAACACAUAG	1866		[2278-2296] 3′UTR
GACAGAGGAAGCCGCUCAA	1252	UUGAGCGGCUUCCUCUGUC	1867		[3211-3229] 3′UTR
UUAAGAAGGCUCUCCAUUU	1253	AAAUGGAGAGCCUUCUUAA	1868		[3267-3285] 3′UTR
UAAGGAGAAUCUCUUGUUU	1254	AAACAAGAGAUUCUCCUUA	1869		[2354-2372] 3′UTR
GUUUCCUGAAGCCAGUGAU	1255	AUCACUGGCUUCAGGAAAC	1870		[2298-2316] 3′UTR
UGAGCACCACCCAGAAGAA	1256	UUCUUCUGGGUGGUGCUCA	1871	Rh, Pg	[708-726] ORF
CUAUUAAUCCUCAGAAUUC	1257	GAAUUCUGAGGAUUAAUAG	1872	Rh	[1573-1591] 3′UTR
CUGGGCGUGGUCUUGCAAA	1258	UUUGCAAGACCACGCCCAG	1873		[2460-2478] 3′UTR
GGAGGAAAGAAGGAAUAUC	1259	GAUAUUCCUUCUUUCCUCC	1874	Rt	[614-632] ORF
CCAAGUUCUUCGCCUGCAU	1260	AUGCAGGCGAAGAACUUGG	1875	Rh, Rb, Cw, Dg, Ms	[864-882] ORF
GUUUCUGCUGAUUGUUUUU	1261	AAAAACAAUCAGCAGAAAC	1876		[2824-2842] 3′UTR
GGUCCAAGGUCCUCAUCCC	1262	GGGAUGAGGACCUUGGACC	1877		[1149-1167] 3′UTR
AGUUGGUAAGAUGUCAUAA	1263	UUAUGACAUCUUACCAACU	1878	Rh	[2690-2708] 3′UTR
GGAAUAUGAAGUCUGAGAC	1264	GUCUCAGACUUCAUAUUCC	1879	Ms	[3508-3526] 3′UTR
GAGUGGAACGCGUGGCCUA	1265	UAGGCCACGCGUUCCACUC	1880		[2972-2990] 3′UTR
GGUUGUGGGUCUGGAGGGA	1266	UCCCUCCAGACCCACAACC	1881	Rh	[1124-1142] 3′UTR
GUUGAUUUUGUUUCCGUUU	1267	AAACGGAAACAAAAUCAAC	1882		[3454-3472] 3′UTR
CACUGUGUUUAUGCUGGAA	1268	UUCCAGCAUAAACACAGUG	1883		[3493-3511] 3′UTR
GAGCUGCGUUCCAGCCUCA	1269	UGAGGCUGGAACGCAGCUC	1884		[1645-1663] 3′UTR
GGACUGGGUCACAGAGAAG	1270	CUUCUCUGUGACCCAGUCC	1885	Rh, Rt, Ms, Pg	[826-844] ORF
AGCUAAGCAUAGUAAGAAG	1271	CUUCUUACUAUGCUUAGCU	1886		[2032-2050] 3′UTR
CACAAGAGUUGUUGAAAGU	1272	ACUUUCAACAACUCUUGUG	1887		[3545-3563] 3′UTR
GGUCAGCACAGAUCUUGAU	1273	AUCAAGAUCUGUGCUGACC	1888	Rh	[2586-2604] 3′UTR
UUCUAAAGGUGAAUUCUCA	1274	UGAGAAUUCACCUUUAGAA	1889		[2158-2176] 3′UTR
AGGGAACUAGGGAACCUAU	1275	AUAGGUUCCCUAGUUCCCU	1890	Rh	[2263-2281] 3′UTR
GGAAGUGGACUCUGGAAAC	1276	GUUUCCAGAGUCCACUUCC	1891		[460-478] ORF
CCUCCCACCUGUGUUGUAA	1277	UUACAACACAGGUGGGAGG	1892	Rh	[2373-2391] 3′UTR
CGGACGAGUGCCUCUGGAU	1278	AUCCAGAGGCACUCGUCCG	1893	Rh, Rb, Cw	[807-825] ORF
CGUGGAAGCAUUUGACCCA	1279	UGGGUCAAAUGCUUCCACG	1894	Rh	[2953-2971] 3′UTR
GCACUGUGUUUAUGCUGGA	1280	UCCAGCAUAAACACAGUGC	1895		[3492-3510] 3′UTR
AGUUGCAGAUAUACCAACU	1281	AGUUGGUAUAUCUGCAACU	1896	Rh	[2194-2212] 3′UTR
AAUGAUAAGGAGAAUCUCU	1282	AGAGAUUCUCCUUAUCAUU	1897		[2349-2367] 3′UTR
CUUGCUGCCGUAAUUUAAA	1283	UUUAAAUUACGGCAGCAAG	1898		[3430-3448] 3′UTR
GGAGAAUCUCUUGUUUCCU	1284	AGGAAACAAGAGAUUCUCC	1899		[2357-2375] 3′UTR
CCUUGGUAGGUAUUAGACU	1285	AGUCUAAUACCUACCAAGG	1900		[2905-2923] 3′UTR
GGACGUUGGAGGAAAGAAG	1286	CUUCUUUCCUCCAACGUCC	1901	Rt, Ms	[607-625] ORF
CGUUGGAGGAAAGAAGGAA	1287	UUCCUUCUUUCCUCCAACG	1902	Rt, Ms	[610-628] ORF
CUGACAUCCCUUCCUGGAA	1288	UUCCAGGAAGGGAUGUCAG	1903	Rh, Rt, Ms	[1031-1049] 3′UTR
UGACAUCCCUUCCUGGAAA	1289	UUUCCAGGAAGGGAUGUCA	1904	Rh, Rt, Ms	[1032-1050] 3′UTR
GAUAUACCAACUUCUGCUU	1290	AAGCAGAAGUUGGUAUAUC	1905	Rh	[2201-2219] 3′UTR
AGAUGGGCUGCGAGUGCAA	1291	UUGCACUCGCAGCCCAUCU	1906	Ck, Rb, Rt	[747-765] ORF
GGCUUAGUGUUCCCUCCCU	1292	AGGGAGGGAACACUAAGCC	1907		[1964-1982] 3′UTR
GUAUGGUGAUAUCAUAUGU	1293	ACAUAUGAUAUCACCAUAC	1908		[2792-2810] 3′UTR
ACCAACUUCUGCUUGUAUU	1294	AAUACAAGCAGAAGUUGGU	1909	Rh	[2206-2224] 3′UTR
CUCACUUCUUUCUCAGCCU	1295	AGGCUGAGAAAGAAGUGAG	1910		[2101-2119] 3′UTR
CUCCCACCUGUGUUGUAAA	1296	UUUACAACACAGGUGGGAG	1911	Rh	[2374-2392] 3′UTR
GGGUCUCGCUGGACGUUGG	1297	CCAACGUCCAGCGAGACCC	1912	Rt, Ms	[597-615] ORF
GAGCCUCCCUCUGAGCCUU	1298	AAGGCUCAGAGGGAGGCUC	1913	Rh	[1598-1616] 3′UTR
GCAUGUCUCUGAUGCUUUG	1299	CAAAGCAUCAGAGACAUGC	1914		[3579-3597] 3′UTR
GGCGUUUUCAUGCUGUACA	1300	UGUACAGCAUGAAAACGCC	1915	Rh	[2662-2680] 3′UTR
AUACCAACUUCUGCUUGUA	1301	UACAAGCAGAAGUUGGUAU	1916	Rh	[2204-2222] 3′UTR
GCAAUGCAGAUGUAGUGAU	1302	AUCACUACAUCUGCAUUGC	1917		[417-435] ORF
ACUUCUGCUUGUAUUUCUU	1303	AAGAAAUACAAGCAGAAGU	1918	Rh	[2210-2228] 3′UTR
UCCAGUUCAAAUUAUUGCA	1304	UGCAAUAAUUUGAACUGGA	1919		[3067-3085] 3′UTR
CCUGGUCAGCACAGAUCUU	1305	AAGAUCUGUGCUGACCAGG	1920	Rh	[2583-2601] 3′UTR
UGUUGAUUUUGUUUCCGUU	1306	AACGGAAACAAAAUCAACA	1921		[3453-3471] 3′UTR
UGCAGAUAUACCAACUUCU	1307	AGAAGUUGGUAUAUCUGCA	1922	Rh	[2197-2215] 3′UTR
GCGGUCAGUGAGAAGGAAG	1308	CUUCCUUCUCACUGACCGC	1923		[446-464] ORF
GGCGUGGUCUUGCAAAAUG	1309	CAUUUUGCAAGACCACGCC	1924		[2463-2481] 3′UTR
GUCCAGCCUAGGAAGGGAA	1310	UUCCCUUCCUAGGCUGGAC	1925	Rh	[2050-2068] 3′UTR
ACUUUCUCGGUAAUGAUAA	1311	UUAUCAUUACCGAGAAAGU	1926		[2338-2356] 3′UTR
CUUCUGCUUGUAUUUCUUA	1312	UAAGAAAUACAAGCAGAAG	1927		[2211-2229] 3′UTR
CAGAGGAAGCCGCUCAAAU	1313	AUUUGAGCGGCUUCCUCUG	1928		[3213-3231] 3′UTR
GAAGGAAGUGGACUCUGGA	1314	UCCAGAGUCCACUUCCUUC	1929		[457-475] ORF
CAGUGAGAAGGAAGUGGAC	1315	GUCCACUUCCUUCUCACUG	1930		[451-469] ORF
GACUUCCCUUUCUAGGGCA	1316	UGCCCUAGAAAGGGAAGUC	1931	Rh	[2605-2623] 3′UTR
CCUCCCUCUGAGCCUUGUA	1317	UACAAGGCUCAGAGGGAGG	1932	Rh	[1601-1619] 3′UTR
CAUGCUGUACAGUGACCUA	1318	UAGGUCACUGUACAGCAUG	1933		[2670-2688] 3′UTR
GAGUGCCUCUGGAUGGACU	1319	AGUCCAUCCAGAGGCACUC	1934	Rh, Rb, Cw, Dg, Rt, Ms	[812-830] ORF
CUGGGAGGGUAUCCAGGAA	1320	UUCCUGGAUACCCUCCCAG	1935	Rh	[2626-2644] 3′UTR
AACCGUGCUGAGCAGAAAA	1321	UUUUCUGCUCAGCACGGUU	1936		[3160-3178] 3′UTR
CAGUCCAUGUGAUUUCAGU	1322	ACUGAAAUCACAUGGACUG	1937	Rh	[2714-2732] 3′UTR
UAGACAUGGUUGUGGGUCU	1323	AGACCCACAACCAUGUCUA	1938		[1117-1135] 3′UTR
GCGCAUGUCUCUGAUGCUU	1324	AAGCAUCAGAGACAUGCGC	1939		[3577-3595] 3′UTR
AAGGUGAAUUCUCAGAUGA	1325	UCAUCUGAGAAUUCACCUU	1940		[2163-2181] 3′UTR
AGAAGAACAUCAACGGGCA	1326	UGCCCGUUGAUGUUCUUCU	1941	Rh, Rb	[840-858] ORF
ACAUACACACGCAAUGAAA	1327	UUUCAUUGCGUGUGUAUGU	1942	Rh	[2426-2444] 3′UTR
CACAGAUCUUGAUGACUUC	1328	GAAGUCAUCAAGAUCUGUG	1943	Rh	[2592-2610] 3′UTR
AGCCGCUCAAAUACCUUCA	1329	UGAAGGUAUUUGAGCGGCU	1944		[3220-3238] 3′UTR
CCAGUAUGAGAUCAAGCAG	1330	CUGCUUGAUCUCAUACUGG	1945	Rh, Rb, Cw, Dg, Ms	[508-526] ORF
GUGAGAAGGAAGUGGACUC	1331	GAGUCCACUUCCUUCUCAC	1946		[453-471] ORF
ACCUUAGCCUGUUCUAUUC	1332	GAAUAGAACAGGCUAAGGU	1947	Rh	[2493-2511] 3′UTR
CCUGUUUCUGCUGAUUGUU	1333	AACAAUCAGCAGAAACAGG	1948		[2821-2839] 3′UTR
GCCAUUGCUUCUUGCCUGU	1334	ACAGGCAAGAAGCAAUGGC	1949		[1817-1835] 3′UTR
GCCUGGAAAUGUGCAUUUU	1335	AAAAUGCACAUUUCCAGGC	1950	Rh	[1322-1340] 3′UTR
GCACAGCUCUCUUCUCCUA	1336	UAGGAGAAGAGAGCUGUGC	1951		[3317-3335] 3′UTR
CGACAUUUAUGGCAACCCU	1337	AGGGUUGCCAUAAAUGUCG	1952		[478-496] ORF
CCUGUGCUGUGUUUUUUAU	1338	AUAAAAAACACAGCACAGG	1953	Rh	[2883-2901] 3′UTR
AGGAAGUGGACUCUGGAAA	1339	UUUCCAGAGUCCACUUCCU	1954		[459-477] ORF
GCUAAGCAUAGUAAGAAGU	1340	ACUUCUUACUAUGCUUAGC	1955		[2033-2051] 3′UTR
CCGUCUUUGGUUCUCCAGU	1341	ACUGGAGAACCAAAGACGG	1956		[3054-3072] 3′UTR
UUUCCUGAAGCCAGUGAUA	1342	UAUCACUGGCUUCAGGAAA	1957		[2299-2317] 3′UTR
AGACGUGGGUCCAAGGUCC	1343	GGACCUUGGACCCACGUCU	1958		[1142-1160] 3′UTR
ACAUUUAUGGCAACCCUAU	1344	AUAGGGUUGCCAUAAAUGU	1959		[480-498] ORF
GUGGACAAUAAACAGUAUU	1345	AAUACUGUUUAUUGUCCAC	1960		[3625-3643] 3′UTR
GGGAACACACAAGAGUUGU	1346	ACAACUCUUGUGUGUUCCC	1961		[3538-3556] 3′UTR
GCUCGGUCCGUGGACAAUA	1347	UAUUGUCCACGGACCGAGC	1962		[3616-3634] 3′UTR
CCGUGCUGAGCAGAAAACA	1348	UGUUUUCUGCUCAGCACGG	1963		[3162-3180] 3′UTR
CCGCUCAAAUACCUUCACA	1349	UGUGAAGGUAUUUGAGCGG	1964		[3222-3240] 3′UTR
GUUCCCUCCCUCAAAGACU	1350	AGUCUUUGAGGGAGGGAAC	1965		[1972-1990] 3′UTR
GGUCGUUGCAAGACUGUGU	1351	ACACAGUCUUGCAACGACC	1966		[1356-1374] 3′UTR
GGUGCUGGGAACACACAAG	1352	CUUGUGUGUUCCCAGCACC	1967		[3532-3550] 3′UTR
AGUAUAUACAACUCCACCA	1353	UGGUGGAGUUGUAUAUACU	1968	Rh	[2730-2748] 3′UTR
GGCAUCAGGCACCUGGAUU	1354	AAUCCAGGUGCCUGAUGCC	1969		[1839-1857] 3′UTR
AGCAGAUAAAGAUGUUCAA	1355	UUGAACAUCUUUAUCUGCU	1970	Cw, Dg, Rt, Ms, Pg	[522-540] ORF
UGGAAUAUGAAGUCUGAGA	1356	UCUCAGACUUCAUAUUCCA	1971	Ms	[3507-3525] 3′UTR
CAGGCACCUGGAUUGAGUU	1357	AACUCAAUCCAGGUGCCUG	1972	Rh	[1844-1862] 3′UTR
AUAAGGAGAAUCUCUUGUU	1358	AACAAGAGAUUCUCCUUAU	1973		[2353-2371] 3′UTR
GCCUGUUUUAAGAGACAUC	1359	GAUGUCUCUUAAAACAGGC	1974	Rh	[2133-2151] 3′UTR
CGCUUCCUGUAUGGUGAUA	1360	UAUCACCAUACAGGAAGCG	1975		[2784-2802] 3′UTR
GCACCGUCACAGAUGCCAA	1361	UUGGCAUCUGUGACGGUGC	1976		[1262-1280] 3′UTR
GUUCCAGCCUCAGCUGAGU	1362	ACUCAGCUGAGGCUGGAAC	1977		[1652-1670] 3′UTR
GGAGGUAGGUGGCUUUGGU	1363	ACCAAAGCCACCUACCUCC	1978	Rh	[2076-2094] 3′UTR
GGAAACGACAUUUAUGGCA	1364	UGCCAUAAAUGUCGUUUCC	1979		[473-491] ORF
GCAAGAUGCACAUCACCCU	1365	AGGGUGAUGUGCAUCUUGC	1980	Rh, Dg	[660-678] ORF
UGUAGAAAUGGGAGCGAGA	1366	UCUCGCUCCCAUUUCUACA	1981	Rh	[1616-1634] 3′UTR
GGCCUAUGCAGGUGGAUUC	1367	GAAUCCACCUGCAUAGGCC	1982	Rh	[2985-3003] 3′UTR
AAGAAGAGCCUGAACCACA	1368	UGUGGUUCAGGCUCUUCUU	1983	Rh, Rb, Cw, Ms, Pg	[722-740] ORF
GGGAGGGUAUCCAGGAAUC	1369	GAUUCCUGGAUACCCUCCC	1984	Rh	[2628-2646] 3′UTR
GUCAUAAUGGACCAGUCCA	1370	UGGACUGGUCCAUUAUGAC	1985	Rh	[2702-2720] 3′UTR
CCAAGGUCCUCAUCCCAUC	1371	GAUGGGAUGAGGACCUUGG	1986		[1152-1170] 3′UTR
AGGUGGCUUUGGUGACACA	1372	UGUGUCACCAAAGCCACCU	1987	Rh	[2082-2100] 3′UTR
AGACUGUGUAGCAGGCCUA	1373	UAGGCCUGCUACACAGUCU	1988	Rh	[1366-1384] 3′UTR
GGCCUGGAAAUGUGCAUUU	1374	AAAUGCACAUUUCCAGGCC	1989	Rh	[1321-1339] 3′UTR
GGUUAGGAUAGGAAGAACU	1375	AGUUCUUCCUAUCCUAACC	1990		[2322-2340] 3′UTR
GGCUAGUUCUUGAAGGAGC	1376	GCUCCUUCAAGAACUAGCC	1991		[1544-1562] 3′UTR
AGCUCUGUUGAUUUUGUUU	1377	AAACAAAAUCAACAGAGCU	1992		[3448-3466] 3′UTR
UGCAUUUUGCAGAAACUUU	1378	AAAGUUUCUGCAAAAUGCA	1993	Rh	[1333-1351] 3′UTR
GUCUGAAAGGUGUGGCCUU	1379	AAGGCCACACCUUUCAGAC	1994		[3112-3130] 3′UTR
CAUCCAAGGGCAGCCUGGA	1380	UCCAGGCUGCCCUUGGAUG	1995		[1519-1537] 3′UTR
UGUUUCUGCUGAUUGUUUU	1381	AAAACAAUCAGCAGAAACA	1996		[2823-2841] 3′UTR
UGCAAGCAACUCAAAAUAU	1382	AUAUUUUGAGUUGCUUGCA	1997		[3345-3363] 3′UTR
AACAUUUACUCCUGUUUCU	1383	AGAAACAGGAGUAAAUGUU	1998	Rh	[2811-2829] 3′UTR
GAAAGGUGUGGCCUUUAUA	1384	UAUAAAGGCCACACCUUUC	1999		[3116-3134] 3′UTR
UCCUGUUUCUGCUGAUUGU	1385	ACAAUCAGCAGAAACAGGA	2000		[2820-2838] 3′UTR
AUCCUAUUAAUCCUCAGAA	1386	UUCUGAGGAUUAAUAGGAU	2001	Rh	[1570-1588] 3′UTR
UCCUGAAGCCAGUGAUAUG	1387	CAUAUCACUGGCUUCAGGA	2002		[2301-2319] 3′UTR
AGGGCCUGAGAAGGAUAUA	1388	UAUAUCCUUCUCAGGCCCU	2003		[541-559] ORF
GUUGCAGAUAUACCAACUU	1389	AAGUUGGUAUAUCUGCAAC	2004	Rh	[2195-2213] 3′UTR
GGGCCUGAGAAGGAUAUAG	1390	CUAUAUCCUUCUCAGGCCC	2005		[542-560] ORF
CGGGCGUUUUCAUGCUGUA	1391	UACAGCAUGAAAACGCCCG	2006	Rh	[2660-2678] 3′UTR
ACCAGUCCAUGUGAUUUCA	1392	UGAAAUCACAUGGACUGGU	2007	Rh	[2712-2730] 3′UTR
CGUGGGUCCAAGGUCCUCA	1393	UGAGGACCUUGGACCCACG	2008		[1145-1163] 3′UTR
GCCUGGAACCAGUGGCUAG	1394	CUAGCCACUGGUUCCAGGC	2009		[1531-1549] 3′UTR
CCUUUCAUCUUGAGAGGGA	1395	UCCCUCUCAAGAUGAAAGG	2010	Rh	[1392-1410] 3′UTR
CCAGUGGGAGCCUCCCUCU	1396	AGAGGGAGGCUCCCACUGG	2011	Rh	[1591-1609] 3′UTR
AAAUGUGCAUUUUGCAGAA	1397	UUCUGCAAAAUGCACAUUU	2012	Rh, Ms	[1328-1346] 3′UTR
UGGUCAGCACAGAUCUUGA	1398	UCAAGAUCUGUGCUGACCA	2013	Rh	[2585-2603] 3′UTR
CUAUGCAGGUGGAUUCCUU	1399	AAGGAAUCCACCUGCAUAG	2014	Rh	[2988-3006] 3′UTR
AGUAAGAAGUCCAGCCUAG	1400	CUAGGCUGGACUUCUUACU	2015	Rh	[2042-2060] 3′UTR
CUCAUCCCAUGGGUCCAAA	1401	UUUGGACCCAUGGGAUGAG	2016		[1067-1085] 3′UTR
AGAGCCGGGUGGCAGCUGA	1402	UCAGCUGCCACCCGGCUCU	2017		[3194-3212] 3′UTR
GCUGGGAACACACAAGAGU	1403	ACUCUUGUGUGUUCCCAGC	2018		[3535-3553] 3′UTR
CCGGACGAGUGCCUCUGGA	1404	UCCAGAGGCACUCGUCCGG	2019	Rh, Rb, Cw	[806-824] ORF
CCCUCAGUGUGGUUUCCUG	1405	CAGGAAACCACACUGAGGG	2020		[2287-2305] 3′UTR
AGUUGCACAGCUUUGCUUU	1406	AAAGCAAAGCUGUGCAACU	2021		[1859-1877] 3′UTR
CCCAUAAGCAGGCCUCCAA	1407	UUGGAGGCCUGCUUAUGGG	2022		[958-976]
					ORF + 3′UTR
CGGUGCUGGGAACACACAA	1408	UUGUGUGUUCCCAGCACCG	2023		[3531-3549] 3′UTR
GGUUUGUUUUUGACAUCAG	1409	CUGAUGUCAAAAACAAACC	2024	Rh	[2853-2871] 3′UTR
GACGAUAUACAGGCACAUU	1410	AAUGUGCCUGUAUAUCGUC	2025		[2401-2419] 3′UTR
CUUAGUGUUCCCUCCCUCA	1411	UGAGGGAGGGAACACUAAG	2026		[1966-1984] 3′UTR
GACACACUCACUUCUUUCU	1412	AGAAAGAAGUGAGUGUGUC	2027		[2095-2113] 3′UTR
GAAGCCGCUCAAAUACCUU	1413	AAGGUAUUUGAGCGGCUUC	2028		[3218-3236] 3′UTR
GGUCCCUUUCAUCUUGAGA	1414	UCUCAAGAUGAAAGGGACC	2029	Rh	[1388-1406] 3′UTR
CCUGGAACCAGUGGCUAGU	1415	ACUAGCCACUGGUUCCAGG	2030		[1532-1550] 3′UTR
UUCAGUAUAUACAACUCCA	1416	UGGAGUUGUAUAUACUGAA	2031	Rh	[2727-2745] 3′UTR
ACCUAUGUGUUCCCUCAGU	1417	ACUGAGGGAACACAUAGGU	2032		[2276-2294] 3′UTR
CUCCUAUUUUCAUCCUGCA	1418	UGCAGGAUGAAAAUAGGAG	2033		[3330-3348] 3′UTR
ACACACAAGAGUUGUUGAA	1419	UUCAACAACUCUUGUGUGU	2034		[3542-3560] 3′UTR
UGUCUCUGAUGCUUUGUAU	1420	AUACAAAGCAUCAGAGACA	2035		[3582-3600] 3′UTR
UAGAAAUGGGAGCGAGAAA	1421	UUUCUCGCUCCCAUUUCUA	2036		[1618-1636] 3′UTR
GAAGCAUUUGACCCAGAGU	1422	ACUCUGGGUCAAAUGCUUC	2037		[2957-2975] 3′UTR
GUUUUUGACAUCAGCUGUA	1423	UACAGCUGAUGUCAAAAAC	2038		[2858-2876] 3′UTR
GGAGUUUCUCGACAUCGAG	1424	CUCGAUGUCGAGAAACUCC	2039	Ck, Dg	[937-955] ORF
GAUAAACUGACGAUAUACA	1425	UGUAUAUCGUCAGUUUAUC	2040		[2393-2411] 3′UTR
GUGUUCCCUCCCUCAAAGA	1426	UCUUUGAGGGAGGGAACAC	2041		[1970-1988] 3′UTR
UUUGUUUCCGUUUGGAUUU	1427	AAAUCCAAACGGAAACAAA	2042		[3460-3478] 3′UTR
AGCUGAGUCUUUUUGGUCU	1428	AGACCAAAAAGACUCAGCU	2043	Rh	[1663-1681] 3′UTR
AACUUUCUCGGUAAUGAUA	1429	UAUCAUUACCGAGAAAGUU	2044		[2337-2355] 3′UTR
CCGGGUGGCAGCUGACAGA	1430	UCUGUCAGCUGCCACCCGG	2045		[3198-3216] 3′UTR
GAGUUGCACAGCUUUGCUU	1431	AAGCAAAGCUGUGCAACUC	2046		[1858-1876] 3′UTR
CCGGGACCUGGUCAGCACA	1432	UGUGCUGACCAGGUCCCGG	2047	Rh	[2577-2595] 3′UTR
CAAAGUAAAGGAUCUUUGA	1433	UCAAAGAUCCUUUACUUUG	2048		[3084-3102] 3′UTR
CAGCUCUCUUCUCCUAUUU	1434	AAAUAGGAGAAGAGAGCUG	2049		[3320-3338] 3′UTR
GACAGAAAAAGCUGGGUCU	1435	AGACCCAGCUUUUUCUGUC	2050	Rh	[1930-1948] 3′UTR
UGCAUGUGACGCCAGCUAA	1436	UUAGCUGGCGUCACAUGCA	2051		[2019-2037] 3′UTR
CCAGCCUCAGCUGAGUCUU	1437	AAGACUCAGCUGAGGCUGG	2052	Rh	[1655-1673] 3′UTR
GACCUAAAGUUGGUAAGAU	1438	AUCUUACCAACUUUAGGUC	2053		[2683-2701] 3′UTR
GGUGUGGCCUUUAUAUUUG	1439	CAAAUAUAAAGGCCACACC	2054		[3120-3138] 3′UTR
GUCCAAGGUCCUCAUCCCA	1440	UGGGAUGAGGACCUUGGAC	2055		[1150-1168] 3′UTR
UAGUAAGAAGUCCAGCCUA	1441	UAGGCUGGACUUCUUACUA	2056	Rh	[2041-2059] 3′UTR
AAGCAUAGUAAGAAGUCCA	1442	UGGACUUCUUACUAUGCUU	2057		[2036-2054] 3′UTR
AGGAUAGGAAGAACUUUCU	1443	AGAAAGUUCUUCCUAUCCU	2058		[2326-2344] 3′UTR
AGGAGAAUCUCUUGUUUCC	1444	GGAAACAAGAGAUUCUCCU	2059		[2356-2374] 3′UTR
CAAGAGUUGUUGAAAGUUG	1445	CAACUUUCAACAACUCUUG	2060		[3547-3565] 3′UTR
CCCAUGAUCCCGUGCUACA	1446	UGUAGCACGGGAUCAUGGG	2061	Rh, Rb	[779-797] ORF
CAUCCCAUGGGUCCAAAUU	1447	AAUUUGGACCCAUGGGAUG	2062		[1069-1087] 3′UTR
CUGAGCAGAAAACAAAACA	1448	UGUUUUGUUUUCUGCUCAG	2063		[3167-3185] 3′UTR
AGCAGAAAACAAAACAGGU	1449	ACCUGUUUUGUUUUCUGCU	2064		[3170-3188] 3′UTR
CUUGUUUCCUCCCACCUGU	1450	ACAGGUGGGAGGAAACAAG	2065		[2366-2384] 3′UTR
GUGGACUCUGGAAACGACA	1451	UGUCGUUUCCAGAGUCCAC	2066	Rh	[464-482] ORF
UGAUAAGGAGAAUCUCUUG	1452	CAAGAGAUUCUCCUUAUCA	2067	Rh	[2351-2369] 3′UTR
UGAGUAGGUUCGGUCUGAA	1453	UUCAGACCGAACCUACUCA	2068		[3100-3118] 3′UTR
CAUUUGGCAUCGUUUAAUU	1454	AAUUAAACGAUGCCAAAUG	2069		[3281-3299] 3′UTR
GCUUCCUGUAUGGUGAUAU	1455	AUAUCACCAUACAGGAAGC	2070		[2785-2803] 3′UTR
GAGGAUCCAGUAUGAGAUC	1456	GAUCUCAUACUGGAUCCUC	2071	Rh, Rb	[502-520] ORF
GCACAUCCUGAGGACAGAA	1457	UUCUGUCCUCAGGAUGUGC	2072	Rh	[1918-1936] 3′UTR
GCAUGAAUAAAACACUCAU	1458	AUGAGUGUUUUAUUCAUGC	2073	Rh	[1053-1071] 3′UTR
GCAACAGGCGUUUUGCAAU	1459	AUUGCAAAACGCCUGUUGC	2074	Cw, Rt, Ms	[403-421] ORF
GGGACGGCAAGAUGCACAU	1460	AUGUGCAUCUUGCCGUCCC	2075		[654-672] ORF
CUGUAAUCAUUCCUGUGCU	1461	AGCACAGGAAUGAUUACAG	2076	Rh	[2872-2890] 3′UTR
GGUCUUUUAACCGUGCUGA	1462	UCAGCACGGUUAAAAGACC	2077		[3152-3170] 3′UTR
ACAGCUCUCUUCUCCUAUU	1463	AAUAGGAGAAGAGAGCUGU	2078		[3319-3337] 3′UTR
ACCCUUGGUAGGUAUUAGA	1464	UCUAAUACCUACCAAGGGU	2079		[2903-2921] 3′UTR
GACUGGUCCAGCUCUGACA	1465	UGUCAGAGCUGGACCAGUC	2080	Rh	[1018-1036] 3′UTR
AUCCUGCAAGCAACUCAAA	1466	UUUGAGUUGCUUGCAGGAU	2081		[3341-3359] 3′UTR
CCAUGAUCCCGUGCUACAU	1467	AUGUAGCACGGGAUCAUGG	2082	Rh, Rb	[780-798] ORF
UUGUAUCAUUCUUGAGCAA	1468	UUGCUCAAGAAUGAUACAA	2083		[3595-3613] 3′UTR
GAGUCUUUUUGGUCUGCAC	1469	GUGCAGACCAAAAAGACUC	2084		[1667-1685] 3′UTR
GUUCAAAGGGCCUGAGAAG	1470	CUUCUCAGGCCCUUUGAAC	2085		[535-553] ORF
AGCCUCAGCUGAGUCUUUU	1471	AAAAGACUCAGCUGAGGCU	2086	Rh	[1657-1675] 3′UTR
GAUAAGGAGAAUCUCUUGU	1472	ACAAGAGAUUCUCCUUAUC	2087		[2352-2370] 3′UTR
ACAUCACCCUCUGUGACUU	1473	AAGUCACAGAGGGUGAUGU	2088	Rh	[669-687] ORF
GCGUGGUCUUGCAAAAUGC	1474	GCAUUUUGCAAGACCACGC	2089		[2464-2482] 3′UTR
GCCUUGGCACCGUCACAGA	1475	UCUGUGACGGUGCCAAGGC	2090	Rh	[1256-1274] 3′UTR
AGAAGAGCCUGAACCACAG	1476	CUGUGGUUCAGGCUCUUCU	2091	Rh, Rb, Cw, Ms, Pg	[723-741] ORF
UGGCCUGUUUUAAGAGACA	1477	UGUCUCUUAAAACAGGCCA	2092	Rh	[2131-2149] 3′UTR
GGGAAGGAUUUUGGAGGUA	1478	UACCUCCAAAAUCCUUCCC	2093	Rh	[2064-2082] 3′UTR
CCCUGUGGCCAACUGCAAA	1479	UUUGCAGUUGGCCACAGGG	2094	Rh	[980-998] 3′UTR
CUUUCUCGGUAAUGAUAAG	1480	CUUAUCAUUACCGAGAAAG	2095		[2339-2357] 3′UTR
CACUCAUCCCAUGGGUCCA	1481	UGGACCCAUGGGAUGAGUG	2096		[1065-1083] 3′UTR
GGUGGCAGCUGACAGAGGA	1482	UCCUCUGUCAGCUGCCACC	2097		[3201-3219] 3′UTR
GUGAAUUCUCAGAUGAUAG	1483	CUAUCAUCUGAGAAUUCAC	2098		[2166-2184] 3′UTR
UCCUGCAAGCAACUCAAAA	1484	UUUUGAGUUGCUUGCAGGA	2099		[3342-3360] 3′UTR
CCUGUUUUAAGAGACAUCU	1485	AGAUGUCUCUUAAAACAGG	2100	Rh	[2134-2152] 3′UTR
GGGCAGCCUGGAACCAGUG	1486	CACUGGUUCCAGGCUGCCC	2101		[1526-1544] 3′UTR
GCAUCAGGCACCUGGAUUG	1487	CAAUCCAGGUGCCUGAUGC	2102		[1840-1858] 3′UTR
AGCCUGGAACCAGUGGCUA	1488	UAGCCACUGGUUCCAGGCU	2103		[1530-1548] 3′UTR
UGCACAUCACCCUCUGUGA	1489	UCACAGAGGGUGAUGUGCA	2104	Rh	[666-684] ORF
AGAUAUACCAACUUCUGCU	1490	AGCAGAAGUUGGUAUAUCU	2105	Rh	[2200-2218] 3′UTR
CUAGCUAAGAAACUUCCUA	1491	UAGGAAGUUUCUUAGCUAG	2106		[2245-2263] 3′UTR
CUCUCUUCUCCUAUUUUCA	1492	UGAAAAUAGGAGAAGAGAG	2107		[3323-3341] 3′UTR
AUCCAAGGGCAGCCUGGAA	1493	UUCCAGGCUGCCCUUGGAU	2108		[1520-1538] 3′UTR
AAAGGAUCUUUGAGUAGGU	1494	ACCUACUCAAAGAUCCUUU	2109		[3090-3108] 3′UTR
CUGAGCACCACCCAGAAGA	1495	UCUUCUGGGUGGUGCUCAG	2110	Rh, Pg	[707-725] ORF
CCUGUUCUGGCAUCAGGCA	1496	UGCCUGAUGCCAGAACAGG	2111		[1831-1849] 3′UTR
UGUGUUUAUGCUGGAAUAU	1497	AUAUUCCAGCAUAAACACA	2112		[3496-3514] 3′UTR
AGGAAGAACUUUCUCGGUA	1498	UACCGAGAAAGUUCUUCCU	2113	Rh	[2331-2349] 3′UTR
AGAGCCUGAACCACAGGUA	1499	UACCUGUGGUUCAGGCUCU	2114	Rh, Rb, Cw, Ms, Pg	[726-744] ORF
GCCAAGCAGGCAGCACUUA	1500	UAAGUGCUGCCUGCUUGGC	2115		[1276-1294] 3′UTR
GGGCUUUCUGCAUGUGACG	1501	CGUCACAUGCAGAAAGCCC	2116		[2011-2029] 3′UTR
ACCCAGAAGAAGAGCCUGA	1502	UCAGGCUCUUCUUCUGGGU	2117	Rh, Cw, Ms, Pg	[716-734] ORF
CGCCUGCAUCAAGAGAAGU	1503	ACUUCUCUUGAUGCAGGCG	2118	Rh, Cw, Dg, Rt, Ms	[874-892] ORF
GCAGAUAUACCAACUUCUG	1504	CAGAAGUUGGUAUAUCUGC	2119	Rh	[2198-2216] 3′UTR
UGGACCAGUCCAUGUGAUU	1505	AAUCACAUGGACUGGUCCA	2120	Rh	[2709-2727] 3′UTR
UGUAACAUUUACUCCUGUU	1506	AACAGGAGUAAAUGUUACA	2121	Rh	[2808-2826] 3′UTR
CAGCUGUAAUCAUUCCUGU	1507	ACAGGAAUGAUUACAGCUG	2122		[2869-2887] 3′UTR
GAGUUGUUGAAAGUUGACA	1508	UGUCAACUUUCAACAACUC	2123		[3550-3568] 3′UTR
AGACUGCGCAUGUCUCUGA	1509	UCAGAGACAUGCGCAGUCU	2124		[3572-3590] 3′UTR
UCCUGUGCUGUGUUUUUUA	1510	UAAAAAACACAGCACAGGA	2125	Rh	[2882-2900] 3′UTR
CCUUCUCCUUUUAGACAUG	1511	CAUGUCUAAAAGGAGAAGG	2126		[1106-1124] 3′UTR
CUAAGAAACUUCCUAGGGA	1512	UCCCUAGGAAGUUUCUUAG	2127		[2249-2267] 3′UTR
GCCAAGUUCUUCGCCUGCA	1513	UGCAGGCGAAGAACUUGGC	2128	Rh, Rb, Cw, Dg, Ms	[863-881] ORF
GCUGGACGUUGGAGGAAAG	1514	CUUUCCUCCAACGUCCAGC	2129	Rt, Ms	[604-622] ORF
AGGCGUUUUGCAAUGCAGA	1515	UCUGCAUUGCAAAACGCCU	2130	Cw, Rt, Ms	[408-426] ORF
UGUGCAUUUUGCAGAAACU	1516	AGUUUCUGCAAAAUGCACA	2131	Rh, Rt, Ms	[1331-1349] 3′UTR
CAGCCUGGAACCAGUGGCU	1517	AGCCACUGGUUCCAGGCUG	2132		[1529-1547] 3′UTR
GCAAAAAAAGCCUCCAAGG	1518	CCUUGGAGGCUUUUUUUGC	2133		[994-1012] 3′UTR
ACCUGGAUUGAGUUGCACA	1519	UGUGCAACUCAAUCCAGGU	2134		[1849-1867] 3′UTR
CGUAAUUUAAAGCUCUGUU	1520	AACAGAGCUUUAAAUUACG	2135		[3438-3456] 3′UTR
CUGUGCUGUGUUUUUUAUU	1521	AAUAAAAAACACAGCACAG	2136	Rh	[2884-2902] 3′UTR
GGCACCAGGCCAAGUUCUU	1522	AAGAACUUGGCCUGGUGCC	2137	Rh, Rb, Rt, Ms	[855-873] ORF
CCUGUGGCCAACUGCAAAA	1523	UUUUGCAGUUGGCCACAGG	2138	Rh	[981-999] 3′UTR
GGUUUCGACUGGUCCAGCU	1524	AGCUGGACCAGUCGAAACC	2139	Rh	[1012-1030] 3′UTR
GAAUAAAACACUCAUCCCA	1525	UGGGAUGAGUGUUUUAUUC	2140	Rh	[1057-1075] 3′UTR
GAGUUGCAGAUAUACCAAC	1526	GUUGGUAUAUCUGCAACUC	2141	Rh	[2193-2211] 3′UTR
CUUCCUGUAUGGUGAUAUC	1527	GAUAUCACCAUACAGGAAG	2142		[2786-2804] 3′UTR
UUUGGUUCUCCAGUUCAAA	1528	UUUGAACUGGAGAACCAAA	2143		[3059-3077] 3′UTR
GCCUGCAUCAAGAGAAGUG	1529	CACUUCUCUUGAUGCAGGC	2144	Rt, Ms	[875-893] ORF
GGCAACCCUAUCAAGAGGA	1530	UCCUCUUGAUAGGGUUGCC	2145		[488-506] ORF
AAGCGGUCAGUGAGAAGGA	1531	UCCUUCUCACUGACCGCUU	2146		[444-462] ORF
GUGGCUUUGGUGACACACU	1532	AGUGUGUCACCAAAGCCAC	2147		[2084-2102] 3′UTR
AGAUCUUGAUGACUUCCCU	1533	AGGGAAGUCAUCAAGAUCU	2148	Rh	[2595-2613] 3′UTR
GAGACGUGGGUCCAAGGUC	1534	GACCUUGGACCCACGUCUC	2149		[1141-1159] 3′UTR
UGACAUCAGCUGUAAUCAU	1535	AUGAUUACAGCUGAUGUCA	2150		[2863-2881] 3′UTR
GGGAUCUCCCAGCUGGGUU	1536	AACCCAGCUGGGAGAUCCC	2151		[1295-1313] 3′UTR
AGCACUUAGGGAUCUCCCA	1537	UGGGAGAUCCCUAAGUGCU	2152	Rh	[1287-1305] 3′UTR
GUCUUUGGUUCUCCAGUUC	1538	GAACUGGAGAACCAAAGAC	2153		[3056-3074] 3′UTR
UAACCGUGCUGAGCAGAAA	1539	UUUCUGCUCAGCACGGUUA	2154		[3159-3177] 3′UTR
CUGGAUGGACUGGGUCACA	1540	UGUGACCCAGUCCAUCCAG	2155	Rh, Rb, Cw, Dg,	[820-838] ORF
				Rt, Ms, Pg
GUGCUGGGAACACACAAGA	1541	UCUUGUGUGUUCCCAGCAC	2156		[3533-3551] 3′UTR
AGUGGGAGCCUCCCUCUGA	1542	UCAGAGGGAGGCUCCCACU	2157	Rh	[1593-1611] 3′UTR
GCAGGCAGCACUUAGGGAU	1543	AUCCCUAAGUGCUGCCUGC	2158	Rh	[1281-1299] 3′UTR
UAUUGGACUUGCUGCCGUA	1544	UACGGCAGCAAGUCCAAUA	2159		[3423-3441] 3′UTR
GAUCUUGAUGACUUCCCUU	1545	AAGGGAAGUCAUCAAGAUC	2160	Rh	[2596-2614] 3′UTR
ACGCCAGCUAAGCAUAGUA	1546	UACUAUGCUUAGCUGGCGU	2161		[2027-2045] 3′UTR
AGGACACUAUGGCCUGUUU	1547	AAACAGGCCAUAGUGUCCU	2162		[2122-2140] 3′UTR
GCCUGAACCACAGGUACCA	1548	UGGUACCUGUGGUUCAGGC	2163	Rh, Rb, Cw, Ms, Pg	[729-747] ORF
UGGUUUGUUUUUGACAUCA	1549	UGAUGUCAAAAACAAACCA	2164	Rh	[2852-2870] 3′UTR
GUGGCAGCUGACAGAGGAA	1550	UUCCUCUGUCAGCUGCCAC	2165		[3202-3220] 3′UTR
CCAUCAAUCCUAUUAAUCC	1551	GGAUUAAUAGGAUUGAUGG	2166	Rh	[1564-1582] 3′UTR
GGACACUAUGGCCUGUUUU	1552	AAAACAGGCCAUAGUGUCC	2167		[2123-2141] 3′UTR
GACCUUCCGGUGCUGGGAA	1553	UUCCCAGCACCGGAAGGUC	2168		[3524-3542] 3′UTR
ACAUCCUGAGGACAGAAAA	1554	UUUUCUGUCCUCAGGAUGU	2169	Rh	[1920-1938] 3′UTR
AUGUAAACAUACACACGCA	1555	UGCGUGUGUAUGUUUACAU	2170	Rh	[2420-2438] 3 ′UTR
GCCUCCAAGGGUUUCGACU	1556	AGUCGAAACCCUUGGAGGC	2171	Rh	[1003-1021] 3′UTR
CUGCAUCAAGAGAAGUGAC	1557	GUCACUUCUCUUGAUGCAG	2172	Rt, Ms	[877-895] ORF
UGGAAGCAUUUGACCCAGA	1558	UCUGGGUCAAAUGCUUCCA	2173		[2955-2973] 3′UTR
AACACACAAGAGUUGUUGA	1559	UCAACAACUCUUGUGUGUU	2174		[3541-3559] 3′UTR
GGGAACUAGGGAACCUAUG	1560	CAUAGGUUCCCUAGUUCCC	2175	Rh	[2264-2282] 3′UTR
AUACAGGCACAUUAUGUAA	1561	UUACAUAAUGUGCCUGUAU	2176		[2407-2425] 3′UTR
GACGUGGGUCCAAGGUCCU	1562	AGGACCUUGGACCCACGUC	2177		[1143-1161] 3′UTR
GGGUUAGGAUAGGAAGAAC	1563	GUUCUUCCUAUCCUAACCC	2178		[2321-2339] 3′UTR
GGACGAGUGCCUCUGGAUG	1564	CAUCCAGAGGCACUCGUCC	2179	Rh, Rb, Cw	[808-826] ORF
AAAAAGCCUCCAAGGGUUU	1565	AAACCCUUGGAGGCUUUUU	2180		[998-1016] 3′UTR
CUUUGAGUAGGUUCGGUCU	1566	AGACCGAACCUACUCAAAG	2181		[3097-3115] 3′UTR
GGCAGACUGGGAGGGUAUC	1567	GAUACCCUCCCAGUCUGCC	2182	Rh	[2620-2638] 3′UTR
GAAGGCUCUCCAUUUGGCA	1568	UGCCAAAUGGAGAGCCUUC	2183		[3271-3289] 3′UTR
GCCUCCCUCUGAGCCUUGU	1569	ACAAGGCUCAGAGGGAGGC	2184	Rh	[1600-1618] 3′UTR
ACAAAACAGGUUAAGAAGA	1570	UCUUCUUAACCUGUUUUGU	2185		[3178-3196] 3′UTR
CCUAUGUGUUCCCUCAGUG	1571	CACUGAGGGAACACAUAGG	2186		[2277-2295] 3′UTR
AAAGGGCCUGAGAAGGAUA	1572	UAUCCUUCUCAGGCCCUUU	2187		[539-557] ORF
GCAGACUGCGCAUGUCUCU	1573	AGAGACAUGCGCAGUCUGC	2188		[3570-3588] 3′UTR
CCCUCCCAGGCUUAGUGUU	1574	AACACUAAGCCUGGGAGGG	2189		[1956-1974] 3′UTR
CCUCCAAGGGUUUCGACUG	1575	CAGUCGAAACCCUUGGAGG	2190	Rh	[1004-1022] 3′UTR
GCUAGUUCUUGAAGGAGCC	1576	GGCUCCUUCAAGAACUAGC	2191		[1545-1563] 3′UTR
CUUGAUGACUUCCCUUUCU	1577	AGAAAGGGAAGUCAUCAAG	2192	Rh	[2599-2617] 3′UTR
AUUAAUCCUCAGAAUUCCA	1578	UGGAAUUCUGAGGAUUAAU	2193	Rh	[1575-1593] 3′UTR
GACCAGUCCAUGUGAUUUC	1579	GAAAUCACAUGGACUGGUC	2194	Rh	[2711-2729] 3′UTR
AGUGAGAAGGAAGUGGACU	1580	AGUCCACUUCCUUCUCACU	2195		[452-470] ORF
GAGAAUCUCUUGUUUCCUC	1581	GAGGAAACAAGAGAUUCUC	2196		[2358-2376] 3′UTR
GGCUCUCCAUUUGGCAUCG	1582	CGAUGCCAAAUGGAGAGCC	2197		[3274-3292] 3′UTR
CUUCUUGCCUGUUCUGGCA	1583	UGCCAGAACAGGCAAGAAG	2198		[1824-1842] 3′UTR
CUUUAUAUUUGAUCCACAC	1584	GUGUGGAUCAAAUAUAAAG	2199		[3128-3146] 3′UTR
GGGCCUGGAAAUGUGCAUU	1585	AAUGCACAUUUCCAGGCCC	2200	Rh	[1320-1338] 3′UTR
CUUUGGUGACACACUCACU	1586	AGUGAGUGUGUCACCAAAG	2201		[2088-2106] 3′UTR
CAGCCUAGGAAGGGAAGGA	1587	UCCUUCCCUUCCUAGGCUG	2202	Rh	[2053-2071] 3′UTR
CUCGCUGGACGUUGGAGGA	1588	UCCUCCAACGUCCAGCGAG	2203	Rt, Ms	[601-619] ORF
GCUUUAUCCGGGCUUGUGU	1589	ACACAAGCCCGGAUAAAGC	2204		[1873-1891] 3′UTR
UGGACUCUGGAAACGACAU	1590	AUGUCGUUUCCAGAGUCCA	2205	Rh	[465-483] ORF
GCAUCGUGGAAGCAUUUGA	1591	UCAAAUGCUUCCACGAUGC	2206	Rh	[2949-2967] 3′UTR
CCUAAAGUUGGUAAGAUGU	1592	ACAUCUUACCAACUUUAGG	2207	Rh	[2685-2703] 3′UTR
GUGGUCUUGCAAAAUGCUU	1593	AAGCAUUUUGCAAGACCAC	2208		[2466-2484] 3′UTR
CAAGGUCCCUUCCCUAGCU	1594	AGCUAGGGAAGGGACCUUG	2209		[1789-1807] 3′UTR
GCUUUGUAUCAUUCUUGAG	1595	CUCAAGAAUGAUACAAAGC	2210		[3592-3610] 3′UTR
GGGCUUCGAUCCUUGGGUG	1596	CACCCAAGGAUCGAAGCCC	2211	Rh	[1198-1216] 3′UTR
UCAUAAUGGACCAGUCCAU	1597	AUGGACUGGUCCAUUAUGA	2212	Rh	[2703-2721] 3′UTR
UAUAGUUUAAGAAGGCUCU	1598	AGAGCCUUCUUAAACUAUA	2213		[3261-3279] 3′UTR
UCGACAUCGAGGACCCAUA	1599	UAUGGGUCCUCGAUGUCGA	2214	Dg	[945-963] ORF
ACUUCUUUCUCAGCCUCCA	1600	UGGAGGCUGAGAAAGAAGU	2215		[2104-2122] 3′UTR
AUUCUCAGAUGAUAGGUGA	1601	UCACCUAUCAUCUGAGAAU	2216		[2170-2188] 3′UTR
UGAGAAGGAAGUGGACUCU	1602	AGAGUCCACUUCCUUCUCA	2217		[454-472] ORF
CAAAGCACCUGUUAAGACU	1603	AGUCUUAACAGGUGCUUUG	2218	Rh	[2523-2541] 3′UTR
GCGUUCCAGCCUCAGCUGA	1604	UCAGCUGAGGCUGGAACGC	2219		[1650-1668] 3′UTR
CCUGGGCGUGGUCUUGCAA	1605	UUGCAAGACCACGCCCAGG	2220		[2459-2477] 3′UTR
GUCUCUGAUGCUUUGUAUC	1606	GAUACAAAGCAUCAGAGAC	2221		[3583-3601] 3′UTR
CUGUGCCCUCCCAGGCUUA	1607	UAAGCCUGGGAGGGCACAG	2222		[1951-1969] 3′UTR
CCUCCAACCCAUAUAACAC	1608	GUGUUAUAUGGGUUGGAGG	2223		[2753-2771] 3′UTR
UUUGUAUCAUUCUUGAGCA	1609	UGCUCAAGAAUGAUACAAA	2224		[3594-3612] 3′UTR
GCCUUUAUAUUUGAUCCAC	1610	GUGGAUCAAAUAUAAAGGC	2225		[3126-3144] 3′UTR
AGGCCUACCAGGUCCCUUU	1611	AAAGGGACCUGGUAGGCCU	2226	Rh	[1378-1396] 3′UTR
GUUCUAAGCACAGCUCUCU	1612	AGAGAGCUGUGCUUAGAAC	2227		[3310-3328] 3′UTR
CUGUGUUUUUUAUUACCCU	1613	AGGGUAAUAAAAAACACAG	2228	Rh	[2889-2907] 3′UTR
CUAGGAAGGGAAGGAUUUU	1614	AAAAUCCUUCCCUUCCUAG	2229	Rh	[2057-2075] 3′UTR
CAGAUGGGCUGCGAGUGCA	1615	UGCACUCGCAGCCCAUCUG	2230	Ck, Rb, Rt	[746-764] ORF
CUGGCAUCAGGCACCUGGA	1616	UCCAGGUGCCUGAUGCCAG	2231		[1837-1855] 3′UTR
UGAUGCUUUGUAUCAUUCU	1617	AGAAUGAUACAAAGCAUCA	2232		[3588-3606] 3′UTR
AGUCCAGCCUAGGAAGGGA	1618	UCCCUUCCUAGGCUGGACU	2233	Rh	[2049-2067] 3′UTR
CAAAGAUUACCUAGCUAAG	1619	CUUAGCUAGGUAAUCUUUG	2234		[2235-2253] 3′UTR
AGAAGGAAGUGGACUCUGG	1620	CCAGAGUCCACUUCCUUCU	2235		[456-474] ORF
UGUACAGUGACCUAAAGUU	1621	AACUUUAGGUCACUGUACA	2236		[2675-2693] 3′UTR

TABLE B2
19-mer siTIMP2 Cross-Species
		SEQ		SEQ
		ID		ID		human-73858577
No.	Sense (5′ > 3′)	NO:	Antisense (5′ > 3′)	NO:	Other Sp	ORF: 303-965
1	UUCGCCUGCAUCAAGAGAA	2237	UUCUCUUGAUGCAGGCGAA	2354	Rh, Cw, Dg, Ms	[872-890] ORF
2	GUGCAUUUUGCAGAAACUU	2238	AAGUUUCUGCAAAAUGCAC	2355	Rh, Rt, Ms	[1332-1350] 3′UTR
3	GGUACCAGAUGGGCUGCGA	2239	UCGCAGCCCAUCUGGUACC	2356	Rh, Ck, Rb, Rt	[741-759] ORF
4	GGUCUCGCUGGACGUUGGA	2240	UCCAACGUCCAGCGAGACC	2357	Rt, Ms	[598-616] ORF
5	UCGCCUGCAUCAAGAGAAG	2241	CUUCUCUUGAUGCAGGCGA	2358	Rh, Cw, Dg, Ms	[873-891] ORF
6	CUUCCUGGAAACAGCAUGA	2242	UCAUGCUGUUUCCAGGAAG	2359	Rh, Rb, Rt, Ms	[1040-1058] 3′UTR
7	GGGCACCAGGCCAAGUUCU	2243	AGAACUUGGCCUGGUGCCC	2360	Rh, Rb, Rt, Ms	[854-872] ORF
8	CCAGAAGAAGAGCCUGAAC	2244	GUUCAGGCUCUUCUUCUGG	2361	Rh, Rb, Cw, Ms, Pg	[718-736] ORF
9	UGGACGUUGGAGGAAAGAA	2245	UUCUUUCCUCCAACGUCCA	2362	Rt, Ms	[606-624] ORF
10	GGGCUGCGAGUGCAAGAUC	2246	GAUCUUGCACUCGCAGCCC	2363	Ck, Rb, Rt	[751-769] ORF
11	CCACCCAGAAGAAGAGCCU	2247	AGGCUCUUCUUCUGGGUGG	2364	Rh, Ck, Cw, Rt, Ms, Pg	[714-732] ORF
12	AUGGGCUGCGAGUGCAAGA	2248	UCUUGCACUCGCAGCCCAU	2365	Ck, Rb, Rt	[749-767] ORF
13	AUGGACUGGGUCACAGAGA	2249	UCUCUGUGACCCAGUCCAU	2366	Rh, Rt, Ms, Pg	[824-842] ORF
14	UGGGCUGCGAGUGCAAGAU	2250	AUCUUGCACUCGCAGCCCA	2367	Ck, Rb, Rt	[750-768] ORF
15	ACGUUGGAGGAAAGAAGGA	2251	UCCUUCUUUCCUCCAACGU	2368	Rt, Ms	[609-627] ORF
16	GACGUUGGAGGAAAGAAGG	2252	CCUUCUUUCCUCCAACGUC	2369	Rt, Ms	[608-626] ORF
17	AGGCCAAGUUCUUCGCCUG	2253	CAGGCGAAGAACUUGGCCU	2370	Rh, Rb, Cw, Dg, Ms	[861-879] ORF
18	GAAGAAGAGCCUGAACCAC	2254	GUGGUUCAGGCUCUUCUUC	2371	Rh, Rb, Cw, Ms, Pg	[721-739] ORF
19	GCACCCGCAACAGGCGUUU	2255	AAACGCCUGUUGCGGGUGC	2372	Cw, Dg, Rt, Ms	[397-415] ORF
20	UUCUUCGCCUGCAUCAAGA	2256	UCUUGAUGCAGGCGAAGAA	2373	Rh, Rb, Cw, Dg, Ms	[869-887] ORF
21	GAGCCUGAACCACAGGUAC	2257	GUACCUGUGGUUCAGGCUC	2374	Rh, Rb, Cw, Ms, Pg	[727-745] ORF
22	CUUCGCCUGCAUCAAGAGA	2258	UCUCUUGAUGCAGGCGAAG	2375	Rh, Rb, Cw, Dg, Ms	[871-889] ORF
23	UGGAAACAGCAUGAAUAAA	2259	UUUAUUCAUGCUGUUUCCA	2376	Rh, Rb, Rt, Ms	[1045-1063] 3′UTR
24	GACAUCCCUUCCUGGAAAC	2260	GUUUCCAGGAAGGGAUGUC	2377	Rh, Rt, Ms	[1033-1051] 3′UTR
25	GUUCUUCGCCUGCAUCAAG	2261	CUUGAUGCAGGCGAAGAAC	2378	Rh, Rb, Cw, Dg, Ms	[868-886] ORF
26	AAGUUCUUCGCCUGCAUCA	2262	UGAUGCAGGCGAAGAACUU	2379	Rh, Rb, Cw, Dg, Ms	[866-884] ORF
27	CCCUUCCUGGAAACAGCAU	2263	AUGCUGUUUCCAGGAAGGG	2380	Rh, Rb, Rt, Ms	[1038-1056] 3′UTR
28	CGCUCGGCCUCCUGCUGCU	2264	AGCAGCAGGAGGCCGAGCG	2381	Dg, Rt, Ms	[333-351] ORF
29	UGAACCACAGGUACCAGAU	2265	AUCUGGUACCUGUGGUUCA	2382	Rh, Rb, Cw, Ms, Pg	[732-750] ORF
30	CUGAACCACAGGUACCAGA	2266	UCUGGUACCUGUGGUUCAG	2383	Rh, Rb, Cw, Ms, Pg	[731-749] ORF
31	CAGAAGAAGAGCCUGAACC	2267	GGUUCAGGCUCUUCUUCUG	2384	Rh, Rb, Cw, Ms, Pg	[719-737] ORF
32	UCCUGGAAACAGCAUGAAU	2268	AUUCAUGCUGUUUCCAGGA	2385	Rh, Rb, Rt, Ms	[1042-1060] 3′UTR
33	GAUGGACUGGGUCACAGAG	2269	CUCUGUGACCCAGUCCAUC	2386	Rh, Rt, Ms, Pg	[823-841] ORF
34	GCCGACGCCUGCAGCUGCU	2270	AGCAGCUGCAGGCGUCGGC	2387	Cw, Dg, Rt, Ms	[371-389] ORF
35	CAGGCGUUUUGCAAUGCAG	2271	CUGCAUUGCAAAACGCCUG	2388	Cw, Rt, Ms	[407-425] ORF
36	UCAAGCAGAUAAAGAUGUU	2272	AACAUCUUUAUCUGCUUGA	2389	Cw, Dg, Rt, Ms, Pg	[519-537] ORF
37	GAACCACAGGUACCAGAUG	2273	CAUCUGGUACCUGUGGUUC	2390	Rh, Rb, Cw, Rt, Ms, Pg	[733-751] ORF
38	CACCCAGAAGAAGAGCCUG	2274	CAGGCUCUUCUUCUGGGUG	2391	Rh, Ck, Cw, Rt, Ms, Pg	[715-733] ORF
39	CCUUCCUGGAAACAGCAUG	2275	CAUGCUGUUUCCAGGAAGG	2392	Rh, Rb, Rt, Ms	[1039-1057] 3′UTR
40	CAACAGGCGUUUUGCAAUG	2276	CAUUGCAAAACGCCUGUUG	2393	Cw, Rt, Ms	[404-422] ORF
41	CACAGGUACCAGAUGGGCU	2277	AGCCCAUCUGGUACCUGUG	2394	Rh, Rb, Cw, Rt, Ms, Pg	[737-755] ORF
42	UCCCUUCCUGGAAACAGCA	2278	UGCUGUUUCCAGGAAGGGA	2395	Rh, Rb, Rt, Ms	[1037-1055] 3′UTR
43	UGAGAUCAAGCAGAUAAAG	2279	CUUUAUCUGCUUGAUCUCA	2396	Rh, Cw, Dg, Rt, Ms	[514-532] ORF
44	GGUGCACCCGCAACAGGCG	2280	CGCCUGUUGCGGGUGCACC	2397	Cw, Dg, Rt, Ms	[394-412] ORF
45	AGUGCCUCUGGAUGGACUG	2281	CAGUCCAUCCAGAGGCACU	2398	Rh, Rb, Cw, Dg, Rt, Ms	[813-831] ORF
46	AAGCAGAUAAAGAUGUUCA	2282	UGAACAUCUUUAUCUGCUU	2399	Cw, Dg, Rt, Ms, Pg	[521-539] ORF
47	UGCACCCGCAACAGGCGUU	2283	AACGCCUGUUGCGGGUGCA	2400	Cw, Dg, Rt, Ms	[396-414] ORF
48	CACCCGCAACAGGCGUUUU	2284	AAAACGCCUGUUGCGGGUG	2401	Cw, Rt, Ms	[398-416] ORF
49	CUGGACGUUGGAGGAAAGA	2285	UCUUUCCUCCAACGUCCAG	2402	Rt, Ms	[605-623] ORF
50	AUCCCUUCCUGGAAACAGC	2286	GCUGUUUCCAGGAAGGGAU	2403	Rh, Rb, Rt, Ms	[1036-1054] 3′UTR
51	ACAGGCGUUUUGCAAUGCA	2287	UGCAUUGCAAAACGCCUGU	2404	Cw, Rt, Ms	[406-424] ORF
52	GAUGGGCUGCGAGUGCAAG	2288	CUUGCACUCGCAGCCCAUC	2405	Ck, Rb, Rt	[748-766] ORF
53	AGCCUGAACCACAGGUACC	2289	GGUACCUGUGGUUCAGGCU	2406	Rh, Rb, Cw, Ms, Pg	[728-746] ORF
54	CCUCUGGAUGGACUGGGUC	2290	GACCCAGUCCAUCCAGAGG	2407	Rh, Rb, Cw, Dg, Rt, Ms,	[817-835] ORF
					Pg
55	CGGGCACCAGGCCAAGUUC	2291	GAACUUGGCCUGGUGCCCG	2408	Rh, Rb, Rt, Ms	[853-871] ORF
56	CAGGCCAAGUUCUUCGCCU	2292	AGGCGAAGAACUUGGCCUG	2409	Rh, Rb, Cw, Dg, Ms	[860-878] ORF
57	CAAGUUCUUCGCCUGCAUC	2293	GAUGCAGGCGAAGAACUUG	2410	Rh, Rb, Cw, Dg, Ms	[865-883] ORF
58	ACUUCAUCGUGCCCUGGGA	2294	UCCCAGGGCACGAUGAAGU	2411	Rh, Rb, Cw, Dg, Pg	[684-702] ORF
59	ACAUCCCUUCCUGGAAACA	2295	UGUUUCCAGGAAGGGAUGU	2412	Rh, Rt, Ms	[1034-1052] 3′UTR
60	UACCAGAUGGGCUGCGAGU	2296	ACUCGCAGCCCAUCUGGUA	2413	Rh, Ck, Rb, Rt	[743-761] ORF
61	GGCCAAGUUCUUCGCCUGC	2297	GCAGGCGAAGAACUUGGCC	2414	Rh, Rb, Cw, Dg, Ms	[862-880] ORF
62	CCAGAUGGGCUGCGAGUGC	2298	GCACUCGCAGCCCAUCUGG	2415	Rh, Ck, Rb, Rt	[745-763] ORF
63	GUGACUUCAUCGUGCCCUG	2299	CAGGGCACGAUGAAGUCAC	2416	Rh, Rb, Cw, Dg, Pg	[681-699] ORF
64	UCGCUGGACGUUGGAGGAA	2300	UUCCUCCAACGUCCAGCGA	2417	Rt, Ms	[602-620] ORF
65	AUCAAGCAGAUAAAGAUGU	2301	ACAUCUUUAUCUGCUUGAU	2418	Cw, Dg, Rt, Ms, Pg	[518-536] ORF
66	GUACCAGAUGGGCUGCGAG	2302	CUCGCAGCCCAUCUGGUAC	2419	Rh, Ck, Rb, Rt	[742-760] ORF
67	CGAGUGCCUCUGGAUGGAC	2303	GUCCAUCCAGAGGCACUCG	2420	Rh, Rb, Cw, Dg, Rt, Ms	[811-829] ORF
68	UCUGGAUGGACUGGGUCAC	2304	GUGACCCAGUCCAUCCAGA	2421	Rh, Rb, Cw, Dg, Rt, Ms,	[819-837] ORF
					Pg
69	ACCAGAUGGGCUGCGAGUG	2305	CACUCGCAGCCCAUCUGGU	2422	Rh, Ck, Rb, Rt	[744-762] ORF
70	ACAGGUACCAGAUGGGCUG	2306	CAGCCCAUCUGGUACCUGU	2423	Rh, Rb, Cw, Rt, Ms, Pg	[738-756] ORF
71	GAAGAGCCUGAACCACAGG	2307	CCUGUGGUUCAGGCUCUUC	2424	Rh, Rb, Cw, Ms, Pg	[724-742] ORF
72	GUGCACCCGCAACAGGCGU	2308	ACGCCUGUUGCGGGUGCAC	2425	Cw, Dg, Rt, Ms	[395-413] ORF
73	UGGAUGGACUGGGUCACAG	2309	CUGUGACCCAGUCCAUCCA	2426	Rh, Rt, Ms, Pg	[821-839] ORF
74	CAAGCAGAUAAAGAUGUUC	2310	GAACAUCUUUAUCUGCUUG	2427	Cw, Dg, Rt, Ms, Pg	[520-538] ORF
75	GUGCCUCUGGAUGGACUGG	2311	CCAGUCCAUCCAGAGGCAC	2428	Rh, Rb, Cw, Dg, Rt, Ms	[814-832] ORF
76	CAUCCCUUCCUGGAAACAG	2312	CUGUUUCCAGGAAGGGAUG	2429	Rh, Rb, Rt, Ms	[1035-1053] 3′UTR
77	CACCAGGCCAAGUUCUUCG	2313	CGAAGAACUUGGCCUGGUG	2430	Rh, Rb, Cw, Ms	[857-875] ORF
78	CCUGAACCACAGGUACCAG	2314	CUGGUACCUGUGGUUCAGG	2431	Rh, Rb, Cw, Ms, Pg	[730-748] ORF
79	AACCACAGGUACCAGAUGG	2315	CCAUCUGGUACCUGUGGUU	2432	Rh, Rb, Cw, Rt, Ms, Pg	[734-752] ORF
80	GUCUCGCUGGACGUUGGAG	2316	CUCCAACGUCCAGCGAGAC	2433	Rt, Ms	[599-617] ORF
81	AGAGUUUAUCUACACGGCC	2317	GGCCGUGUAGAUAAACUCU	2434	Dg, Ms, Pg	[559-577] ORF
82	UUCCUGGAAACAGCAUGAA	2318	UUCAUGCUGUUUCCAGGAA	2435	Rh, Rb, Rt, Ms	[1041-1059] 3′UTR
83	GAUAAAGAUGUUCAAAGGG	2319	CCCUUUGAACAUCUUUAUC	2436	Dg, Rt, Ms	[526-544] ORF
84	UCUUCGCCUGCAUCAAGAG	2320	CUCUUGAUGCAGGCGAAGA	2437	Rh, Rb, Cw, Dg, Ms	[870-888] ORF
85	UGGCGCUCGGCCUCCUGCU	2321	AGCAGGAGGCCGAGCGCCA	2438	Dg, Rt, Ms	[330-348] ORF
86	CCCGGUGCACCCGCAACAG	2322	CUGUUGCGGGUGCACCGGG	2439	Cw, Dg, Rt, Ms	[391-409] ORF
87	CCCGCAACAGGCGUUUUGC	2323	GCAAAACGCCUGUUGCGGG	2440	Cw, Rt, Ms	[400-418] ORF
88	CAGGGCCAAAGCGGUCAGU	2324	ACUGACCGCUUUGGCCCUG	2441	Rb, Dg	[436-454] ORF
89	AAGAGCCUGAACCACAGGU	2325	ACCUGUGGUUCAGGCUCUU	2442	Rh, Rb, Cw, Ms, Pg	[725-743] ORF
90	ACCACAGGUACCAGAUGGG	2326	CCCAUCUGGUACCUGUGGU	2443	Rh, Rb, Cw, Rt, Ms, Pg	[735-753] ORF
91	CAGGUACCAGAUGGGCUGC	2327	GCAGCCCAUCUGGUACCUG	2444	Rh, Rb, Cw, Dg, Rt, Ms,	[739-757] ORF
					Pg
92	CGGUGCACCCGCAACAGGC	2328	GCCUGUUGCGGGUGCACCG	2445	Cw, Dg, Rt, Ms	[393-411] ORF
93	GCUCGGCCUCCUGCUGCUG	2329	CAGCAGCAGGAGGCCGAGC	2446	Dg, Rt, Ms	[334-352] ORF
94	GACGCCUGCAGCUGCUCCC	2330	GGGAGCAGCUGCAGGCGUC	2447	Cw, Dg, Rt, Ms	[374-392] ORF
95	ACCCGCAACAGGCGUUUUG	2331	CAAAACGCCUGUUGCGGGU	2448	Cw, Rt, Ms	[399-417] ORF
96	CCGGUGCACCCGCAACAGG	2332	CCUGUUGCGGGUGCACCGG	2449	Cw, Dg, Rt, Ms	[392-410] ORF
97	UCUCGCUGGACGUUGGAGG	2333	CCUCCAACGUCCAGCGAGA	2450	Rt, Ms	[600-618] ORF
98	AACAGCAUGAAUAAAACAC	2334	GUGUUUUAUUCAUGCUGUU	2451	Rh, Rt, Ms	[1049-1067] 3′UTR
99	CCACAGGUACCAGAUGGGC	2335	GCCCAUCUGGUACCUGUGG	2452	Rh, Rb, Cw, Rt, Ms, Pg	[736-754] ORF
100	CCGACGCCUGCAGCUGCUC	2336	GAGCAGCUGCAGGCGUCGG	2453	Cw, Dg, Rt, Ms	[372-390] ORF
101	UUCAUCGUGCCCUGGGACA	2337	UGUCCCAGGGCACGAUGAA	2454	Rh, Rb, Cw, Dg, Pg	[686-704] ORF
102	CUUCAUCGUGCCCUGGGAC	2338	GUCCCAGGGCACGAUGAAG	2455	Rh, Rb, Cw, Dg, Pg	[685-703] ORF
103	CGACGCCUGCAGCUGCUCC	2339	GGAGCAGCUGCAGGCGUCG	2456	Cw, Dg, Rt, Ms	[373-391] ORF
104	UGCCUCUGGAUGGACUGGG	2340	CCCAGUCCAUCCAGAGGCA	2457	Rh, Rb, Cw, Dg, Rt, Ms	[815-833] ORF
105	ACCAGGCCAAGUUCUUCGC	2341	GCGAAGAACUUGGCCUGGU	2458	Rh, Rb, Cw, Ms	[858-876] ORF
106	AGGUACCAGAUGGGCUGCG	2342	CGCAGCCCAUCUGGUACCU	2459	Rh, Ck, Rb, Rt	[740-758] ORF
107	CUCGGCCUCCUGCUGCUGG	2343	CCAGCAGCAGGAGGCCGAG	2460	Dg, Rt	[335-353] ORF
108	AACAGGCGUUUUGCAAUGC	2344	GCAUUGCAAAACGCCUGUU	2461	Cw, Rt, Ms	[405-423] ORF
109	UCGGCCUCCUGCUGCUGGC	2345	GCCAGCAGCAGGAGGCCGA	2462	Dg, Rt	[336-354] ORF
110	CCAGGCCAAGUUCUUCGCC	2346	GGCGAAGAACUUGGCCUGG	2463	Rh, Rb, Cw, Dg, Ms	[859-877] ORF
111	UGUGACUUCAUCGUGCCCU	2347	AGGGCACGAUGAAGUCACA	2464	Rh, Rb, Cw, Dg, Pg	[680-698] ORF
112	GACUUCAUCGUGCCCUGGG	2348	CCCAGGGCACGAUGAAGUC	2465	Rh, Rb, Cw, Dg, Pg	[683-701] ORF
113	CUGUGACUUCAUCGUGCCC	2349	GGGCACGAUGAAGUCACAG	2466	Rh, Rb, Cw, Dg, Pg	[679-697] ORF
114	UGACUUCAUCGUGCCCUGG	2350	CCAGGGCACGAUGAAGUCA	2467	Rh, Rb, Cw, Dg, Pg	[682-700] ORF
616	GCAGGAGUUUCUCGACAUC	2351	GAUGUCGAGAAACUCCUGC	2468	Dg, Ck	[934-952] ORF
617	GCACCACCCAGAAGAAGAG	2352	CUCUUCUUCUGGGUGGUGC	2469	Pg, Rh	[711-729] ORF
618	AGCUCUGACAUCCCUUCCU	2353	AGGAAGGGAUGUCAGAGCU	2470	Rh	[1027-1045] 3′UTR

TABLE B3
Preferred 19-mer siTIMP2
		SEQ		SEQ
		ID		ID
siTIMP2_pNo.	Sense (5′ > 3′)	NO:	Antisense (5′ > 3′)	NO:	length	position
siTIMP2_p4	GGCUGCGAGUGCAAGAUCA	2471	UGAUCUUGCACUCGCAGCC	2524	19	[752-770] ORF
siTIMP2_p16	GUAUGAGAUCAAGCAGAUA	2472	UAUCUGCUUGAUCUCAUAC	2525	19	[511-529] ORF
siTIMP2_p17	GAGGAAAGAAGGAAUAUCU	2473	AGAUAUUCCUUCUUUCCUC	2526	19	[615-633] ORF
siTIMP2_p18	CCUGCAUCAAGAGAAGUGA	2474	UCACUUCUCUUGAUGCAGG	2527	19	[876-894] ORF
siTIMP2_p20	AUGAGAUCAAGCAGAUAAA	2475	UUUAUCUGCUUGAUCUCAU	2528	19	[513-531] ORF
siTIMP2_p24	GUUGGAGGAAAGAAGGAAU	2476	AUUCCUUCUUUCCUCCAAC	2529	19	[611-629] ORF
siTIMP2_p25	ACUGGGUCACAGAGAAGAA	2477	UUCUUCUCUGUGACCCAGU	2530	19	[828-846] ORF
siTIMP2_p27	CUCUGGAUGGACUGGGUCA	2478	UGACCCAGUCCAUCCAGAG	2531	19	[818-836] ORF
siTIMP2_p29	GGCGUUUUGCAAUGCAGAU	2479	AUCUGCAUUGCAAAACGCC	2532	19	[409-427] ORF
siTIMP2_p30	GCCUCUGGAUGGACUGGGU	2480	ACCCAGUCCAUCCAGAGGC	2533	19	[816-834] ORF
siTIMP2_p33	GGAGGAAAGAAGGAAUAUC	2481	GAUAUUCCUUCUUUCCUCC	2534	19	[614-632] ORF
siTIMP2_p35	GGACUGGGUCACAGAGAAG	2482	CUUCUCUGUGACCCAGUCC	2535	19	[826-844] ORF
siTIMP2_p37	GGACGUUGGAGGAAAGAAG	2483	CUUCUUUCCUCCAACGUCC	2536	19	[607-625] ORF
siTIMP2_p38	CGUUGGAGGAAAGAAGGAA	2484	UUCCUUCUUUCCUCCAACG	2537	19	[610-628] ORF
siTIMP2_p39	CUGACAUCCCUUCCUGGAA	2485	UUCCAGGAAGGGAUGUCAG	2538	19	[1031-1049]3′UTR
siTIMP2_p40	UGACAUCCCUUCCUGGAAA	2486	UUUCCAGGAAGGGAUGUCA	2539	19	[1032-1050]3′UTR
siTIMP2_p41	AGAUGGGCUGCGAGUGCAA	2487	UUGCACUCGCAGCCCAUCU	2540	19	[747-765] ORF
siTIMP2_p44	GGGUCUCGCUGGACGUUGG	2488	CCAACGUCCAGCGAGACCC	2541	19	[597-615] ORF
siTIMP2_p46	GAGUGCCUCUGGAUGGACU	2489	AGUCCAUCCAGAGGCACUC	2542	19	[812-830] ORF
siTIMP2_p51	AGCAGAUAAAGAUGUUCAA	2490	UUGAACAUCUUUAUCUGCU	2543	19	[522-540] ORF
siTIMP2_p55	GCAACAGGCGUUUUGCAAU	2491	AUUGCAAAACGCCUGUUGC	2544	19	[403-421] ORF
siTIMP2_p61	GCUGGACGUUGGAGGAAAG	2492	CUUUCCUCCAACGUCCAGC	2545	19	[604-622] ORF
siTIMP2_p62	UGUGCAUUUUGCAGAAACU	2493	AGUUUCUGCAAAAUGCACA	2546	19	[1331-1349]3′UTR
siTIMP2_p64	GGCACCAGGCCAAGUUCUU	2494	AAGAACUUGGCCUGGUGCC	2547	19	[855-873] ORF
siTIMP2_p65	GCCUGCAUCAAGAGAAGUG	2495	CACUUCUCUUGAUGCAGGC	2548	19	[875-893] ORF
siTIMP2_p67	CUGGAUGGACUGGGUCACA	2496	UGUGACCCAGUCCAUCCAG	2549	19	[820-838] ORF
siTIMP2_p68	CUGCAUCAAGAGAAGUGAC	2497	GUCACUUCUCUUGAUGCAG	2550	19	[877-895] ORF
siTIMP2_p69	CUCGCUGGACGUUGGAGGA	2498	UCCUCCAACGUCCAGCGAG	2551	19	[601-619] ORF
siTIMP2_p71	CAGAUGGGCUGCGAGUGCA	2499	UGCACUCGCAGCCCAUCUG	2552	19	[746-764] ORF
siTIMP2_p75	GUGCAUUUUGCAGAAACUU	2500	AAGUUUCUGCAAAAUGCAC	2553	19	[1332-1350]3′UTR
siTIMP2_p76	GGUACCAGAUGGGCUGCGA	2501	UCGCAGCCCAUCUGGUACC	2554	19	[741-759] ORF
siTIMP2_p78	GGUCUCGCUGGACGUUGGA	2502	UCCAACGUCCAGCGAGACC	2555	19	[598-616] ORF
siTIMP2_p79	CUUCCUGGAAACAGCAUGA	2503	UCAUGCUGUUUCCAGGAAG	2556	19	[1040-1058]3′UTR
siTIMP2_p82	GGGCACCAGGCCAAGUUCU	2504	AGAACUUGGCCUGGUGCCC	2557	19	[854-872] ORF
siTIMP2_p83	GUCACAGAGAAGAACAUCA	2505	UGAUGUUCUUCUCUGUGAC	2558	19	[833-851] ORF
siTIMP2_p84	AGGAGUUUCUCGACAUCGA	2506	UCGAUGUCGAGAAACUCCU	2559	19	[936-954] ORF
siTIMP2_p85	CCCAGAAGAAGAGCCUGAA	2507	UUCAGGCUCUUCUUCUGGG	2560	19	[717-735] ORF
siTIMP2_p86	GGGUCACAGAGAAGAACAU	2508	AUGUUCUUCUCUGUGACCC	2561	19	[831-849] ORF
siTIMP2_p87	CCAAGUUCUUCGCCUGCAU	2509	AUGCAGGCGAAGAACUUGG	2562	19	[864-882] ORF
siTIMP2_p88	AGCACCACCCAGAAGAAGA	2510	UCUUCUUCUGGGUGGUGCU	2563	19	[710-728] ORF
siTIMP2_p89	GUUUUGCAAUGCAGAUGUA	2511	UACAUCUGCAUUGCAAAAC	2564	19	[412-430] ORF
siTIMP2_p90	AGCAGGAGUUUCUCGACAU	2512	AUGUCGAGAAACUCCUGCU	2565	19	[933-951] ORF
siTIMP2_p91	GGAGUUUCUCGACAUCGAG	2513	CUCGAUGUCGAGAAACUCC	2566	19	[937-955] ORF
siTIMP2_p92	GCCUGAACCACAGGUACCA	2514	UGGUACCUGUGGUUCAGGC	2567	19	[729-747] ORF
siTIMP2_p93	UUCGCCUGCAUCAAGAGAA	2515	UUCUCUUGAUGCAGGCGAA	2568	19	[872-890] ORF
siTIMP2_p94	AGAGCCUGAACCACAGGUA	2516	UACCUGUGGUUCAGGCUCU	2569	19	[726-744] ORF
siTIMP2_p95	GCAGGAGUUUCUCGACAUC	2517	GAUGUCGAGAAACUCCUGC	2570	19	[934-952] ORF
siTIMP2_p96	GCACCACCCAGAAGAAGAG	2518	CUCUUCUUCUGGGUGGUGC	2571	19	[711-729] ORF
siTIMP2_p97	GGACGAGUGCCUCUGGAUG	2519	CAUCCAGAGGCACUCGUCC	2572	19	[808-826] ORF
siTIMP2_p98	GACUGGUCCAGCUCUGACA	2520	UGUCAGAGCUGGACCAGUC	2573	19	[1018-1036] 3′UTR
siTIMP2_p99	ACAUCACCCUCUGUGACUU	2521	AAGUCACAGAGGGUGAUGU	2574	19	[669-687] ORF
siTIMP2_p100	CCGGACGAGUGCCUCUGGA	2522	UCCAGAGGCACUCGUCCGG	2575	19	[806-824] ORF
siTIMP2_p101	UCGCCUGCAUCAAGAGAAG	2523	CUUCUCUUGAUGCAGGCGA	2576	19	[873-891] ORF
SiTIMP2_p102	GGAAGAACUUUCUCGGUAA	1007	UUACCGAGAAAGUUCUUCC	1622	19	[2332-2350]3′UTR

TABLE B4
19 mer siTIMP2 with lowest predicted OT effect
			SEQ		SEQ
			ID		ID	No. in Table
Cross species:	Ranking	Sense (5′ > 3′)	NO:	Antisense (5′ > 3′)	NO:	B3
H/Rt	4	CUCUGGAUGGACUGGGUCA	2478	UGACCCAGUCCAUCCAGAG	2531	siTIMP2_p27
H/Rt	3	GGCGUUUUGCAAUGCAGAU	2479	AUCUGCAUUGCAAAACGCC	2532	siTIMP2_p29
H/Rt	4	GCCUCUGGAUGGACUGGGU	2480	ACCCAGUCCAUCCAGAGGC	2533	siTIMP2_p30
H/Rt	4	CUGACAUCCCUUCCUGGAA	2485	UUCCAGGAAGGGAUGUCAG	2538	siTIMP2_p39
H/Rt	3	UGACAUCCCUUCCUGGAAA	2486	UUUCCAGGAAGGGAUGUCA	2539	siTIMP2_p40
H/Rt	4	AGAUGGGCUGCGAGUGCAA	2487	UUGCACUCGCAGCCCAUCU	2540	siTIMP2_p41
H/Rt	4	GAGUGCCUCUGGAUGGACU	2489	AGUCCAUCCAGAGGCACUC	2542	siTIMP2_p46
H/Rt	2	GCAACAGGCGUUUUGCAAU	2491	AUUGCAAAACGCCUGUUGC	2544	siTIMP2_p55
H/Rt	4	UGUGCAUUUUGCAGAAACU	2493	AGUUUCUGCAAAAUGCACA	2546	siTIMP2_p62
H/Rt	3	CUGCAUCAAGAGAAGUGAC	2497	GUCACUUCUCUUGAUGCAG	2550	siTIMP2_p68
H/Rt	1	CUCGCUGGACGUUGGAGGA	2498	UCCUCCAACGUCCAGCGAG	2551	siTIMP2_p69
H/Rt	4	CAGAUGGGCUGCGAGUGCA	2499	UGCACUCGCAGCCCAUCUG	2552	siTIMP2_p71
H/Rt	2	GGUACCAGAUGGGCUGCGA	2501	UCGCAGCCCAUCUGGUACC	2554	siTIMP2_p76
H/Rt	2	GGUCUCGCUGGACGUUGGA	2502	UCCAACGUCCAGCGAGACC	2555	siTIMP2_p78
H/Rt (Rt Cross 1MM)	4	GUUUUGCAAUGCAGAUGUA	2511	UACAUCUGCAUUGCAAAAC	2564	siTIMP2_p89
H/Rt (Rt Cross 1MM)	3	GGAGUUUCUCGACAUCGAG	2513	CUCGAUGUCGAGAAACUCC	2566	siTIMP2_p91
H/Rt (Rt Cross 1MM)	2	UUCGCCUGCAUCAAGAGAA	2515	UUCUCUUGAUGCAGGCGAA	2568	siTIMP2_p93
H/Rt (Rt Cross 1MM)	4	GCAGGAGUUUCUCGACAUC	2517	GAUGUCGAGAAACUCCUGC	2570	siTIMP2_p95
H/Rt (Rt Cross 1MM)	3	GGACGAGUGCCUCUGGAUG	2519	CAUCCAGAGGCACUCGUCC	2572	siTIMP2_p97
H/Rt (Rt Cross 1MM)	4	GACUGGUCCAGCUCUGACA	2520	UGUCAGAGCUGGACCAGUC	2573	siTIMP2_p98
H/Rt (Rt Cross 1MM)	2	CCGGACGAGUGCCUCUGGA	2522	UCCAGAGGCACUCGUCCGG	2575	siTIMP2_p100

TABLE B5
18-mer siTIMP2
		SEQ		SEQ
		ID		ID		human-73858577
No.	Sense (5′ > 3′)	NO:	Antisense (5′ > 3′)	NO:	Other Sp	ORF: 303-965
1	CCAUGUGAUUUCAGUAUA	2577	UAUACUGAAAUCACAUGG	3612	Rh	[2718-2735] 3′UTR
2	CUCUGAGCCUUGUAGAAA	2578	UUUCUACAAGGCUCAGAG	3613	Rh	[1606-1623] 3′UTR
3	GGUAAUGAUAAGGAGAAU	2579	AUUCUCCUUAUCAUUACC	3614		[2346-2363] 3′UTR
4	GAUGCUUUGUAUCAUUCU	2580	AGAAUGAUACAAAGCAUC	3615		[3589-3606] 3′UTR
5	GGGUCUGGAGGGAGACGU	2581	ACGUCUCCCUCCAGACCC	3616		[1130-1147] 3′UTR
6	GAUCCAGUAUGAGAUCAA	2582	UUGAUCUCAUACUGGAUC	3617	Rh, Rb	[505-522] ORF
7	CUGAGAAGGAUAUAGAGU	2583	ACUCUAUAUCCUUCUCAG	3618		[546-563] ORF
8	GUAUCAUUCUUGAGCAAU	2584	AUUGCUCAAGAAUGAUAC	3619		[3597-3614] 3′UTR
9	GCCUGAGAAGGAUAUAGA	2585	UCUAUAUCCUUCUCAGGC	3620		[544-561] ORF
10	GGCUAGUUCUUGAAGGAG	2586	CUCCUUCAAGAACUAGCC	3621		[1544-1561] 3′UTR
11	GGGUCACAGAGAAGAACA	2587	UGUUCUUCUCUGUGACCC	3622	Rh	[831-848] ORF
12	GGAUCUUUGAGUAGGUUC	2588	GAACCUACUCAAAGAUCC	3623		[3093-3110] 3′UTR
13	GGAAGUGGACUCUGGAAA	2589	UUUCCAGAGUCCACUUCC	3624		[460-477] ORF
14	GAACCUGAGUUGCAGAUA	2590	UAUCUGCAACUCAGGUUC	3625	Rh	[2187-2204] 3′UTR
15	GGUCCAAGGUCCUCAUCC	2591	GGAUGAGGACCUUGGACC	3626		[1149-1166] 3′UTR
16	GUAUUAGACUUGCACUUU	2592	AAAGUGCAAGUCUAAUAC	3627		[2914-2931] 3′UTR
17	CCUGCAAGCAACUCAAAA	2593	UUUUGAGUUGCUUGCAGG	3628		[3343-3360] 3′UTR
18	GGAGGAAAGAAGGAAUAU	2594	AUAUUCCUUCUUUCCUCC	3629	Rt	[614-631] ORF
19	GGAAUAUGAAGUCUGAGA	2595	UCUCAGACUUCAUAUUCC	3630	Ms	[3508-3525] 3′UTR
20	GGACGUUGGAGGAAAGAA	2596	UUCUUUCCUCCAACGUCC	3631	Rt, Ms	[607-624] ORF
21	CAGUGAGAAGGAAGUGGA	2597	UCCACUUCCUUCUCACUG	3632		[451-468] ORF
22	AGAGGAUCCAGUAUGAGA	2598	UCUCAUACUGGAUCCUCU	3633	Rh, Rb	[501-518] ORF
23	GGUCAGUGAGAAGGAAGU	2599	ACUUCCUUCUCACUGACC	3634		[448-465] ORF
24	CUUGGUAGGUAUUAGACU	2600	AGUCUAAUACCUACCAAG	3635		[2906-2923] 3′UTR
25	GGGCAGACUGGGAGGGUA	2601	UACCCUCCCAGUCUGCCC	3636	Rh	[2619-2636] 3′UTR
26	CCAGUAUGAGAUCAAGCA	2602	UGCUUGAUCUCAUACUGG	3637	Rh, Rb, Cw, Dg, Ms	[508-525] ORF
27	GGGUCUCGCUGGACGUUG	2603	CAACGUCCAGCGAGACCC	3638	Rt, Ms	[597-614] ORF
28	GCAGAUAUACCAACUUCU	2604	AGAAGUUGGUAUAUCUGC	3639	Rh	[2198-2215] 3′UTR
29	AGACGUGGGUCCAAGGUC	2605	GACCUUGGACCCACGUCU	3640		[1142-1159] 3′UTR
30	CACAGAUCUUGAUGACUU	2606	AAGUCAUCAAGAUCUGUG	3641	Rh	[2592-2609] 3′UTR
31	GGAUUGAGUUGCACAGCU	2607	AGCUGUGCAACUCAAUCC	3642		[1853-1870] 3′UTR
32	GGGUCCAAAUUAAUAUGA	2608	UCAUAUUAAUUUGGACCC	3643		[1077-1094] 3′UTR
33	GUGAGAAGGAAGUGGACU	2609	AGUCCACUUCCUUCUCAC	3644		[453-470] ORF
34	ACCUUAGCCUGUUCUAUU	2610	AAUAGAACAGGCUAAGGU	3645	Rh	[2493-2510] 3′UTR
35	GGUGCUGGGAACACACAA	2611	UUGUGUGUUCCCAGCACC	3646		[3532-3549] 3′UTR
36	GCAUGUCUCUGAUGCUUU	2612	AAAGCAUCAGAGACAUGC	3647		[3579-3596] 3′UTR
37	GCAAGCAACUCAAAAUAU	2613	AUAUUUUGAGUUGCUUGC	3648		[3346-3363] 3′UTR
38	GGCGUGGUCUUGCAAAAU	2614	AUUUUGCAAGACCACGCC	3649		[2463-2480] 3′UTR
39	CGUCUUUGGUUCUCCAGU	2615	ACUGGAGAACCAAAGACG	3650		[3055-3072] 3′UTR
40	GUUCUCCAGUUCAAAUUA	2616	UAAUUUGAACUGGAGAAC	3651		[3063-3080] 3′UTR
41	AGUAUGAGAUCAAGCAGA	2617	UCUGCUUGAUCUCAUACU	3652	Rh, Rb, Cw, Dg, Ms	[510-527] ORF
42	GCCUGUUUUAAGAGACAU	2618	AUGUCUCUUAAAACAGGC	3653	Rh	[2133-2150] 3′UTR
43	GGGCCUGAGAAGGAUAUA	2619	UAUAUCCUUCUCAGGCCC	3654		[542-559] ORF
44	GCCUGGAACCAGUGGCUA	2620	UAGCCACUGGUUCCAGGC	3655		[1531-1548] 3′UTR
45	CCAACUUCUGCUUGUAUU	2621	AAUACAAGCAGAAGUUGG	3656	Rh	[2207-2224] 3′UTR
46	CGAUAUACAGGCACAUUA	2622	UAAUGUGCCUGUAUAUCG	3657		[2403-2420] 3′UTR
47	GGCCUAUGCAGGUGGAUU	2623	AAUCCACCUGCAUAGGCC	3658	Rh	[2985-3002] 3′UTR
48	GGGAGGGUAUCCAGGAAU	2624	AUUCCUGGAUACCCUCCC	3659	Rh	[2628-2645] 3′UTR
49	CCUAUUAAUCCUCAGAAU	2625	AUUCUGAGGAUUAAUAGG	3660	Rh	[1572-1589] 3′UTR
50	GGGAGACGUGGGUCCAAG	2626	CUUGGACCCACGUCUCCC	3661		[1139-1156] 3′UTR
51	GCUCAAAUACCUUCACAA	2627	UUGUGAAGGUAUUUGAGC	3662		[3224-3241] 3′UTR
52	CCAAGGUCCUCAUCCCAU	2628	AUGGGAUGAGGACCUUGG	3663		[1152-1169] 3′UTR
53	AGUAAGAAGUCCAGCCUA	2629	UAGGCUGGACUUCUUACU	3664	Rh	[2042-2059] 3′UTR
54	GGACUGGGUCACAGAGAA	2630	UUCUCUGUGACCCAGUCC	3665	Rh, Rt, Ms, Pg	[826-843] ORF
55	AGCUAAGCAUAGUAAGAA	2631	UUCUUACUAUGCUUAGCU	3666		[2032-2049] 3′UTR
56	GGUUUGUUUUUGACAUCA	2632	UGAUGUCAAAAACAAACC	3667	Rh	[2853-2870] 3′UTR
57	GGAGUUUCUCGACAUCGA	2633	UCGAUGUCGAGAAACUCC	3668	Ck, Dg	[937-954] ORF
58	GAGUCUUUUUGGUCUGCA	2634	UGCAGACCAAAAAGACUC	3669		[1667-1684] 3′UTR
59	AGGAGAAUCUCUUGUUUC	2635	GAAACAAGAGAUUCUCCU	3670		[2356-2373] 3′UTR
60	CGGUAAUGAUAAGGAGAA	2636	UUCUCCUUAUCAUUACCG	3671		[2345-2362] 3′UTR
61	GGUAUUAGACUUGCACUU	2637	AAGUGCAAGUCUAAUACC	3672		[2913-2930] 3′UTR
62	CGGUCAGUGAGAAGGAAG	2638	CUUCCUUCUCACUGACCG	3673		[447-464] ORF
63	GCGGUCAGUGAGAAGGAA	2639	UUCCUUCUCACUGACCGC	3674		[446-463] ORF
64	UCCUGAAGCCAGUGAUAU	2640	AUAUCACUGGCUUCAGGA	3675		[2301-2318] 3′UTR
65	AGAAGAGCCUGAACCACA	2641	UGUGGUUCAGGCUCUUCU	3676	Rh, Rb, Cw, Ms, Pg	[723-740] ORF
66	GAAAGAAGGAAUAUCUCA	2642	UGAGAUAUUCCUUCUUUC	3677		[618-635] ORF
67	GCCGUAAUUUAAAGCUCU	2643	AGAGCUUUAAAUUACGGC	3678		[3436-3453] 3′UTR
68	CGUGGACAAUAAACAGUA	2644	UACUGUUUAUUGUCCACG	3679		[3624-3641] 3′UTR
69	GUGAAUUCUCAGAUGAUA	2645	UAUCAUCUGAGAAUUCAC	3680		[2166-2183] 3′UTR
70	GGAACACACAAGAGUUGU	2646	ACAACUCUUGUGUGUUCC	3681		[3539-3556] 3′UTR
71	GAGGAUCCAGUAUGAGAU	2647	AUCUCAUACUGGAUCCUC	3682	Rh, Rb	[502-519] ORF
72	UGAGAAGGAUAUAGAGUU	2648	AACUCUAUAUCCUUCUCA	3683		[547-564] ORF
73	GCGUGGUCUUGCAAAAUG	2649	CAUUUUGCAAGACCACGC	3684		[2464-2481] 3′UTR
74	CUGUUUUAAGAGACAUCU	2650	AGAUGUCUCUUAAAACAG	3685	Rh	[2135-2152] 3′UTR
75	CCCUCAGUGUGGUUUCCU	2651	AGGAAACCACACUGAGGG	3686		[2287-2304] 3′UTR
76	GAGUUGCAGAUAUACCAA	2652	UUGGUAUAUCUGCAACUC	3687	Rh	[2193-2210] 3′UTR
77	CUGGGAACACACAAGAGU	2653	ACUCUUGUGUGUUCCCAG	3688		[3536-3553] 3′UTR
78	GCUGAGUCUUUUUGGUCU	2654	AGACCAAAAAGACUCAGC	3689	Rh	[1664-1681] 3′UTR
79	CUGCAUCAAGAGAAGUGA	2655	UCACUUCUCUUGAUGCAG	3690	Rt, Ms	[877-894] ORF
80	GAGGAAAGAAGGAAUAUC	2656	GAUAUUCCUUCUUUCCUC	3691	Rt	[615-632] ORF
81	GCUGGACGUUGGAGGAAA	2657	UUUCCUCCAACGUCCAGC	3692	Rt, Ms	[604-621] ORF
82	GGUGUGGCCUUUAUAUUU	2658	AAAUAUAAAGGCCACACC	3693		[3120-3137] 3′UTR
83	GCAUUUUGCAGAAACUUU	2659	AAAGUUUCUGCAAAAUGC	3694	Rh	[1334-1351] 3′UTR
84	GGACCAGUCCAUGUGAUU	2660	AAUCACAUGGACUGGUCC	3695	Rh	[2710-2727] 3′UTR
85	CACCUUAGCCUGUUCUAU	2661	AUAGAACAGGCUAAGGUG	3696	Rh	[2492-2509] 3′UTR
86	UGAUAAGGAGAAUCUCUU	2662	AAGAGAUUCUCCUUAUCA	3697	Rh	[2351-2368] 3′UTR
87	CUCAAAGACUGACAGCCA	2663	UGGCUGUCAGUCUUUGAG	3698	Rh	[1981-1998] 3′UTR
88	GGGACAUGGCCCUUGUUU	2664	AAACAAGGGCCAUGUCCC	3699		[1407-1424] 3′UTR
89	CCAUCAAUCCUAUUAAUC	2665	GAUUAAUAGGAUUGAUGG	3700	Rh	[1564-1581] 3′UTR
90	GAACCAGUGGCUAGUUCU	2666	AGAACUAGCCACUGGUUC	3701		[1536-1553] 3′UTR
91	AGACAUGGUUGUGGGUCU	2667	AGACCCACAACCAUGUCU	3702		[1118-1135] 3′UTR
92	GUUUAAGAAGGCUCUCCA	2668	UGGAGAGCCUUCUUAAAC	3703		[3265-3282] 3′UTR
93	CUUCCUGUAUGGUGAUAU	2669	AUAUCACCAUACAGGAAG	3704		[2786-2803] 3′UTR
94	GGACCUGGUCAGCACAGA	2670	UCUGUGCUGACCAGGUCC	3705	Rh	[2580-2597] 3′UTR
95	GAGACGUGGGUCCAAGGU	2671	ACCUUGGACCCACGUCUC	3706		[1141-1158] 3′UTR
96	GGAACCAGUGGCUAGUUC	2672	GAACUAGCCACUGGUUCC	3707		[1535-1552] 3′UTR
97	GGGCAGCCUGGAACCAGU	2673	ACUGGUUCCAGGCUGCCC	3708		[1526-1543] 3′UTR
98	GCAUCAGGCACCUGGAUU	2674	AAUCCAGGUGCCUGAUGC	3709		[1840-1857] 3′UTR
99	GGCGUUUUGCAAUGCAGA	2675	UCUGCAUUGCAAAACGCC	3710	Cw, Rt, Ms	[409-426] ORF
100	CCUCCAACCCAUAUAACA	2676	UGUUAUAUGGGUUGGAGG	3711		[2753-2770] 3′UTR
101	GCCUUUAUAUUUGAUCCA	2677	UGGAUCAAAUAUAAAGGC	3712		[3126-3143] 3′UTR
102	GCACAGAUCUUGAUGACU	2678	AGUCAUCAAGAUCUGUGC	3713	Rh	[2591-2608] 3′UTR
103	GUCCCUUUCAUCUUGAGA	2679	UCUCAAGAUGAAAGGGAC	3714	Rh	[1389-1406] 3′UTR
104	GGAAGCAUUUGACCCAGA	2680	UCUGGGUCAAAUGCUUCC	3715		[2956-2973] 3′UTR
105	GGCAGACUGGGAGGGUAU	2681	AUACCCUCCCAGUCUGCC	3716	Rh	[2620-2637] 3′UTR
106	GCUUUGUAUCAUUCUUGA	2682	UCAAGAAUGAUACAAAGC	3717		[3592-3609] 3′UTR
107	GAGGAAGCCGCUCAAAUA	2683	UAUUUGAGCGGCUUCCUC	3718		[3215-3232] 3′UTR
108	CCUUCUCCUUUUAGACAU	2684	AUGUCUAAAAGGAGAAGG	3719		[1106-1123] 3′UTR
109	GGGCGUGGUCUUGCAAAA	2685	UUUUGCAAGACCACGCCC	3720		[2462-2479] 3′UTR
110	GCUGAGCAGAAAACAAAA	2686	UUUUGUUUUCUGCUCAGC	3721		[3166-3183] 3′UTR
111	GACCAGUCCAUGUGAUUU	2687	AAAUCACAUGGACUGGUC	3722	Rh	[2711-2728] 3′UTR
112	GAGAAUCUCUUGUUUCCU	2688	AGGAAACAAGAGAUUCUC	3723		[2358-2375] 3′UTR
113	UCCUAUUAAUCCUCAGAA	2689	UUCUGAGGAUUAAUAGGA	3724	Rh	[1571-1588] 3′UTR
114	CACAGAGAAGAACAUCAA	2690	UUGAUGUUCUUCUCUGUG	3725	Rh	[835-852] ORF
115	GCCUGCAUCAAGAGAAGU	2691	ACUUCUCUUGAUGCAGGC	3726	Rt, Ms	[875-892] ORF
116	GGUGACACACUCACUUCU	2692	AGAAGUGAGUGUGUCACC	3727		[2092-2109] 3′UTR
117	AGGAAAGAAGGAAUAUCU	2693	AGAUAUUCCUUCUUUCCU	3728	Rt	[616-633] ORF
118	CCACCUGUGUUGUAAAGA	2694	UCUUUACAACACAGGUGG	3729	Rh	[2377-2394] 3′UTR
119	GUCCAUGUGAUUUCAGUA	2695	UACUGAAAUCACAUGGAC	3730	Rh	[2716-2733] 3′UTR
120	AGUGGACUCUGGAAACGA	2696	UCGUUUCCAGAGUCCACU	3731	Rh	[463-480] ORF
121	GACAUCAGCUGUAAUCAU	2697	AUGAUUACAGCUGAUGUC	3732		[2864-2881] 3′UTR
122	GCCUGUUCUAUUCAGCGG	2698	CCGCUGAAUAGAACAGGC	3733		[2499-2516] 3′UTR
123	AGAUCAAGCAGAUAAAGA	2699	UCUUUAUCUGCUUGAUCU	3734	Cw, Dg, Rt, Ms	[516-533] ORF
124	GUCUCUGAUGCUUUGUAU	2700	AUACAAAGCAUCAGAGAC	3735		[3583-3600] 3′UTR
125	GUUCAAAGGGCCUGAGAA	2701	UUCUCAGGCCCUUUGAAC	3736		[535-552] ORF
126	GGGAACUAGGGAACCUAU	2702	AUAGGUUCCCUAGUUCCC	3737	Rh	[2264-2281] 3′UTR
127	AUGAUAAGGAGAAUCUCU	2703	AGAGAUUCUCCUUAUCAU	3738		[2350-2367] 3′UTR
128	CUUAGCCUGUUCUAUUCA	2704	UGAAUAGAACAGGCUAAG	3739	Rh	[2495-2512] 3′UTR
129	GUAAUGAUAAGGAGAAUC	2705	GAUUCUCCUUAUCAUUAC	3740		[2347-2364] 3′UTR
130	GGACGAGUGCCUCUGGAU	2706	AUCCAGAGGCACUCGUCC	3741	Rh, Rb, Cw	[808-825] ORF
131	CACAAUAAAUAGUGGCAA	2707	UUGCCACUAUUUAUUGUG	3742		[3237-3254] 3′UTR
132	GUUGGAGGAAAGAAGGAA	2708	UUCCUUCUUUCCUCCAAC	3743	Rt	[611-628] ORF
133	AGGUAUUAGACUUGCACU	2709	AGUGCAAGUCUAAUACCU	3744		[2912-2929] 3′UTR
134	ACACAAGAGUUGUUGAAA	2710	UUUCAACAACUCUUGUGU	3745		[3544-3561] 3′UTR
135	CCUAUGUGUUCCCUCAGU	2711	ACUGAGGGAACACAUAGG	3746		[2277-2294] 3′UTR
136	CAAUGCAGAUGUAGUGAU	2712	AUCACUACAUCUGCAUUG	3747		[418-435] ORF
137	GAAUAUGAAGUCUGAGAC	2713	GUCUCAGACUUCAUAUUC	3748		[3509-3526] 3′UTR
138	CCUCCAAGGGUUUCGACU	2714	AGUCGAAACCCUUGGAGG	3749	Rh	[1004-1021] 3′UTR
139	GUGGUUUCCUGAAGCCAG	2715	CUGGCUUCAGGAAACCAC	3750		[2295-2312] 3′UTR
140	UGUUCUAUUCAGCGGCAA	2716	UUGCCGCUGAAUAGAACA	3751		[2502-2519] 3′UTR
141	GAUGAUAGGUGAACCUGA	2717	UCAGGUUCACCUAUCAUC	3752		[2177-2194] 3′UTR
142	GCCUCAGCUGAGUCUUUU	2718	AAAAGACUCAGCUGAGGC	3753	Rh	[1658-1675] 3′UTR
143	AGGUGAAUUCUCAGAUGA	2719	UCAUCUGAGAAUUCACCU	3754		[2164-2181] 3′UTR
144	AGGGAGACGUGGGUCCAA	2720	UUGGACCCACGUCUCCCU	3755		[1138-1155] 3′UTR
145	AGAAGGAAGUGGACUCUG	2721	CAGAGUCCACUUCCUUCU	3756		[456-473] ORF
146	GGAAGCCGCUCAAAUACC	2722	GGUAUUUGAGCGGCUUCC	3757		[3217-3234] 3′UTR
147	GCUGUACAGUGACCUAAA	2723	UUUAGGUCACUGUACAGC	3758		[2673-2690] 3′UTR
148	GGAUAGGAAGAACUUUCU	2724	AGAAAGUUCUUCCUAUCC	3759		[2327-2344] 3′UTR
149	CCCUUCUCCUUUUAGACA	2725	UGUCUAAAAGGAGAAGGG	3760		[1105-1122] 3′UTR
150	CCACCUUAGCCUGUUCUA	2726	UAGAACAGGCUAAGGUGG	3761	Rh	[2491-2508] 3′UTR
151	GGGCUUCGAUCCUUGGGU	2727	ACCCAAGGAUCGAAGCCC	3762	Rh	[1198-1215] 3′UTR
152	AGUGUUCCCUCCCUCAAA	2728	UUUGAGGGAGGGAACACU	3763		[1969-1986] 3′UTR
153	GAACUUUCUCGGUAAUGA	2729	UCAUUACCGAGAAAGUUC	3764		[2336-2353] 3′UTR
154	GAGAAGGAAGUGGACUCU	2730	AGAGUCCACUUCCUUCUC	3765		[455-472] ORF
155	CAUCAAUCCUAUUAAUCC	2731	GGAUUAAUAGGAUUGAUG	3766	Rh	[1565-1582] 3′UTR
156	GCAGGAGUUUCUCGACAU	2732	AUGUCGAGAAACUCCUGC	3767	Ck, Dg	[934-951] ORF
157	GGGUUAGGAUAGGAAGAA	2733	UUCUUCCUAUCCUAACCC	3768		[2321-2338] 3′UTR
158	CUGAUGCUUUGUAUCAUU	2734	AAUGAUACAAAGCAUCAG	3769		[3587-3604] 3′UTR
159	CAGCCUCAGCUGAGUCUU	2735	AAGACUCAGCUGAGGCUG	3770	Rh	[1656-1673] 3′UTR
160	GGCCUGUUUUAAGAGACA	2736	UGUCUCUUAAAACAGGCC	3771	Rh	[2132-2149] 3′UTR
161	CAUACACACGCAAUGAAA	2737	UUUCAUUGCGUGUGUAUG	3772	Rh	[2427-2444] 3′UTR
162	GCACCACCCAGAAGAAGA	2738	UCUUCUUCUGGGUGGUGC	3773	Rh, Pg	[711-728] ORF
163	CUCUGAUGCUUUGUAUCA	2739	UGAUACAAAGCAUCAGAG	3774		[3585-3602] 3′UTR
164	GGGCUUUCUGCAUGUGAC	2740	GUCACAUGCAGAAAGCCC	3775		[2011-2028] 3′UTR
165	CUCUGGAAACGACAUUUA	2741	UAAAUGUCGUUUCCAGAG	3776	Rh	[469-486] ORF
166	GAUUGAGUUGCACAGCUU	2742	AAGCUGUGCAACUCAAUC	3777		[1854-1871] 3′UTR
167	GUCAGUGAGAAGGAAGUG	2743	CACUUCCUUCUCACUGAC	3778		[449-466] ORF
168	CCAGCUUGCAGGAGGAAU	2744	AUUCCUCCUGCAAGCUGG	3779		[1723-1740] 3′UTR
169	CCCUGUUCGCUUCCUGUA	2745	UACAGGAAGCGAACAGGG	3780		[2777-2794] 3′UTR
170	CAUGGGUCCAAAUUAAUA	2746	UAUUAAUUUGGACCCAUG	3781		[1074-1091] 3′UTR
171	CUCUGUUGAUUUUGUUUC	2747	GAAACAAAAUCAACAGAG	3782		[3450-3467] 3′UTR
172	GGAAGGAUUUUGGAGGUA	2748	UACCUCCAAAAUCCUUCC	3783	Rh	[2065-2082] 3′UTR
173	GGAACUAGGGAACCUAUG	2749	CAUAGGUUCCCUAGUUCC	3784	Rh	[2265-2282] 3′UTR
174	CCUGGAUUGAGUUGCACA	2750	UGUGCAACUCAAUCCAGG	3785		[1850-1867] 3′UTR
175	GCCUGGAAAUGUGCAUUU	2751	AAAUGCACAUUUCCAGGC	3786	Rh	[1322-1339] 3′UTR
176	GGCCAAAGCGGUCAGUGA	2752	UCACUGACCGCUUUGGCC	3787		[439-456] ORF
177	ACUUCUGCUUGUAUUUCU	2753	AGAAAUACAAGCAGAAGU	3788	Rh	[2210-2227] 3′UTR
178	CCCUUUCUAGGGCAGACU	2754	AGUCUGCCCUAGAAAGGG	3789	Rh	[2610-2627] 3′UTR
179	CCUGGUCAGCACAGAUCU	2755	AGAUCUGUGCUGACCAGG	3790	Rh	[2583-2600] 3′UTR
180	GGGUCCAAGGUCCUCAUC	2756	GAUGAGGACCUUGGACCC	3791		[1148-1165] 3′UTR
181	CUGUAUGGUGAUAUCAUA	2757	UAUGAUAUCACCAUACAG	3792		[2790-2807] 3′UTR
182	UGGACUUGCUGCCGUAAU	2758	AUUACGGCAGCAAGUCCA	3793		[3426-3443] 3′UTR
183	CCUGUUCGCUUCCUGUAU	2759	AUACAGGAAGCGAACAGG	3794		[2778-2795] 3′UTR
184	GUGACACACUCACUUCUU	2760	AAGAAGUGAGUGUGUCAC	3795		[2093-2110] 3′UTR
185	GGUGGAUUCCUUCAGGUC	2761	GACCUGAAGGAAUCCACC	3796	Rh	[2995-3012] 3′UTR
186	CCCAUCAAUCCUAUUAAU	2762	AUUAAUAGGAUUGAUGGG	3797	Rh	[1563-1580] 3′UTR
187	GCUAGUUCUUGAAGGAGC	2763	GCUCCUUCAAGAACUAGC	3798		[1545-1562] 3′UTR
188	GUGGGUCCAAGGUCCUCA	2764	UGAGGACCUUGGACCCAC	3799		[1146-1163] 3′UTR
189	GCUUCCAAAGCCACCUUA	2765	UAAGGUGGCUUUGGAAGC	3800	Rh	[2481-2498] 3′UTR
190	GGUCACAGAGAAGAACAU	2766	AUGUUCUUCUCUGUGACC	3801	Rh	[832-849] ORF
191	GCAUCAAGAGAAGUGACG	2767	CGUCACUUCUCUUGAUGC	3802		[879-896] ORF
192	UGGUCUUGCAAAAUGCUU	2768	AAGCAUUUUGCAAGACCA	3803		[2467-2484] 3′UTR
193	AGCAGGAGUUUCUCGACA	2769	UGUCGAGAAACUCCUGCU	3804	Ck, Dg	[933-950] ORF
194	GUUGAAAGUUGACAAGCA	2770	UGCUUGUCAACUUUCAAC	3805		[3555-3572] 3′UTR
195	GGUCUUGCAAAAUGCUUC	2771	GAAGCAUUUUGCAAGACC	3806		[2468-2485] 3′UTR
196	GUGUUUAUGCUGGAAUAU	2772	AUAUUCCAGCAUAAACAC	3807		[3497-3514] 3′UTR
197	GCAGAAAACAAAACAGGU	2773	ACCUGUUUUGUUUUCUGC	3808		[3171-3188] 3′UTR
198	ACCUAAAGUUGGUAAGAU	2774	AUCUUACCAACUUUAGGU	3809		[2684-2701] 3′UTR
199	AGCAGACUGCGCAUGUCU	2775	AGACAUGCGCAGUCUGCU	3810		[3569-3586] 3′UTR
200	AGCCUGUUCUAUUCAGCG	2776	CGCUGAAUAGAACAGGCU	3811		[2498-2515] 3′UTR
201	GGCAGCACUUAGGGAUCU	2777	AGAUCCCUAAGUGCUGCC	3812	Rh	[1284-1301] 3′UTR
202	CAUUUAUGGCAACCCUAU	2778	AUAGGGUUGCCAUAAAUG	3813		[481-498] ORF
203	GGCUCUCCAUUUGGCAUC	2779	GAUGCCAAAUGGAGAGCC	3814		[3274-3291] 3′UTR
204	UGUUUCUGCUGAUUGUUU	2780	AAACAAUCAGCAGAAACA	3815		[2823-2840] 3′UTR
205	GCUGCGAGUGCAAGAUCA	2781	UGAUCUUGCACUCGCAGC	3816	Rt	[753-770] ORF
206	CUUUCUCGGUAAUGAUAA	2782	UUAUCAUUACCGAGAAAG	3817		[2339-2356] 3′UTR
207	GUUUCCGUUUGGAUUUUU	2783	AAAAAUCCAAACGGAAAC	3818		[3463-3480] 3′UTR
208	GGGCUGCGAGUGCAAGAU	2784	AUCUUGCACUCGCAGCCC	3819	Ck, Rb, Rt	[751-768] ORF
209	CCUGAGUUGCAGAUAUAC	2785	GUAUAUCUGCAACUCAGG	3820	Rh	[2190-2207] 3′UTR
210	GUUUCCUGAAGCCAGUGA	2786	UCACUGGCUUCAGGAAAC	3821		[2298-2315] 3′UTR
211	GGAUUUUGGAGGUAGGUG	2787	CACCUACCUCCAAAAUCC	3822	Rh	[2069-2086] 3′UTR
212	GCAAAAAAAGCCUCCAAG	2788	CUUGGAGGCUUUUUUUGC	3823		[994-1011] 3′UTR
213	CCAAGUUCUUCGCCUGCA	2789	UGCAGGCGAAGAACUUGG	3824	Rh, Rb, Cw, Dg, Ms	[864-881] ORF
214	GUUCCCUCAGUGUGGUUU	2790	AAACCACACUGAGGGAAC	3825		[2284-2301] 3′UTR
215	GGAGCACUGUGUUUAUGC	2791	GCAUAAACACAGUGCUCC	3826		[3489-3506] 3′UTR
216	UAAGAAGGCUCUCCAUUU	2792	AAAUGGAGAGCCUUCUUA	3827		[3268-3285] 3′UTR
217	GCGUUUUCAUGCUGUACA	2793	UGUACAGCAUGAAAACGC	3828	Rh	[2663-2680] 3′UTR
218	GGUUCGGUCUGAAAGGUG	2794	CACCUUUCAGACCGAACC	3829		[3106-3123] 3′UTR
219	GAUUACCUAGCUAAGAAA	2795	UUUCUUAGCUAGGUAAUC	3830		[2239-2256] 3′UTR
220	CUUUCAUCUUGAGAGGGA	2796	UCCCUCUCAAGAUGAAAG	3831		[1393-1410] 3′UTR
221	AGGGCAGCCUGGAACCAG	2797	CUGGUUCCAGGCUGCCCU	3832		[1525-1542] 3′UTR
222	GGGACACGCGGCUUCCCU	2798	AGGGAAGCCGCGUGUCCC	3833		[1228-1245] 3′UTR
223	CCUAGGAAGGGAAGGAUU	2799	AAUCCUUCCCUUCCUAGG	3834	Rh	[2056-2073] 3′UTR
224	CCAAGGGCAGCCUGGAAC	2800	GUUCCAGGCUGCCCUUGG	3835		[1522-1539] 3′UTR
225	AUAUGAAGUCUGAGACCU	2801	AGGUCUCAGACUUCAUAU	3836		[3511-3528] 3′UTR
226	GGACUCUGGAAACGACAU	2802	AUGUCGUUUCCAGAGUCC	3837	Rh	[466-483] ORF
227	CCUGAAGCCAGUGAUAUG	2803	CAUAUCACUGGCUUCAGG	3838		[2302-2319] 3′UTR
228	GGACUUGCUGCCGUAAUU	2804	AAUUACGGCAGCAAGUCC	3839		[3427-3444] 3′UTR
229	ACGGCAAGAUGCACAUCA	2805	UGAUGUGCAUCUUGCCGU	3840	Dg, Pg	[657-674] ORF
230	CAAGAGUUGUUGAAAGUU	2806	AACUUUCAACAACUCUUG	3841		[3547-3564] 3′UTR
231	GGUCAGCACAGAUCUUGA	2807	UCAAGAUCUGUGCUGACC	3842	Rh	[2586-2603] 3′UTR
232	AGGGAACUAGGGAACCUA	2808	UAGGUUCCCUAGUUCCCU	3843	Rh	[2263-2280] 3′UTR
233	CGGACGAGUGCCUCUGGA	2809	UCCAGAGGCACUCGUCCG	3844	Rh, Rb, Cw	[807-824] ORF
234	CUCCAGUUCAAAUUAUUG	2810	CAAUAAUUUGAACUGGAG	3845		[3066-3083] 3′UTR
235	CAUGGUUGUGGGUCUGGA	2811	UCCAGACCCACAACCAUG	3846		[1121-1138] 3′UTR
236	AGGUGAACCUGAGUUGCA	2812	UGCAACUCAGGUUCACCU	3847	Rh	[2183-2200] 3′UTR
237	GGUGAGGUCCUGUCCUGA	2813	UCAGGACAGGACCUCACC	3848	Rh	[1742-1759] 3′UTR
238	CAGUGUGGUUUCCUGAAG	2814	CUUCAGGAAACCACACUG	3849		[2291-2308] 3′UTR
239	GAAGAAGAGCCUGAACCA	2815	UGGUUCAGGCUCUUCUUC	3850	Rh, Rb, Cw, Ms, Pg	[721-738] ORF
240	GGUAGGUGGCUUUGGUGA	2816	UCACCAAAGCCACCUACC	3851	Rh	[2079-2096] 3′UTR
241	CCCUCAAGGUCCCUUCCC	2817	GGGAAGGGACCUUGAGGG	3852		[1785-1802] 3′UTR
242	UCGCCUGCAUCAAGAGAA	2818	UUCUCUUGAUGCAGGCGA	3853	Rh, Cw, Dg, Ms	[873-890] ORF
243	AGCAUUUGACCCAGAGUG	2819	CACUCUGGGUCAAAUGCU	3854		[2959-2976] 3′UTR
244	GGGUCUUGCUGUGCCCUC	2820	GAGGGCACAGCAAGACCC	3855	Rh	[1943-1960] 3′UTR
245	GCCUCCUGCUGCUGGCGA	2821	UCGCCAGCAGCAGGAGGC	3856	Dg	[339-356] ORF
246	CAGGCUUAGUGUUCCCUC	2822	GAGGGAACACUAAGCCUG	3857		[1962-1979] 3′UTR
247	CCAGAAGAAGAGCCUGAA	2823	UUCAGGCUCUUCUUCUGG	3858	Rh, Rb, Cw, Ms, Pg	[718-735] ORF
248	GACCCAGAGUGGAACGCG	2824	CGCGUUCCACUCUGGGUC	3859		[2966-2983] 3′UTR
249	AGGUGUGGCCUUUAUAUU	2825	AAUAUAAAGGCCACACCU	3860		[3119-3136] 3′UTR
250	CAGUGGGAGCCUCCCUCU	2826	AGAGGGAGGCUCCCACUG	3861	Rh	[1592-1609] 3′UTR
251	UGGUUCUCCAGUUCAAAU	2827	AUUUGAACUGGAGAACCA	3862		[3061-3078] 3′UTR
252	GGUUAAGAAGAGCCGGGU	2828	ACCCGGCUCUUCUUAACC	3863		[3186-3203] 3′UTR
253	AAGGAGAAUCUCUUGUUU	2829	AAACAAGAGAUUCUCCUU	3864		[2355-2372] 3′UTR
254	UCUGAUGCUUUGUAUCAU	2830	AUGAUACAAAGCAUCAGA	3865		[3586-3603] 3′UTR
255	CCAGGUCCCUUUCAUCUU	2831	AAGAUGAAAGGGACCUGG	3866	Rh	[1385-1402] 3′UTR
256	CACCCUCUGUGACUUCAU	2832	AUGAAGUCACAGAGGGUG	3867	Rh, Cw, Ms	[673-690] ORF
257	CCCUUGGUAGGUAUUAGA	2833	UCUAAUACCUACCAAGGG	3868		[2904-2921] 3′UTR
258	CUAUGUGUUCCCUCAGUG	2834	CACUGAGGGAACACAUAG	3869		[2278-2295] 3′UTR
259	GAGCCUGAACCACAGGUA	2835	UACCUGUGGUUCAGGCUC	3870	Rh, Rb, Cw, Ms, Pg	[727-744] ORF
260	GGCAAGUGCUCCCAUCGC	2836	GCGAUGGGAGCACUUGCC	3871		[1460-1477] 3′UTR
261	GAAUUCCAGUGGGAGCCU	2837	AGGCUCCCACUGGAAUUC	3872	Rh	[1586-1603] 3′UTR
262	GCAAUGCAGAUGUAGUGA	2838	UCACUACAUCUGCAUUGC	3873		[417-434] ORF
263	CCUGAGAAGGAUAUAGAG	2839	CUCUAUAUCCUUCUCAGG	3874		[545-562] ORF
264	ACCUGAGUUGCAGAUAUA	2840	UAUAUCUGCAACUCAGGU	3875	Rh	[2189-2206] 3′UTR
265	GACCUAAAGUUGGUAAGA	2841	UCUUACCAACUUUAGGUC	3876		[2683-2700] 3′UTR
266	GUCUUUGGUUCUCCAGUU	2842	AACUGGAGAACCAAAGAC	3877		[3056-3073] 3′UTR
267	GCCUAGGAAGGGAAGGAU	2843	AUCCUUCCCUUCCUAGGC	3878	Rh	[2055-2072] 3′UTR
268	CGCAUGUCUCUGAUGCUU	2844	AAGCAUCAGAGACAUGCG	3879		[3578-3595] 3′UTR
269	CAAUCCUAUUAAUCCUCA	2845	UGAGGAUUAAUAGGAUUG	3880	Rh	[1568-1585] 3′UTR
270	AGCCUCAGCUGAGUCUUU	2846	AAAGACUCAGCUGAGGCU	3881	Rh	[1657-1674] 3′UTR
271	GCUCUGUUGAUUUUGUUU	2847	AAACAAAAUCAACAGAGC	3882		[3449-3466] 3′UTR
272	GUGGGAGCCUCCCUCUGA	2848	UCAGAGGGAGGCUCCCAC	3883	Rh	[1594-1611] 3′UTR
273	GACUCUGGAAACGACAUU	2849	AAUGUCGUUUCCAGAGUC	3884	Rh	[467-484] ORF
274	AGCAUAGUAAGAAGUCCA	2850	UGGACUUCUUACUAUGCU	3885		[2037-2054] 3′UTR
275	CAGAGGAAGCCGCUCAAA	2851	UUUGAGCGGCUUCCUCUG	3886		[3213-3230] 3′UTR
276	GUUGGUAAGAUGUCAUAA	2852	UUAUGACAUCUUACCAAC	3887	Rh	[2691-2708] 3′UTR
277	CUAUUUUCAUCCUGCAAG	2853	CUUGCAGGAUGAAAAUAG	3888		[3333-3350] 3′UTR
278	AGUUGCAGAUAUACCAAC	2854	GUUGGUAUAUCUGCAACU	3889	Rh	[2194-2211] 3′UTR
279	AAUGAUAAGGAGAAUCUC	2855	GAGAUUCUCCUUAUCAUU	3890		[2349-2366] 3′UTR
280	GGAGAAUCUCUUGUUUCC	2856	GGAAACAAGAGAUUCUCC	3891		[2357-2374] 3′UTR
281	GUAAGAUGUCAUAAUGGA	2857	UCCAUUAUGACAUCUUAC	3892	Rh	[2695-2712] 3′UTR
282	CCUUGGUAGGUAUUAGAC	2858	GUCUAAUACCUACCAAGG	3893		[2905-2922] 3′UTR
283	GGCUGGGACACGCGGCUU	2859	AAGCCGCGUGUCCCAGCC	3894		[1224-1241] 3′UTR
284	CACAAGAGUUGUUGAAAG	2860	CUUUCAACAACUCUUGUG	3895		[3545-3562] 3′UTR
285	GAGGGUCGUUGCAAGACU	2861	AGUCUUGCAACGACCCUC	3896		[1353-1370] 3′UTR
286	AAACGACAUUUAUGGCAA	2862	UUGCCAUAAAUGUCGUUU	3897		[475-492] ORF
287	UGAUGACUUCCCUUUCUA	2863	UAGAAAGGGAAGUCAUCA	3898	Rh	[2601-2618] 3′UTR
288	GGCUUAGUGUUCCCUCCC	2864	GGGAGGGAACACUAAGCC	3899		[1964-1981] 3′UTR
289	CAGAGAAGAACAUCAACG	2865	CGUUGAUGUUCUUCUCUG	3900	Rh	[837-854] ORF
290	CCAGCCUCAGCUGAGUCU	2866	AGACUCAGCUGAGGCUGG	3901	Rh	[1655-1672] 3′UTR
291	GGGACACCCUGAGCACCA	2867	UGGUGCUCAGGGUGUCCC	3902	Rh, Pg	[699-716] ORF
292	CUCACUUCUUUCUCAGCC	2868	GGCUGAGAAAGAAGUGAG	3903		[2101-2118] 3′UTR
293	GACAUCCCUUCCUGGAAA	2869	UUUCCAGGAAGGGAUGUC	3904	Rh, Rt, Ms	[1033-1050] 3′UTR
294	CCUGGCAAGUGCUCCCAU	2870	AUGGGAGCACUUGCCAGG	3905		[1457-1474] 3′UTR
295	AGAAAUGGGAGCGAGAAA	2871	UUUCUCGCUCCCAUUUCU	3906		[1619-1636] 3′UTR
296	GCAAUGAAACCGAAGCUU	2872	AAGCUUCGGUUUCAUUGC	3907		[2436-2453] 3′UTR
297	AUGUCAUAAUGGACCAGU	2873	ACUGGUCCAUUAUGACAU	3908	Rh	[2700-2717] 3′UTR
298	UGUGGUUUCCUGAAGCCA	2874	UGGCUUCAGGAAACCACA	3909		[2294-2311] 3′UTR
299	GAUAUACAGGCACAUUAU	2875	AUAAUGUGCCUGUAUAUC	3910		[2404-2421] 3′UTR
300	AAAAAAGCCUCCAAGGGU	2876	ACCCUUGGAGGCUUUUUU	3911		[997-1014] 3′UTR
301	GUAUGGUGAUAUCAUAUG	2877	CAUAUGAUAUCACCAUAC	3912		[2792-2809] 3′UTR
302	CCUGUGCUGUGUUUUUUA	2878	UAAAAAACACAGCACAGG	3913	Rh	[2883-2900] 3′UTR
303	AGGCCAAGUUCUUCGCCU	2879	AGGCGAAGAACUUGGCCU	3914	Rh, Rb, Cw, Dg, Ms	[861-878] ORF
304	UGCAGAUAUACCAACUUC	2880	GAAGUUGGUAUAUCUGCA	3915	Rh	[2197-2214] 3′UTR
305	AGAAGGAAUAUCUCAUUG	2881	CAAUGAGAUAUUCCUUCU	3916		[621-638] ORF
306	GAAGGAUUUUGGAGGUAG	2882	CUACCUCCAAAAUCCUUC	3917	Rh	[2066-2083] 3′UTR
307	GCGGCUUCCCUCCCAGUC	2883	GACUGGGAGGGAAGCCGC	3918		[1235-1252] 3′UTR
308	CUCAGAAUUCCAGUGGGA	2884	UCCCACUGGAAUUCUGAG	3919	Rh	[1582-1599] 3′UTR
309	GAUGGACUGGGUCACAGA	2885	UCUGUGACCCAGUCCAUC	3920	Rh, Rt, Ms, Pg	[823-840] ORF
310	AUAUCUCAUUGCAGGAAA	2886	UUUCCUGCAAUGAGAUAU	3921		[628-645] ORF
311	ACAUUUAUGGCAACCCUA	2887	UAGGGUUGCCAUAAAUGU	3922		[480-497] ORF
312	UUAAGAAGGCUCUCCAUU	2888	AAUGGAGAGCCUUCUUAA	3923		[3267-3284] 3′UTR
313	GCAAAAUGCUUCCAAAGC	2889	GCUUUGGAAGCAUUUUGC	3924	Rh	[2474-2491] 3′UTR
314	CUCCCUCAAAGACUGACA	2890	UGUCAGUCUUUGAGGGAG	3925	Rh	[1977-1994] 3′UTR
315	GCCUCUGGAUGGACUGGG	2891	CCCAGUCCAUCCAGAGGC	3926	Rh, Rb, Cw, Dg, Rt, Ms	[816-833] ORF
316	CGUUGGUCUUUUAACCGU	2892	ACGGUUAAAAGACCAACG	3927		[3148-3165] 3′UTR
317	AGGAAUAUCUCAUUGCAG	2893	CUGCAAUGAGAUAUUCCU	3928		[624-641] ORF
318	GAGUUUAUCUACACGGCC	2894	GGCCGUGUAGAUAAACUC	3929	Ms, Pg	[560-577] ORF
319	UUUUCAUCCUGCAAGCAA	2895	UUGCUUGCAGGAUGAAAA	3930		[3336-3353] 3′UTR
320	CAAAGCGGUCAGUGAGAA	2896	UUCUCACUGACCGCUUUG	3931		[442-459] ORF
321	GUUUCUGCUGAUUGUUUU	2897	AAAACAAUCAGCAGAAAC	3932		[2824-2841] 3′UTR
322	AAAGGUGAAUUCUCAGAU	2898	AUCUGAGAAUUCACCUUU	3933		[2162-2179] 3′UTR
323	GAGUGCCUCUGGAUGGAC	2899	GUCCAUCCAGAGGCACUC	3934	Rh, Rb, Cw, Dg, Rt, Ms	[812-829] ORF
324	CAAAGAUUACCUAGCUAA	2900	UUAGCUAGGUAAUCUUUG	3935		[2235-2252] 3′UTR
325	CCAGCUCUGACAUCCCUU	2901	AAGGGAUGUCAGAGCUGG	3936	Rh	[1025-1042] 3′UTR
326	GUUCUUCGCCUGCAUCAA	2902	UUGAUGCAGGCGAAGAAC	3937	Rh, Rb, Cw, Dg, Ms	[868-885] ORF
327	GGCUCCUGUGCGUGGUAC	2903	GUACCACGCACAGGAGCC	3938	Rh	[896-913] ORF
328	UAGACAUGGUUGUGGGUC	2904	GACCCACAACCAUGUCUA	3939		[1117-1134] 3′UTR
329	AGAAGUCCAGCCUAGGAA	2905	UUCCUAGGCUGGACUUCU	3940	Rh	[2046-2063] 3′UTR
330	GCAAGACUGUGUAGCAGG	2906	CCUGCUACACAGUCUUGC	3941	Rh	[1363-1380] 3′UTR
331	GCUCUCUUCUCCUAUUUU	2907	AAAAUAGGAGAAGAGAGC	3942		[3322-3339] 3′UTR
332	GGCAAGAUGCACAUCACC	2908	GGUGAUGUGCAUCUUGCC	3943	Rh, Dg	[659-676] ORF
333	GAAGAACUUUCUCGGUAA	2909	UUACCGAGAAAGUUCUUC	3944	Rh	[2333-2350] 3′UTR
334	AGAGUUGUUGAAAGUUGA	2910	UCAACUUUCAACAACUCU	3945		[3549-3566] 3′UTR
335	GUAUAUACAACUCCACCA	2911	UGGUGGAGUUGUAUAUAC	3946	Rh	[2731-2748] 3′UTR
336	GCUUAGUGUUCCCUCCCU	2912	AGGGAGGGAACACUAAGC	3947		[1965-1982] 3′UTR
337	GCUCUGACAUCCCUUCCU	2913	AGGAAGGGAUGUCAGAGC	3948	Rh	[1028-1045] 3′UTR
338	CCCAUGGGUCCAAAUUAA	2914	UUAAUUUGGACCCAUGGG	3949		[1072-1089] 3′UTR
339	UGGCCAACUGCAAAAAAA	2915	UUUUUUUGCAGUUGGCCA	3950		[985-1002] 3′UTR
340	GGACACUAUGGCCUGUUU	2916	AAACAGGCCAUAGUGUCC	3951		[2123-2140] 3′UTR
341	GCCAGCUAAGCAUAGUAA	2917	UUACUAUGCUUAGCUGGC	3952		[2029-2046] 3′UTR
342	CCAAGGGUUUCGACUGGU	2918	ACCAGUCGAAACCCUUGG	3953	Rh	[1007-1024] 3′UTR
343	AGAUGCACAUCACCCUCU	2919	AGAGGGUGAUGUGCAUCU	3954	Rh	[663-680] ORF
344	GGCAGGGCCUGGAAAUGU	2920	ACAUUUCCAGGCCCUGCC	3955		[1316-1333] 3′UTR
345	GGUCCUCAUCCCAUCCUC	2921	GAGGAUGGGAUGAGGACC	3956	Rh	[1156-1173] 3′UTR
346	CGACAUUUAUGGCAACCC	2922	GGGUUGCCAUAAAUGUCG	3957		[478-495] ORF
347	GCCUUGUAGAAAUGGGAG	2923	CUCCCAUUUCUACAAGGC	3958	Rh	[1612-1629] 3′UTR
348	CAGUCCAUGUGAUUUCAG	2924	CUGAAAUCACAUGGACUG	3959	Rh	[2714-2731] 3′UTR
349	GGAGACGUGGGUCCAAGG	2925	CCUUGGACCCACGUCUCC	3960		[1140-1157] 3′UTR
350	CAGCUUUGCUUUAUCCGG	2926	CCGGAUAAAGCAAAGCUG	3961		[1866-1883] 3′UTR
351	UGCAAGCAACUCAAAAUA	2927	UAUUUUGAGUUGCUUGCA	3962		[3345-3362] 3′UTR
352	CCUUUCUAGGGCAGACUG	2928	CAGUCUGCCCUAGAAAGG	3963	Rh	[2611-2628] 3′UTR
353	CCUGGAAAUGUGCAUUUU	2929	AAAAUGCACAUUUCCAGG	3964	Rh	[1323-1340] 3′UTR
354	AUGGCAACCCUAUCAAGA	2930	UCUUGAUAGGGUUGCCAU	3965		[486-503] ORF
355	GCCAUUGCUUCUUGCCUG	2931	CAGGCAAGAAGCAAUGGC	3966		[1817-1834] 3′UTR
356	GGAACCUAUGUGUUCCCU	2932	AGGGAACACAUAGGUUCC	3967	Rh	[2273-2290] 3′UTR
357	GAUAUACCAACUUCUGCU	2933	AGCAGAAGUUGGUAUAUC	3968	Rh	[2201-2218] 3′UTR
358	GUUUGUUUUUGACAUCAG	2934	CUGAUGUCAAAAACAAAC	3969		[2854-2871] 3′UTR
359	UGCACAGCUUUGCUUUAU	2935	AUAAAGCAAAGCUGUGCA	3970		[1862-1879] 3′UTR
360	CCUAUUUUCAUCCUGCAA	2936	UUGCAGGAUGAAAAUAGG	3971		[3332-3349] 3′UTR
361	UGCCAUUGCUUCUUGCCU	2937	AGGCAAGAAGCAAUGGCA	3972		[1816-1833] 3′UTR
362	ACCAACUUCUGCUUGUAU	2938	AUACAAGCAGAAGUUGGU	3973	Rh	[2206-2223] 3′UTR
363	GGUCCUGUCCUGAGGCUG	2939	CAGCCUCAGGACAGGACC	3974	Rh	[1747-1764] 3′UTR
364	AUGCAGAUGUAGUGAUCA	2940	UGAUCACUACAUCUGCAU	3975		[420-437] ORF
365	GCUAAGCAUAGUAAGAAG	2941	CUUCUUACUAUGCUUAGC	3976		[2033-2050] 3′UTR
366	GUUCCCUCCCUCAAAGAC	2942	GUCUUUGAGGGAGGGAAC	3977		[1972-1989] 3′UTR
367	AGCUGUAAUCAUUCCUGU	2943	ACAGGAAUGAUUACAGCU	3978		[2870-2887] 3′UTR
368	GCAUGUGACGCCAGCUAA	2944	UUAGCUGGCGUCACAUGC	3979		[2020-2037] 3′UTR
369	GCACAGCUUUGCUUUAUC	2945	GAUAAAGCAAAGCUGUGC	3980		[1863-1880] 3′UTR
370	GAGCCUCCCUCUGAGCCU	2946	AGGCUCAGAGGGAGGCUC	3981	Rh	[1598-1615] 3′UTR
371	GGCACCAGGCCAAGUUCU	2947	AGAACUUGGCCUGGUGCC	3982	Rh, Rb, Rt, Ms	[855-872] ORF
372	CAGCACAGAUCUUGAUGA	2948	UCAUCAAGAUCUGUGCUG	3983	Rh	[2589-2606] 3′UTR
373	UGUUCUAAGCACAGCUCU	2949	AGAGCUGUGCUUAGAACA	3984		[3309-3326] 3′UTR
374	UGAGCAGAAAACAAAACA	2950	UGUUUUGUUUUCUGCUCA	3985		[3168-3185] 3′UTR
375	GGGAACACACAAGAGUUG	2951	CAACUCUUGUGUGUUCCC	3986		[3538-3555] 3′UTR
376	CCCUCAAAGACUGACAGC	2952	GCUGUCAGUCUUUGAGGG	3987	Rh	[1979-1996] 3′UTR
377	CCUUGUUUUCUGCAGCUU	2953	AAGCUGCAGAAAACAAGG	3988	Rh	[1417-1434] 3′UTR
378	CUGGAAACGACAUUUAUG	2954	CAUAAAUGUCGUUUCCAG	3989		[471-488] ORF
379	GCAAGAUGCACAUCACCC	2955	GGGUGAUGUGCAUCUUGC	3990	Rh, Dg	[660-677] ORF
380	UCAGAAUUCCAGUGGGAG	2956	CUCCCACUGGAAUUCUGA	3991	Rh	[1583-1600] 3′UTR
381	UGUUGAUUUUGUUUCCGU	2957	ACGGAAACAAAAUCAACA	3992		[3453-3470] 3′UTR
382	UGCUGGAAUAUGAAGUCU	2958	AGACUUCAUAUUCCAGCA	3993	Ms	[3504-3521] 3′UTR
383	GUUGUUGAAAGUUGACAA	2959	UUGUCAACUUUCAACAAC	3994		[3552-3569] 3′UTR
384	GGUCGUUGCAAGACUGUG	2960	CACAGUCUUGCAACGACC	3995		[1356-1373] 3′UTR
385	GUAGGUAUUAGACUUGCA	2961	UGCAAGUCUAAUACCUAC	3996		[2910-2927] 3′UTR
386	CUUUGUAUCAUUCUUGAG	2962	CUCAAGAAUGAUACAAAG	3997		[3593-3610] 3′UTR
387	GGGAGCACUGUGUUUAUG	2963	CAUAAACACAGUGCUCCC	3998		[3488-3505] 3′UTR
388	UGUCUCUGAUGCUUUGUA	2964	UACAAAGCAUCAGAGACA	3999		[3582-3599] 3′UTR
389	GUUCCAGCCUCAGCUGAG	2965	CUCAGCUGAGGCUGGAAC	4000		[1652-1669] 3′UTR
390	GGUUAGGAUAGGAAGAAC	2966	GUUCUUCCUAUCCUAACC	4001		[2322-2339] 3′UTR
391	AUAUACAACUCCACCAGA	2967	UCUGGUGGAGUUGUAUAU	4002	Rh	[2733-2750] 3′UTR
392	UCUGAGCCUUGUAGAAAU	2968	AUUUCUACAAGGCUCAGA	4003	Rh	[1607-1624] 3′UTR
393	GUGAGGUCCUGUCCUGAG	2969	CUCAGGACAGGACCUCAC	4004	Rh	[1743-1760] 3′UTR
394	GGGUGGCAGCUGACAGAG	2970	CUCUGUCAGCUGCCACCC	4005		[3200-3217] 3′UTR
395	CAAGCAGACUGCGCAUGU	2971	ACAUGCGCAGUCUGCUUG	4006		[3567-3584] 3′UTR
396	CUCCCUCUGAGCCUUGUA	2972	UACAAGGCUCAGAGGGAG	4007	Rh	[1602-1619] 3′UTR
397	GGAGGUAGGUGGCUUUGG	2973	CCAAAGCCACCUACCUCC	4008	Rh	[2076-2093] 3′UTR
398	GAGCAGAAAACAAAACAG	2974	CUGUUUUGUUUUCUGCUC	4009		[3169-3186] 3′UTR
399	AGAAGGCUCUCCAUUUGG	2975	CCAAAUGGAGAGCCUUCU	4010		[3270-3287] 3′UTR
400	UAUGAAGUCUGAGACCUU	2976	AAGGUCUCAGACUUCAUA	4011		[3512-3529] 3′UTR
401	AACAUUUACUCCUGUUUC	2977	GAAACAGGAGUAAAUGUU	4012	Rh	[2811-2828] 3′UTR
402	GACGAGUGCCUCUGGAUG	2978	CAUCCAGAGGCACUCGUC	4013	Rh, Rb, Cw	[809-826] ORF
403	CUGGGUCACAGAGAAGAA	2979	UUCUUCUCUGUGACCCAG	4014	Rh	[829-846] ORF
404	CUAGGAAGGGAAGGAUUU	2980	AAAUCCUUCCCUUCCUAG	4015	Rh	[2057-2074] 3′UTR
405	CGGCUUCCCUCCCAGUCC	2981	GGACUGGGAGGGAAGCCG	4016		[1236-1253] 3′UTR
406	CCAGUGGGAGCCUCCCUC	2982	GAGGGAGGCUCCCACUGG	4017	Rh	[1591-1608] 3′UTR
407	GAGUUUCUCGACAUCGAG	2983	CUCGAUGUCGAGAAACUC	4018	Ck, Dg	[938-955] ORF
408	AGAAGAGCCGGGUGGCAG	2984	CUGCCACCCGGCUCUUCU	4019		[3191-3208] 3′UTR
409	ACAUCAGCUGUAAUCAUU	2985	AAUGAUUACAGCUGAUGU	4020		[2865-2882] 3′UTR
410	CUCAGAUGAUAGGUGAAC	2986	GUUCACCUAUCAUCUGAG	4021		[2173-2190] 3′UTR
411	GCAGGUGGAUUCCUUCAG	2987	CUGAAGGAAUCCACCUGC	4022	Rh	[2992-3009] 3′UTR
412	GCGCAUGUCUCUGAUGCU	2988	AGCAUCAGAGACAUGCGC	4023		[3577-3594] 3′UTR
413	CAGUAUAUACAACUCCAC	2989	GUGGAGUUGUAUAUACUG	4024	Rh	[2729-2746] 3′UTR
414	CAUUCUUGAGCAAUCGCU	2990	AGCGAUUGCUCAAGAAUG	4025		[3601-3618] 3′UTR
415	CCUCCUCGGCAGUGUGUG	2991	CACACACUGCCGAGGAGG	4026		[579-596] ORF
416	UCCUGUUUCUGCUGAUUG	2992	CAAUCAGCAGAAACAGGA	4027		[2820-2837] 3′UTR
417	CCCUCCUCGGCAGUGUGU	2993	ACACACUGCCGAGGAGGG	4028		[578-595] ORF
418	UACCCUUGGUAGGUAUUA	2994	UAAUACCUACCAAGGGUA	4029		[2902-2919] 3′UTR
419	GCUUCCUGUAUGGUGAUA	2995	UAUCACCAUACAGGAAGC	4030		[2785-2802] 3′UTR
420	GGACAUGGCCCUUGUUUU	2996	AAAACAAGGGCCAUGUCC	4031		[1408-1425] 3′UTR
421	GCAUGAAUAAAACACUCA	2997	UGAGUGUUUUAUUCAUGC	4032	Rh	[1053-1070] 3′UTR
422	CCUGUUUCUGCUGAUUGU	2998	ACAAUCAGCAGAAACAGG	4033		[2821-2838] 3′UTR
423	GCACAUCACCCUCUGUGA	2999	UCACAGAGGGUGAUGUGC	4034	Rh	[667-684] ORF
424	GCCGCUCAAAUACCUUCA	3000	UGAAGGUAUUUGAGCGGC	4035		[3221-3238] 3′UTR
425	GCAACAGGCGUUUUGCAA	3001	UUGCAAAACGCCUGUUGC	4036	Cw, Rt, Ms	[403-420] ORF
426	GGGACGGCAAGAUGCACA	3002	UGUGCAUCUUGCCGUCCC	4037		[654-671] ORF
427	GCCAGGCACUAUGUGUCU	3003	AGACACAUAGUGCCUGGC	4038		[1179-1196] 3′UTR
428	GACACACUCACUUCUUUC	3004	GAAAGAAGUGAGUGUGUC	4039		[2095-2112] 3′UTR
429	CUGAGACCUUCCGGUGCU	3005	AGCACCGGAAGGUCUCAG	4040		[3520-3537] 3′UTR
430	CAGAAGAAGAGCCUGAAC	3006	GUUCAGGCUCUUCUUCUG	4041	Rh, Rb, Cw, Ms, Pg	[719-736] ORF
431	GAUAGGUGAACCUGAGUU	3007	AACUCAGGUUCACCUAUC	4042		[2180-2197] 3′UTR
432	GUUCUAUUCAGCGGCAAC	3008	GUUGCCGCUGAAUAGAAC	4043		[2503-2520] 3′UTR
433	AGACUGGGAGGGUAUCCA	3009	UGGAUACCCUCCCAGUCU	4044	Rh	[2623-2640] 3′UTR
434	GGCCAACUGCAAAAAAAG	3010	CUUUUUUUGCAGUUGGCC	4045		[986-1003] 3′UTR
435	UGGCCUUUAUAUUUGAUC	3011	GAUCAAAUAUAAAGGCCA	4046		[3124-3141] 3′UTR
436	GCUGGGAACACACAAGAG	3012	CUCUUGUGUGUUCCCAGC	4047		[3535-3552] 3′UTR
437	GUGGAAGCAUUUGACCCA	3013	UGGGUCAAAUGCUUCCAC	4048		[2954-2971] 3′UTR
438	CCAUGAUCCCGUGCUACA	3014	UGUAGCACGGGAUCAUGG	4049	Rh, Rb	[780-797] ORF
439	CAGGCAGCACUUAGGGAU	3015	AUCCCUAAGUGCUGCCUG	4050	Rh	[1282-1299] 3′UTR
440	GCAAAGUAAAGGAUCUUU	3016	AAAGAUCCUUUACUUUGC	4051		[3083-3100] 3′UTR
441	GUGGACAAUAAACAGUAU	3017	AUACUGUUUAUUGUCCAC	4052		[3625-3642] 3′UTR
442	UGCAAAAAAAGCCUCCAA	3018	UUGGAGGCUUUUUUUGCA	4053		[993-1010] 3′UTR
443	CAAGCAGGAGUUUCUCGA	3019	UCGAGAAACUCCUGCUUG	4054	Ck, Dg	[931-948] ORF
444	CGUUCCAGCCUCAGCUGA	3020	UCAGCUGAGGCUGGAACG	4055		[1651-1668] 3′UTR
445	CGGUCCGUGGACAAUAAA	3021	UUUAUUGUCCACGGACCG	4056		[3619-3636] 3′UTR
446	UAGGAUAGGAAGAACUUU	3022	AAAGUUCUUCCUAUCCUA	4057		[2325-2342] 3′UTR
447	AGCUGAGUCUUUUUGGUC	3023	GACCAAAAAGACUCAGCU	4058	Rh	[1663-1680] 3′UTR
448	UGGCUUUGGUGACACACU	3024	AGUGUGUCACCAAAGCCA	4059		[2085-2102] 3′UTR
449	GCCGGUGGCUGCCCUCAA	3025	UUGAGGGCAGCCACCGGC	4060	Rh	[1774-1791] 3′UTR
450	CCUGGAACCAGUGGCUAG	3026	CUAGCCACUGGUUCCAGG	4061		[1532-1549] 3′UTR
451	GCCUGUUCUGGCAUCAGG	3027	CCUGAUGCCAGAACAGGC	4062		[1830-1847] 3′UTR
452	GACAGAAAAAGCUGGGUC	3028	GACCCAGCUUUUUCUGUC	4063	Rh	[1930-1947] 3′UTR
453	CAGCCUCCAGGACACUAU	3029	AUAGUGUCCUGGAGGCUG	4064		[2114-2131] 3′UTR
454	GAAGCAUUUGACCCAGAG	3030	CUCUGGGUCAAAUGCUUC	4065		[2957-2974] 3′UTR
455	GGCAUCAGGCACCUGGAU	3031	AUCCAGGUGCCUGAUGCC	4066		[1839-1856] 3′UTR
456	AGGAUAGGAAGAACUUUC	3032	GAAAGUUCUUCCUAUCCU	4067		[2326-2343] 3′UTR
457	AGUGCAAGAUCACGCGCU	3033	AGCGCGUGAUCUUGCACU	4068	Dg, Pg	[759-776] ORF
458	CUUCGAUCCUUGGGUGCA	3034	UGCACCCAAGGAUCGAAG	4069	Rh	[1201-1218] 3′UTR
459	GUAAAGGAUCUUUGAGUA	3035	UACUCAAAGAUCCUUUAC	4070		[3088-3105] 3′UTR
460	CAGGCACCUGGAUUGAGU	3036	ACUCAAUCCAGGUGCCUG	4071	Rh	[1844-1861] 3′UTR
461	AUAAGGAGAAUCUCUUGU	3037	ACAAGAGAUUCUCCUUAU	4072		[2353-2370] 3′UTR
462	UUCCCUCCCUCAAAGACU	3038	AGUCUUUGAGGGAGGGAA	4073		[1973-1990] 3′UTR
463	UCUGGAAACGACAUUUAU	3039	AUAAAUGUCGUUUCCAGA	4074		[470-487] ORF
464	GUAAGAAGUCCAGCCUAG	3040	CUAGGCUGGACUUCUUAC	4075	Rh	[2043-2060] 3′UTR
465	CAAAACAGGUUAAGAAGA	3041	UCUUCUUAACCUGUUUUG	4076		[3179-3196] 3′UTR
466	GGUUGCCAUUGCUUCUUG	3042	CAAGAAGCAAUGGCAACC	4077	Rh	[1813-1830] 3′UTR
467	AGGUCCUCAUCCCAUCCU	3043	AGGAUGGGAUGAGGACCU	4078	Rh	[1155-1172] 3′UTR
468	GUCCGUGGACAAUAAACA	3044	UGUUUAUUGUCCACGGAC	4079		[3621-3638] 3′UTR
469	UGUGUUUAUGCUGGAAUA	3045	UAUUCCAGCAUAAACACA	4080		[3496-3513] 3′UTR
470	GGGCGUUUUCAUGCUGUA	3046	UACAGCAUGAAAACGCCC	4081	Rh	[2661-2678] 3′UTR
471	GGCACCUGGAUUGAGUUG	3047	CAACUCAAUCCAGGUGCC	4082		[1846-1863] 3′UTR
472	CUGUAAUCAUUCCUGUGC	3048	GCACAGGAAUGAUUACAG	4083	Rh	[2872-2889] 3′UTR
473	GGCCUGGAAAUGUGCAUU	3049	AAUGCACAUUUCCAGGCC	4084	Rh	[1321-1338] 3′UTR
474	GGGUCGUUGCAAGACUGU	3050	ACAGUCUUGCAACGACCC	4085		[1355-1372] 3′UTR
475	CAGGCGUUUUGCAAUGCA	3051	UGCAUUGCAAAACGCCUG	4086	Cw, Rt, Ms	[407-424] ORF
476	AGGGUAUCCAGGAAUCGG	3052	CCGAUUCCUGGAUACCCU	4087		[2631-2648] 3′UTR
477	CUGGAAAUGUGCAUUUUG	3053	CAAAAUGCACAUUUCCAG	4088	Rh	[1324-1341] 3′UTR
478	GGUGGCUGCCCUCAAGGU	3054	ACCUUGAGGGCAGCCACC	4089	Rh	[1777-1794] 3′UTR
479	GGUCCAGCUCUGACAUCC	3055	GGAUGUCAGAGCUGGACC	4090	Rh	[1022-1039] 3′UTR
480	GCGGCCUGGGCGUGGUCU	3056	AGACCACGCCCAGGCCGC	4091		[2455-2472] 3′UTR
481	UGCAUUUUGCAGAAACUU	3057	AAGUUUCUGCAAAAUGCA	4092	Rh	[1333-1350] 3′UTR
482	GUCUUUUAACCGUGCUGA	3058	UCAGCACGGUUAAAAGAC	4093		[3153-3170] 3′UTR
483	CUCAAGGUCCCUUCCCUA	3059	UAGGGAAGGGACCUUGAG	4094		[1787-1804] 3′UTR
484	AUCCAGUAUGAGAUCAAG	3060	CUUGAUCUCAUACUGGAU	4095	Rh, Rb	[506-523] ORF
485	GUCUGAAAGGUGUGGCCU	3061	AGGCCACACCUUUCAGAC	4096		[3112-3129] 3′UTR
486	GACGUUGGAGGAAAGAAG	3062	CUUCUUUCCUCCAACGUC	4097	Rt, Ms	[608-625] ORF
487	CUUGUUUCCUCCCACCUG	3063	CAGGUGGGAGGAAACAAG	4098		[2366-2383] 3′UTR
488	GACCUGGUCAGCACAGAU	3064	AUCUGUGCUGACCAGGUC	4099	Rh	[2581-2598] 3′UTR
489	GUUGCAGAUAUACCAACU	3065	AGUUGGUAUAUCUGCAAC	4100	Rh	[2195-2212] 3′UTR
490	CCACACACGUUGGUCUUU	3066	AAAGACCAACGUGUGUGG	4101		[3141-3158] 3′UTR
491	CCCUCUGUGACUUCAUCG	3067	CGAUGAAGUCACAGAGGG	4102	Rh, Cw	[675-692] ORF
492	GAUCCUUGGGUGCAGGCA	3068	UGCCUGCACCCAAGGAUC	4103	Rh	[1205-1222] 3′UTR
493	CAAUGAAACCGAAGCUUG	3069	CAAGCUUCGGUUUCAUUG	4104		[2437-2454] 3′UTR
494	AGCCUUGUAGAAAUGGGA	3070	UCCCAUUUCUACAAGGCU	4105	Rh	[1611-1628] 3′UTR
495	CUGUUCGCUUCCUGUAUG	3071	CAUACAGGAAGCGAACAG	4106		[2779-2796] 3′UTR
496	AUGUGUUCCCUCAGUGUG	3072	CACACUGAGGGAACACAU	4107		[2280-2297] 3′UTR
497	CCAAGCAGGCAGCACUUA	3073	UAAGUGCUGCCUGCUUGG	4108		[1277-1294] 3′UTR
498	GCGAGUGCAAGAUCACGC	3074	GCGUGAUCUUGCACUCGC	4109		[756-773] ORF
499	AUAGUUUAAGAAGGCUCU	3075	AGAGCCUUCUUAAACUAU	4110		[3262-3279] 3′UTR
500	CAGACUGCGCAUGUCUCU	3076	AGAGACAUGCGCAGUCUG	4111		[3571-3588] 3′UTR
501	CCUGUUUUAAGAGACAUC	3077	GAUGUCUCUUAAAACAGG	4112	Rh	[2134-2151] 3′UTR
502	UCAGUAUAUACAACUCCA	3078	UGGAGUUGUAUAUACUGA	4113	Rh	[2728-2745] 3′UTR
503	CGGCAAGAUGCACAUCAC	3079	GUGAUGUGCAUCUUGCCG	4114	Rh, Ck, Dg, Pg	[658-675] ORF
504	CAUCAGCUGUAAUCAUUC	3080	GAAUGAUUACAGCUGAUG	4115		[2866-2883] 3′UTR
505	GCACCUGUUAAGACUCCU	3081	AGGAGUCUUAACAGGUGC	4116	Rh	[2527-2544] 3′UTR
506	GUCUGAGACCUUCCGGUG	3082	CACCGGAAGGUCUCAGAC	4117		[3518-3535] 3′UTR
507	CUUCUUUCUCAGCCUCCA	3083	UGGAGGCUGAGAAAGAAG	4118		[2105-2122] 3′UTR
508	GAUAAGGAGAAUCUCUUG	3084	CAAGAGAUUCUCCUUAUC	4119		[2352-2369] 3′UTR
509	AGAUAUACCAACUUCUGC	3085	GCAGAAGUUGGUAUAUCU	4120	Rh	[2200-2217] 3′UTR
510	CUAUGCAGGUGGAUUCCU	3086	AGGAAUCCACCUGCAUAG	4121	Rh	[2988-3005] 3′UTR
511	AGGAAGCCGCUCAAAUAC	3087	GUAUUUGAGCGGCUUCCU	4122		[3216-3233] 3′UTR
512	CGUGCUACAUCUCCUCCC	3088	GGGAGGAGAUGUAGCACG	4123	Rh	[789-806] ORF
513	AAAAAAGGUUUCUGCAUC	3089	GAUGCAGAAACCUUUUUU	4124		[2936-2953] 3′UTR
514	GGACACGCGGCUUCCCUC	3090	GAGGGAAGCCGCGUGUCC	4125		[1229-1246] 3′UTR
515	UAGAGUUUAUCUACACGG	3091	CCGUGUAGAUAAACUCUA	4126	Dg, Pg	[558-575] ORF
516	UCAAAGACUGACAGCCAU	3092	AUGGCUGUCAGUCUUUGA	4127	Rh	[1982-1999] 3′UTR
517	UGACAUCAGCUGUAAUCA	3093	UGAUUACAGCUGAUGUCA	4128		[2863-2880] 3′UTR
518	AGUUGCACAGCUUUGCUU	3094	AAGCAAAGCUGUGCAACU	4129		[1859-1876] 3′UTR
519	AGUGGCUAGUUCUUGAAG	3095	CUUCAAGAACUAGCCACU	4130		[1541-1558] 3′UTR
520	UGGCAACCCUAUCAAGAG	3096	CUCUUGAUAGGGUUGCCA	4131		[487-504] ORF
521	GUGGCUGCCCUCAAGGUC	3097	GACCUUGAGGGCAGCCAC	4132	Rh	[1778-1795] 3′UTR
522	GCGUUUUGCAAUGCAGAU	3098	AUCUGCAUUGCAAAACGC	4133		[410-427] ORF
523	GAUCAAGCAGAUAAAGAU	3099	AUCUUUAUCUGCUUGAUC	4134	Cw, Dg, Rt, Ms, Pg	[517-534] ORF
524	GCAGGCAGCACUUAGGGA	3100	UCCCUAAGUGCUGCCUGC	4135	Rh	[1281-1298] 3′UTR
525	CUCCAACCCAUAUAACAC	3101	GUGUUAUAUGGGUUGGAG	4136		[2754-2771] 3′UTR
526	GAACUAGGGAACCUAUGU	3102	ACAUAGGUUCCCUAGUUC	4137	Rh	[2266-2283] 3′UTR
527	GACGAUAUACAGGCACAU	3103	AUGUGCCUGUAUAUCGUC	4138		[2401-2418] 3′UTR
528	GAAAUAUUGGACUUGCUG	3104	CAGCAAGUCCAAUAUUUC	4139		[3419-3436] 3′UTR
529	GAAGCCGCUCAAAUACCU	3105	AGGUAUUUGAGCGGCUUC	4140		[3218-3235] 3′UTR
530	GGCAGCCUGGAACCAGUG	3106	CACUGGUUCCAGGCUGCC	4141		[1527-1544] 3′UTR
531	GUCUGGAGGGAGACGUGG	3107	CCACGUCUCCCUCCAGAC	4142		[1132-1149] 3′UTR
532	CAUAGUAAGAAGUCCAGC	3108	GCUGGACUUCUUACUAUG	4143		[2039-2056] 3′UTR
533	CUCCUGUUUCUGCUGAUU	3109	AAUCAGCAGAAACAGGAG	4144		[2819-2836] 3′UTR
534	CAGAAUUCCAGUGGGAGC	3110	GCUCCCACUGGAAUUCUG	4145	Rh	[1584-1601] 3′UTR
535	AGCACUGUGUUUAUGCUG	3111	CAGCAUAAACACAGUGCU	4146		[3491-3508] 3′UTR
536	GUAACAUUUACUCCUGUU	3112	AACAGGAGUAAAUGUUAC	4147	Rh	[2809-2826] 3′UTR
537	UGAGCUGCGUUCCAGCCU	3113	AGGCUGGAACGCAGCUCA	4148		[1644-1661] 3′UTR
538	AGGUGGAUUCCUUCAGGU	3114	ACCUGAAGGAAUCCACCU	4149	Rh	[2994-3011] 3′UTR
539	UUUGUUUCCGUUUGGAUU	3115	AAUCCAAACGGAAACAAA	4150		[3460-3477] 3′UTR
540	AAAGGAUCUUUGAGUAGG	3116	CCUACUCAAAGAUCCUUU	4151		[3090-3107] 3′UTR
541	GGUCUGGAGGGAGACGUG	3117	CACGUCUCCCUCCAGACC	4152		[1131-1148] 3′UTR
542	UGAGAUCAAGCAGAUAAA	3118	UUUAUCUGCUUGAUCUCA	4153	Rh, Cw, Dg, Rt, Ms	[514-531] ORF
543	GGAGGGUAUCCAGGAAUC	3119	GAUUCCUGGAUACCCUCC	4154		[2629-2646] 3′UTR
544	GAGUUGCACAGCUUUGCU	3120	AGCAAAGCUGUGCAACUC	4155		[1858-1875] 3′UTR
545	CCUUCACAAUAAAUAGUG	3121	CACUAUUUAUUGUGAAGG	4156		[3233-3250] 3′UTR
546	CUUGUUUUCUGCAGCUUC	3122	GAAGCUGCAGAAAACAAG	4157	Rh	[1418-1435] 3′UTR
547	AUUGAGUUGCACAGCUUU	3123	AAAGCUGUGCAACUCAAU	4158		[1855-1872] 3′UTR
548	UGAUUUUGUUUCCGUUUG	3124	CAAACGGAAACAAAAUCA	4159		[3456-3473] 3′UTR
549	CAGCUCUCUUCUCCUAUU	3125	AAUAGGAGAAGAGAGCUG	4160		[3320-3337] 3′UTR
550	GGCCUACCAGGUCCCUUU	3126	AAAGGGACCUGGUAGGCC	4161	Rh	[1379-1396] 3′UTR
551	UGUUAUGUUCUAAGCACA	3127	UGUGCUUAGAACAUAACA	4162		[3304-3321] 3′UTR
552	GAGCCGGGUGGCAGCUGA	3128	UCAGCUGCCACCCGGCUC	4163		[3195-3212] 3′UTR
553	GGAGGAAUCGGUGAGGUC	3129	GACCUCACCGAUUCCUCC	4164		[1733-1750] 3′UTR
554	CCUGGGACACCCUGAGCA	3130	UGCUCAGGGUGUCCCAGG	4165	Rh, Dg, Pg	[696-713] ORF
555	UGUGCAUUUUGCAGAAAC	3131	GUUUCUGCAAAAUGCACA	4166	Rh, Rt, Ms	[1331-1348] 3′UTR
556	CCCUCUGCCAGGCACUAU	3132	AUAGUGCCUGGCAGAGGG	4167		[1173-1190] 3′UTR
557	AGUCUGAGACCUUCCGGU	3133	ACCGGAAGGUCUCAGACU	4168		[3517-3534] 3′UTR
558	CAACUUCUGCUUGUAUUU	3134	AAAUACAAGCAGAAGUUG	4169	Rh	[2208-2225] 3′UTR
559	CAGCCUGGAACCAGUGGC	3135	GCCACUGGUUCCAGGCUG	4170		[1529-1546] 3′UTR
560	GCUUUGGUGACACACUCA	3136	UGAGUGUGUCACCAAAGC	4171		[2087-2104] 3′UTR
561	CGCCUGCAUCAAGAGAAG	3137	CUUCUCUUGAUGCAGGCG	4172	Rh, Cw, Dg, Rt, Ms	[874-891] ORF
562	CUCCAAGGGUUUCGACUG	3138	CAGUCGAAACCCUUGGAG	4173	Rh	[1005-1022] 3′UTR
563	UGCUGGGAACACACAAGA	3139	UCUUGUGUGUUCCCAGCA	4174		[3534-3551] 3′UTR
564	ACAUUUACUCCUGUUUCU	3140	AGAAACAGGAGUAAAUGU	4175	Rh	[2812-2829] 3′UTR
565	GGUUUCGACUGGUCCAGC	3141	GCUGGACCAGUCGAAACC	4176	Rh	[1012-1029] 3′UTR
566	CAGCUGUAAUCAUUCCUG	3142	CAGGAAUGAUUACAGCUG	4177		[2869-2886] 3′UTR
567	CCAUCUGCACAUCCUGAG	3143	CUCAGGAUGUGCAGAUGG	4178	Rh	[1912-1929] 3′UTR
568	CAUCCCAUGGGUCCAAAU	3144	AUUUGGACCCAUGGGAUG	4179		[1069-1086] 3′UTR
569	CUGUUUCUGCUGAUUGUU	3145	AACAAUCAGCAGAAACAG	4180		[2822-2839] 3′UTR
570	GUGGCUUUGGUGACACAC	3146	GUGUGUCACCAAAGCCAC	4181		[2084-2101] 3′UTR
571	GGCAGCUGACAGAGGAAG	3147	CUUCCUCUGUCAGCUGCC	4182		[3204-3221] 3′UTR
572	AGAUCUUGAUGACUUCCC	3148	GGGAAGUCAUCAAGAUCU	4183	Rh	[2595-2612] 3′UTR
573	UGCAAGACUGUGUAGCAG	3149	CUGCUACACAGUCUUGCA	4184	Rh	[1362-1379] 3′UTR
574	CAGAUGUAGUGAUCAGGG	3150	CCCUGAUCACUACAUCUG	4185		[423-440] ORF
575	CAUUUGGCAUCGUUUAAU	3151	AUUAAACGAUGCCAAAUG	4186		[3281-3298] 3′UTR
576	CAGAAAAAGCUGGGUCUU	3152	AAGACCCAGCUUUUUCUG	4187	Rh	[1932-1949] 3′UTR
577	CCCAGAGUGGAACGCGUG	3153	CACGCGUUCCACUCUGGG	4188		[2968-2985] 3′UTR
578	ACCUGUUAAGACUCCUGA	3154	UCAGGAGUCUUAACAGGU	4189	Rh	[2529-2546] 3′UTR
579	CAUCACCCUCUGUGACUU	3155	AAGUCACAGAGGGUGAUG	4190	Rh, Cw	[670-687] ORF
580	GGCUUCGAUCCUUGGGUG	3156	CACCCAAGGAUCGAAGCC	4191	Rh	[1199-1216] 3′UTR
581	CCUUGGCACCGUCACAGA	3157	UCUGUGACGGUGCCAAGG	4192	Rh	[1257-1274] 3′UTR
582	CAAGAGAAGUGACGGCUC	3158	GAGCCGUCACUUCUCUUG	4193		[883-900] ORF
583	AGCUCUCUUCUCCUAUUU	3159	AAAUAGGAGAAGAGAGCU	4194		[3321-3338] 3′UTR
584	GCAGCCUGGAACCAGUGG	3160	CCACUGGUUCCAGGCUGC	4195		[1528-1545] 3′UTR
585	UGGACUCUGGAAACGACA	3161	UGUCGUUUCCAGAGUCCA	4196	Rh	[465-482] ORF
586	CACUCACUUCUUUCUCAG	3162	CUGAGAAAGAAGUGAGUG	4197		[2099-2116] 3′UTR
587	ACCGUGCUGAGCAGAAAA	3163	UUUUCUGCUCAGCACGGU	4198		[3161-3178] 3′UTR
588	AGAAUCUCUUGUUUCCUC	3164	GAGGAAACAAGAGAUUCU	4199		[2359-2376] 3′UTR
589	ACAGCUCUCUUCUCCUAU	3165	AUAGGAGAAGAGAGCUGU	4200		[3319-3336] 3′UTR
590	UCCUCAGAAUUCCAGUGG	3166	CCACUGGAAUUCUGAGGA	4201	Rh	[1580-1597] 3′UTR
591	GGCCCUUGUUUUCUGCAG	3167	CUGCAGAAAACAAGGGCC	4202	Rh	[1414-1431] 3′UTR
592	GUGGGUCUGGAGGGAGAC	3168	GUCUCCCUCCAGACCCAC	4203	Rh	[1128-1145] 3′UTR
593	AUCUCUUGUUUCCUCCCA	3169	UGGGAGGAAACAAGAGAU	4204		[2362-2379] 3′UTR
594	GAACCACAGGUACCAGAU	3170	AUCUGGUACCUGUGGUUC	4205	Rh, Rb, Cw, Rt, Ms, Pg	[733-750] ORF
595	GCCUCCAAGGGUUUCGAC	3171	GUCGAAACCCUUGGAGGC	4206	Rh	[1003-1020] 3′UTR
596	CAGCAUGAAUAAAACACU	3172	AGUGUUUUAUUCAUGCUG	4207	Rh	[1051-1068] 3′UTR
597	CACCCAGAAGAAGAGCCU	3173	AGGCUCUUCUUCUGGGUG	4208	Rh, Ck, Cw, Rt, Ms, Pg	[715-732] ORF
598	UCAUAAUGGACCAGUCCA	3174	UGGACUGGUCCAUUAUGA	4209	Rh	[2703-2720] 3′UTR
599	ACAUCACCCUCUGUGACU	3175	AGUCACAGAGGGUGAUGU	4210	Rh	[669-686] ORF
600	CCUUCCUGGAAACAGCAU	3176	AUGCUGUUUCCAGGAAGG	4211	Rh, Rb, Rt, Ms	[1039-1056] 3′UTR
601	AGCCUCCAAGGGUUUCGA	3177	UCGAAACCCUUGGAGGCU	4212	Rh	[1002-1019] 3′UTR
602	UGACACACUCACUUCUUU	3178	AAAGAAGUGAGUGUGUCA	4213		[2094-2111] 3′UTR
603	UGUGGGUCUGGAGGGAGA	3179	UCUCCCUCCAGACCCACA	4214	Rh	[1127-1144] 3′UTR
604	AGGCUCUCCAUUUGGCAU	3180	AUGCCAAAUGGAGAGCCU	4215		[3273-3290] 3′UTR
605	CCAGUCCAUGUGAUUUCA	3181	UGAAAUCACAUGGACUGG	4216	Rh	[2713-2730] 3′UTR
606	GACGUGGGUCCAAGGUCC	3182	GGACCUUGGACCCACGUC	4217		[1143-1160] 3′UTR
607	GGACAGAAAAAGCUGGGU	3183	ACCCAGCUUUUUCUGUCC	4218	Rh	[1929-1946] 3′UTR
608	CUACCAGGUCCCUUUCAU	3184	AUGAAAGGGACCUGGUAG	4219	Rh	[1382-1399] 3′UTR
609	AAUCCUCAGAAUUCCAGU	3185	ACUGGAAUUCUGAGGAUU	4220	Rh	[1578-1595] 3′UTR
610	CUUUGAGUAGGUUCGGUC	3186	GACCGAACCUACUCAAAG	4221		[3097-3114] 3′UTR
611	GCCGGGUGGCAGCUGACA	3187	UGUCAGCUGCCACCCGGC	4222		[3197-3214] 3′UTR
612	GCAGAAACUUUUGAGGGU	3188	ACCCUCAAAAGUUUCUGC	4223	Rh	[1341-1358] 3′UTR
613	CAGUGGCUAGUUCUUGAA	3189	UUCAAGAACUAGCCACUG	4224		[1540-1557] 3′UTR
614	GAAAUGGGAGCGAGAAAC	3190	GUUUCUCGCUCCCAUUUC	4225		[1620-1637] 3′UTR
615	GCAGACUGCGCAUGUCUC	3191	GAGACAUGCGCAGUCUGC	4226		[3570-3587] 3′UTR
616	UGUAAUCAUUCCUGUGCU	3192	AGCACAGGAAUGAUUACA	4227	Rh	[2873-2890] 3′UTR
617	UGGUAGGUAUUAGACUUG	3193	CAAGUCUAAUACCUACCA	4228		[2908-2925] 3′UTR
618	CAUUUACUCCUGUUUCUG	3194	CAGAAACAGGAGUAAAUG	4229	Rh	[2813-2830] 3′UTR
619	AUGAAGUCUGAGACCUUC	3195	GAAGGUCUCAGACUUCAU	4230		[3513-3530] 3′UTR
620	CUUGAUGACUUCCCUUUC	3196	GAAAGGGAAGUCAUCAAG	4231	Rh	[2599-2616] 3′UTR
621	CAACAGGCGUUUUGCAAU	3197	AUUGCAAAACGCCUGUUG	4232	Cw, Rt, Ms	[404-421] ORF
622	CCAUAAGCAGGCCUCCAA	3198	UUGGAGGCCUGCUUAUGG	4233		[959-976]
						ORF + 3′UTR
623	GUACAGUGACCUAAAGUU	3199	AACUUUAGGUCACUGUAC	4234		[2676-2693] 3′UTR
624	GCAUAGUAAGAAGUCCAG	3200	CUGGACUUCUUACUAUGC	4235		[2038-2055] 3′UTR
625	ACACUCACUUCUUUCUCA	3201	UGAGAAAGAAGUGAGUGU	4236		[2098-2115] 3′UTR
626	AUCAAGAGGAUCCAGUAU	3202	AUACUGGAUCCUCUUGAU	4237	Rh, Rb	[497-514] ORF
627	AGUGAGAAGGAAGUGGAC	3203	GUCCACUUCCUUCUCACU	4238		[452-469] ORF
628	GCCUAUGCAGGUGGAUUC	3204	GAAUCCACCUGCAUAGGC	4239	Rh	[2986-3003] 3′UTR
629	CACCGUCACAGAUGCCAA	3205	UUGGCAUCUGUGACGGUG	4240		[1263-1280] 3′UTR
630	CUUUCUAGGGCAGACUGG	3206	CCAGUCUGCCCUAGAAAG	4241	Rh	[2612-2629] 3′UTR
631	CCCUCCCUCAAAGACUGA	3207	UCAGUCUUUGAGGGAGGG	4242		[1975-1992] 3′UTR
632	CUAAGCAUAGUAAGAAGU	3208	ACUUCUUACUAUGCUUAG	4243		[2034-2051] 3′UTR
633	CAGAUAUACCAACUUCUG	3209	CAGAAGUUGGUAUAUCUG	4244	Rh	[2199-2216] 3′UTR
634	UUGCAGAUAUACCAACUU	3210	AAGUUGGUAUAUCUGCAA	4245	Rh	[2196-2213] 3′UTR
635	GCCUCCCUCUGAGCCUUG	3211	CAAGGCUCAGAGGGAGGC	4246	Rh	[1600-1617] 3′UTR
636	GGAAAUGUGCAUUUUGCA	3212	UGCAAAAUGCACAUUUCC	4247	Rh	[1326-1343] 3′UTR
637	CUCCCAGGCUUAGUGUUC	3213	GAACACUAAGCCUGGGAG	4248		[1958-1975] 3′UTR
638	CUUUGGUGACACACUCAC	3214	GUGAGUGUGUCACCAAAG	4249		[2088-2105] 3′UTR
639	CAUCAAGAGAAGUGACGG	3215	CCGUCACUUCUCUUGAUG	4250		[880-897] ORF
640	CAGCCAUCGUUCUGCACG	3216	CGUGCAGAACGAUGGCUG	4251	Rh	[1993-2010] 3′UTR
641	CAAAGACUGACAGCCAUC	3217	GAUGGCUGUCAGUCUUUG	4252	Rh	[1983-2000] 3′UTR
642	AGCAGAAAACAAAACAGG	3218	CCUGUUUUGUUUUCUGCU	4253		[3170-3187] 3′UTR
643	GCACUUAGGGAUCUCCCA	3219	UGGGAGAUCCCUAAGUGC	4254	Rh	[1288-1305] 3′UTR
644	UGGACCAGUCCAUGUGAU	3220	AUCACAUGGACUGGUCCA	4255	Rh	[2709-2726] 3′UTR
645	AUGUGCAUUUUGCAGAAA	3221	UUUCUGCAAAAUGCACAU	4256	Rh, Ms	[1330-1347] 3′UTR
646	UGUAACAUUUACUCCUGU	3222	ACAGGAGUAAAUGUUACA	4257	Rh	[2808-2825] 3′UTR
647	GCUGUAAUCAUUCCUGUG	3223	CACAGGAAUGAUUACAGC	4258	Rh	[2871-2888] 3′UTR
648	UAAGGAGAAUCUCUUGUU	3224	AACAAGAGAUUCUCCUUA	4259		[2354-2371] 3′UTR
649	UGACAAGCAGACUGCGCA	3225	UGCGCAGUCUGCUUGUCA	4260		[3564-3581] 3′UTR
650	UCCUGUAUGGUGAUAUCA	3226	UGAUAUCACCAUACAGGA	4261		[2788-2805] 3′UTR
651	GAUAGGAAGAACUUUCUC	3227	GAGAAAGUUCUUCCUAUC	4262	Rh	[2328-2345] 3′UTR
652	CAUUCCUGUGCUGUGUUU	3228	AAACACAGCACAGGAAUG	4263	Rh	[2879-2896] 3′UTR
653	CAAGGUCCCUUCCCUAGC	3229	GCUAGGGAAGGGACCUUG	4264		[1789-1806] 3′UTR
654	CCGUCUUUGGUUCUCCAG	3230	CUGGAGAACCAAAGACGG	4265		[3054-3071] 3′UTR
655	GCUUCUUGCCUGUUCUGG	3231	CCAGAACAGGCAAGAAGC	4266		[1823-1840] 3′UTR
656	UGGGCUGCGAGUGCAAGA	3232	UCUUGCACUCGCAGCCCA	4267	Ck, Rb, Rt	[750-767] ORF
657	GAUGGGCUGCGAGUGCAA	3233	UUGCACUCGCAGCCCAUC	4268	Ck, Rb, Rt	[748-765] ORF
658	CUGUUCUGGCAUCAGGCA	3234	UGCCUGAUGCCAGAACAG	4269		[1832-1849] 3′UTR
659	GGGUAUCCAGGAAUCGGC	3235	GCCGAUUCCUGGAUACCC	4270		[2632-2649] 3′UTR
660	GCAACCCUAUCAAGAGGA	3236	UCCUCUUGAUAGGGUUGC	4271		[489-506] ORF
661	CCCAUCUGCACAUCCUGA	3237	UCAGGAUGUGCAGAUGGG	4272	Rh	[1911-1928] 3′UTR
662	UAUAGUUUAAGAAGGCUC	3238	GAGCCUUCUUAAACUAUA	4273		[3261-3278] 3′UTR
663	AGCCUGAACCACAGGUAC	3239	GUACCUGUGGUUCAGGCU	4274	Rh, Rb, Cw, Ms, Pg	[728-745] ORF
664	CGUUGCAAGACUGUGUAG	3240	CUACACAGUCUUGCAACG	4275		[1359-1376] 3′UTR
665	CGUCACAGAUGCCAAGCA	3241	UGCUUGGCAUCUGUGACG	4276		[1266-1283] 3′UTR
666	UGAGAAGGAAGUGGACUC	3242	GAGUCCACUUCCUUCUCA	4277		[454-471] ORF
667	AUCCCUUCCUGGAAACAG	3243	CUGUUUCCAGGAAGGGAU	4278	Rh, Rb, Rt, Ms	[1036-1053] 3′UTR
668	CAAAGCACCUGUUAAGAC	3244	GUCUUAACAGGUGCUUUG	4279	Rh	[2523-2540] 3′UTR
669	AGGUCCCUUUCAUCUUGA	3245	UCAAGAUGAAAGGGACCU	4280	Rh	[1387-1404] 3′UTR
670	CCUUUUAGACAUGGUUGU	3246	ACAACCAUGUCUAAAAGG	4281		[1112-1129] 3′UTR
671	AGCCUAGGAAGGGAAGGA	3247	UCCUUCCCUUCCUAGGCU	4282	Rh	[2054-2071] 3′UTR
672	GCUUUAUCCGGGCUUGUG	3248	CACAAGCCCGGAUAAAGC	4283		[1873-1890] 3′UTR
673	CUCUUCUCCUAUUUUCAU	3249	AUGAAAAUAGGAGAAGAG	4284		[3325-3342] 3′UTR
674	CGUAAUUUAAAGCUCUGU	3250	ACAGAGCUUUAAAUUACG	4285		[3438-3455] 3′UTR
675	CCUAAAGUUGGUAAGAUG	3251	CAUCUUACCAACUUUAGG	4286	Rh	[2685-2702] 3′UTR
676	CUGUGCUGUGUUUUUUAU	3252	AUAAAAAACACAGCACAG	4287	Rh	[2884-2901] 3′UTR
677	ACCCAGAGUGGAACGCGU	3253	ACGCGUUCCACUCUGGGU	4288		[2967-2984] 3′UTR
678	GUUCUAAGCACAGCUCUC	3254	GAGAGCUGUGCUUAGAAC	4289		[3310-3327] 3′UTR
679	CUGUGUUUUUUAUUACCC	3255	GGGUAAUAAAAAACACAG	4290	Rh	[2889-2906] 3′UTR
680	GGACGGCAAGAUGCACAU	3256	AUGUGCAUCUUGCCGUCC	4291		[655-672] ORF
681	GUUGAUUUUGUUUCCGUU	3257	AACGGAAACAAAAUCAAC	4292		[3454-3471] 3′UTR
682	CUCCUUUUAGACAUGGUU	3258	AACCAUGUCUAAAAGGAG	4293		[1110-1127] 3′UTR
683	UGAUGCUUUGUAUCAUUC	3259	GAAUGAUACAAAGCAUCA	4294		[3588-3605] 3′UTR
684	CUUUAUCCGGGCUUGUGU	3260	ACACAAGCCCGGAUAAAG	4295		[1874-1891] 3′UTR
685	AUAGAGUUUAUCUACACG	3261	CGUGUAGAUAAACUCUAU	4296	Dg, Pg	[557-574] ORF
686	GGGAUCUCCCAGCUGGGU	3262	ACCCAGCUGGGAGAUCCC	4297		[1295-1312] 3′UTR
687	GUGAACCUGAGUUGCAGA	3263	UCUGCAACUCAGGUUCAC	4298	Rh	[2185-2202] 3′UTR
688	AGUGCCUCUGGAUGGACU	3264	AGUCCAUCCAGAGGCACU	4299	Rh, Rb, Cw, Dg, Rt, Ms	[813-830] ORF
689	GAAAGUUGACAAGCAGAC	3265	GUCUGCUUGUCAACUUUC	4300		[3558-3575] 3′UTR
690	UUGCAAAAUGCUUCCAAA	3266	UUUGGAAGCAUUUUGCAA	4301	Rh	[2472-2489] 3′UTR
691	GUAAAGAUAAACUGACGA	3267	UCGUCAGUUUAUCUUUAC	4302	Rh	[2388-2405] 3′UTR
692	CCAAAGCCACCUUAGCCU	3268	AGGCUAAGGUGGCUUUGG	4303	Rh	[2485-2502] 3′UTR
693	AGAAAAAGCUGGGUCUUG	3269	CAAGACCCAGCUUUUUCU	4304	Rh	[1933-1950] 3′UTR
694	CUGCCGUAAUUUAAAGCU	3270	AGCUUUAAAUUACGGCAG	4305		[3434-3451] 3′UTR
695	UCCCUUUCAUCUUGAGAG	3271	CUCUCAAGAUGAAAGGGA	4306	Rh	[1390-1407] 3′UTR
696	GAUCUUGAUGACUUCCCU	3272	AGGGAAGUCAUCAAGAUC	4307	Rh	[2596-2613] 3′UTR
697	UCAGUGUGGUUUCCUGAA	3273	UUCAGGAAACCACACUGA	4308		[2290-2307] 3′UTR
698	GGAGCCUCCCUCUGAGCC	3274	GGCUCAGAGGGAGGCUCC	4309	Rh	[1597-1614] 3′UTR
699	UGGUAAGAUGUCAUAAUG	3275	CAUUAUGACAUCUUACCA	4310	Rh	[2693-2710] 3′UTR
700	AAGCAUUUGACCCAGAGU	3276	ACUCUGGGUCAAAUGCUU	4311		[2958-2975] 3′UTR
701	AGCUAAGAAACUUCCUAG	3277	CUAGGAAGUUUCUUAGCU	4312		[2247-2264] 3′UTR
702	CAGGUUAAGAAGAGCCGG	3278	CCGGCUCUUCUUAACCUG	4313		[3184-3201] 3′UTR
703	GACUGCGCAUGUCUCUGA	3279	UCAGAGACAUGCGCAGUC	4314		[3573-3590] 3′UTR
704	GUAGGUUCGGUCUGAAAG	3280	CUUUCAGACCGAACCUAC	4315		[3103-3120] 3′UTR
705	UGAAAGUUGACAAGCAGA	3281	UCUGCUUGUCAACUUUCA	4316		[3557-3574] 3′UTR
706	AACUUCUGCUUGUAUUUC	3282	GAAAUACAAGCAGAAGUU	4317	Rh	[2209-2226] 3′UTR
707	GACAAGCAGACUGCGCAU	3283	AUGCGCAGUCUGCUUGUC	4318		[3565-3582] 3′UTR
708	AAGUCUGAGACCUUCCGG	3284	CCGGAAGGUCUCAGACUU	4319		[3516-3533] 3′UTR
709	CUCUGACAUCCCUUCCUG	3285	CAGGAAGGGAUGUCAGAG	4320	Rh	[1029-1046] 3′UTR
710	GUAAACAUACACACGCAA	3286	UUGCGUGUGUAUGUUUAC	4321	Rh	[2422-2439] 3′UTR
711	CCUCUGGAUGGACUGGGU	3287	ACCCAGUCCAUCCAGAGG	4322	Rh, Rb, Cw, Dg, Rt, Ms,	[817-834] ORF
					Pg
712	GAUGACUUCCCUUUCUAG	3288	CUAGAAAGGGAAGUCAUC	4323	Rh	[2602-2619] 3′UTR
713	CCUACCAGGUCCCUUUCA	3289	UGAAAGGGACCUGGUAGG	4324	Rh	[1381-1398] 3′UTR
714	CAAGGUCCUCAUCCCAUC	3290	GAUGGGAUGAGGACCUUG	4325		[1153-1170] 3′UTR
715	GAUCUUUGAGUAGGUUCG	3291	CGAACCUACUCAAAGAUC	4326		[3094-3111] 3′UTR
716	AGAAAUAUUGGACUUGCU	3292	AGCAAGUCCAAUAUUUCU	4327		[3418-3435] 3′UTR
717	CUGCCCUCAAGGUCCCUU	3293	AAGGGACCUUGAGGGCAG	4328	Rh	[1782-1799] 3′UTR
718	CUAGGGAACCUAUGUGUU	3294	AACACAUAGGUUCCCUAG	4329	Rh	[2269-2286] 3′UTR
719	CAAGCAGGCAGCACUUAG	3295	CUAAGUGCUGCCUGCUUG	4330		[1278-1295] 3′UTR
720	CCCACCGGGACCUGGUCA	3296	UGACCAGGUCCCGGUGGG	4331		[2573-2590] 3′UTR
721	GUUUCUGCAUCGUGGAAG	3297	CUUCCACGAUGCAGAAAC	4332	Rh	[2943-2960] 3′UTR
722	GUGACCUAAAGUUGGUAA	3298	UUACCAACUUUAGGUCAC	4333		[2681-2698] 3′UTR
723	UGGGAACACACAAGAGUU	3299	AACUCUUGUGUGUUCCCA	4334		[3537-3554] 3′UTR
724	GAAUCGGUGAGGUCCUGU	3300	ACAGGACCUCACCGAUUC	4335		[1737-1754] 3′UTR
725	CCCUCCCAGGCUUAGUGU	3301	ACACUAAGCCUGGGAGGG	4336		[1956-1973] 3′UTR
726	CCCACAUCCAAGGGCAGC	3302	GCUGCCCUUGGAUGUGGG	4337		[1515-1532] 3′UTR
727	AGCCUCCCUCUGAGCCUU	3303	AAGGCUCAGAGGGAGGCU	4338	Rh	[1599-1616] 3′UTR
728	CAUGAUCCCGUGCUACAU	3304	AUGUAGCACGGGAUCAUG	4339	Rh, Rb	[781-798] ORF
729	CAUAAUGGACCAGUCCAU	3305	AUGGACUGGUCCAUUAUG	4340	Rh	[2704-2721] 3′UTR
730	GUCACAGAUGCCAAGCAG	3306	CUGCUUGGCAUCUGUGAC	4341		[1267-1284] 3′UTR
731	UGCAUCAAGAGAAGUGAC	3307	GUCACUUCUCUUGAUGCA	4342		[878-895] ORF
732	GAGACCUUCCGGUGCUGG	3308	CCAGCACCGGAAGGUCUC	4343		[3522-3539] 3′UTR
733	UACCUAGCUAAGAAACUU	3309	AAGUUUCUUAGCUAGGUA	4344	Rh	[2242-2259] 3′UTR
734	GCUGCGUUCCAGCCUCAG	3310	CUGAGGCUGGAACGCAGC	4345		[1647-1664] 3′UTR
735	UGGUUUCCUGAAGCCAGU	3311	ACUGGCUUCAGGAAACCA	4346		[2296-2313] 3′UTR
736	GCAGAUGUAGUGAUCAGG	3312	CCUGAUCACUACAUCUGC	4347		[422-439] ORF
737	CACCUGGAUUGAGUUGCA	3313	UGCAACUCAAUCCAGGUG	4348		[1848-1865] 3′UTR
738	UUGGUUCUCCAGUUCAAA	3314	UUUGAACUGGAGAACCAA	4349		[3060-3077] 3′UTR
739	CUUGGCACCGUCACAGAU	3315	AUCUGUGACGGUGCCAAG	4350	Rh	[1258-1275] 3′UTR
740	CUUCCAAAGCCACCUUAG	3316	CUAAGGUGGCUUUGGAAG	4351	Rh	[2482-2499] 3′UTR
741	GGGCCUGGAAAUGUGCAU	3317	AUGCACAUUUCCAGGCCC	4352	Rh	[1320-1337] 3′UTR
742	CACGCGGCUUCCCUCCCA	3318	UGGGAGGGAAGCCGCGUG	4353		[1232-1249] 3′UTR
743	CAAGUUCUUCGCCUGCAU	3319	AUGCAGGCGAAGAACUUG	4354	Rh, Rb, Cw, Dg, Ms	[865-882] ORF
744	CUGAAGCCAGUGAUAUGG	3320	CCAUAUCACUGGCUUCAG	4355		[2303-2320] 3′UTR
745	UUCUCAGCCUCCAGGACA	3321	UGUCCUGGAGGCUGAGAA	4356		[2110-2127] 3′UTR
746	UAUUACCCUUGGUAGGUA	3322	UACCUACCAAGGGUAAUA	4357		[2899-2916] 3′UTR
747	AGGAUCUUUGAGUAGGUU	3323	AACCUACUCAAAGAUCCU	4358		[3092-3109] 3′UTR
748	GGCUUCCCUCCCAGUCCC	3324	GGGACUGGGAGGGAAGCC	4359		[1237-1254] 3′UTR
749	UCUCGGUAAUGAUAAGGA	3325	UCCUUAUCAUUACCGAGA	4360		[2342-2359] 3′UTR
750	GCUUGCAGGAGGAAUCGG	3326	CCGAUUCCUCCUGCAAGC	4361		[1726-1743] 3′UTR
751	GUGGUCUUGCAAAAUGCU	3327	AGCAUUUUGCAAGACCAC	4362		[2466-2483] 3′UTR
752	CCUCAGCUGAGUCUUUUU	3328	AAAAAGACUCAGCUGAGG	4363	Rh	[1659-1676] 3′UTR
753	AGAAGUGACGGCUCCUGU	3329	ACAGGAGCCGUCACUUCU	4364		[887-904] ORF
754	CGUGGUCUUGCAAAAUGC	3330	GCAUUUUGCAAGACCACG	4365		[2465-2482] 3′UTR
755	ACCGGGACCUGGUCAGCA	3331	UGCUGACCAGGUCCCGGU	4366		[2576-2593] 3′UTR
756	GAUCCACACACGUUGGUC	3332	GACCAACGUGUGUGGAUC	4367		[3138-3155] 3′UTR
757	UAUAUUUGAUCCACACAC	3333	GUGUGUGGAUCAAAUAUA	4368		[3131-3148] 3′UTR
758	ACCUAUGUGUUCCCUCAG	3334	CUGAGGGAACACAUAGGU	4369		[2276-2293] 3′UTR
759	GUUUUUUAUUACCCUUGG	3335	CCAAGGGUAAUAAAAAAC	4370	Rh	[2893-2910] 3′UTR
760	GAAGUGGACUCUGGAAAC	3336	GUUUCCAGAGUCCACUUC	4371		[461-478] ORF
761	CGCGGCUUCCCUCCCAGU	3337	ACUGGGAGGGAAGCCGCG	4372		[1234-1251] 3′UTR
762	CCCUAUCAAGAGGAUCCA	3338	UGGAUCCUCUUGAUAGGG	4373		[493-510] ORF
763	CCCGGACGAGUGCCUCUG	3339	CAGAGGCACUCGUCCGGG	4374	Rh, Rb, Cw	[805-822] ORF
764	CGGUUGCCAUUGCUUCUU	3340	AAGAAGCAAUGGCAACCG	4375	Rh	[1812-1829] 3′UTR
765	GCUGUGUUUUUUAUUACC	3341	GGUAAUAAAAAACACAGC	4376	Rh	[2888-2905] 3′UTR
766	CUUCCACGCCUCUGCACU	3342	AGUGCAGAGGCGUGGAAG	4377		[1432-1449] 3′UTR
767	GGACCCAUAAGCAGGCCU	3343	AGGCCUGCUUAUGGGUCC	4378	Rh	[955-972]
						ORF + 3′UTR
768	CUGGCAAGUGCUCCCAUC	3344	GAUGGGAGCACUUGCCAG	4379		[1458-1475] 3′UTR
769	AAAGGUGUGGCCUUUAUA	3345	UAUAAAGGCCACACCUUU	4380		[3117-3134] 3′UTR
770	ACAGGCACAUUAUGUAAA	3346	UUUACAUAAUGUGCCUGU	4381		[2409-2426] 3′UTR
771	ACUUCCCUUUCUAGGGCA	3347	UGCCCUAGAAAGGGAAGU	4382	Rh	[2606-2623] 3′UTR
772	CUGUUGAUUUUGUUUCCG	3348	CGGAAACAAAAUCAACAG	4383		[3452-3469] 3′UTR
773	CAAAGGGCCUGAGAAGGA	3349	UCCUUCUCAGGCCCUUUG	4384		[538-555] ORF
774	CCUGAGCACCACCCAGAA	3350	UUCUGGGUGGUGCUCAGG	4385	Rh, Pg	[706-723] ORF
775	UCUUGAUGACUUCCCUUU	3351	AAAGGGAAGUCAUCAAGA	4386	Rh	[2598-2615] 3′UTR
776	GAGUGCAAGAUCACGCGC	3352	GCGCGUGAUCUUGCACUC	4387	Dg, Pg	[758-775] ORF
777	UUGUUUCCGUUUGGAUUU	3353	AAAUCCAAACGGAAACAA	4388		[3461-3478] 3′UTR
778	CCUCCCAGUCCCUGCCUU	3354	AAGGCAGGGACUGGGAGG	4389	Rh	[1243-1260] 3′UTR
779	AGGCCUACCAGGUCCCUU	3355	AAGGGACCUGGUAGGCCU	4390	Rh	[1378-1395] 3′UTR
780	CAAGAUGCACAUCACCCU	3356	AGGGUGAUGUGCAUCUUG	4391	Rh, Dg	[661-678] ORF
781	UGGAGGAAAGAAGGAAUA	3357	UAUUCCUUCUUUCCUCCA	4392	Rt	[613-630] ORF
782	UGACAAAGAUUACCUAGC	3358	GCUAGGUAAUCUUUGUCA	4393		[2232-2249] 3′UTR
783	GGUGGCUUUGGUGACACA	3359	UGUGUCACCAAAGCCACC	4394		[2083-2100] 3′UTR
784	UCACUUCUUUCUCAGCCU	3360	AGGCUGAGAAAGAAGUGA	4395		[2102-2119] 3′UTR
785	UAAUCAUUCCUGUGCUGU	3361	ACAGCACAGGAAUGAUUA	4396	Rh	[2875-2892] 3′UTR
786	AGUAGGUUCGGUCUGAAA	3362	UUUCAGACCGAACCUACU	4397		[3102-3119] 3′UTR
787	CGUUUUGCAAUGCAGAUG	3363	CAUCUGCAUUGCAAAACG	4398		[411-428] ORF
788	GGGCACCAGGCCAAGUUC	3364	GAACUUGGCCUGGUGCCC	4399	Rh, Rb, Rt, Ms	[854-871] ORF
789	ACAGAGAAGAACAUCAAC	3365	GUUGAUGUUCUUCUCUGU	4400	Rh	[836-853] ORF
790	CAAAAAAAGCCUCCAAGG	3366	CCUUGGAGGCUUUUUUUG	4401		[995-1012] 3′UTR
791	UUGGUAGGUAUUAGACUU	3367	AAGUCUAAUACCUACCAA	4402		[2907-2924] 3′UTR
792	GAGCACUGUGUUUAUGCU	3368	AGCAUAAACACAGUGCUC	4403		[3490-3507] 3′UTR
793	UGUACAGUGACCUAAAGU	3369	ACUUUAGGUCACUGUACA	4404		[2675-2692] 3′UTR
794	AAGAAAUAUUGGACUUGC	3370	GCAAGUCCAAUAUUUCUU	4405		[3417-3434] 3′UTR
795	CAGAAACUUUUGAGGGUC	3371	GACCCUCAAAAGUUUCUG	4406	Rh	[1342-1359] 3′UTR
796	UUCCCUUUCUAGGGCAGA	3372	UCUGCCCUAGAAAGGGAA	4407	Rh	[2608-2625] 3′UTR
797	CACAUCCAAGGGCAGCCU	3373	AGGCUGCCCUUGGAUGUG	4408		[1517-1534] 3′UTR
798	CAUCUUGAGAGGGACAUG	3374	CAUGUCCCUCUCAAGAUG	4409		[1397-1414] 3′UTR
799	GGCUUUCUGCAUGUGACG	3375	CGUCACAUGCAGAAAGCC	4410		[2012-2029] 3′UTR
800	UAGCUAAGAAACUUCCUA	3376	UAGGAAGUUUCUUAGCUA	4411		[2246-2263] 3′UTR
801	ACAUCCAAGGGCAGCCUG	3377	CAGGCUGCCCUUGGAUGU	4412		[1518-1535] 3′UTR
802	UGUUCCCUCCCUCAAAGA	3378	UCUUUGAGGGAGGGAACA	4413		[1971-1988] 3′UTR
803	GUCUUUUUGGUCUGCACC	3379	GGUGCAGACCAAAAAGAC	4414		[1669-1686] 3′UTR
804	CCAUGAGCUCCCAGCACC	3380	GGUGCUGGGAGCUCAUGG	4415		[1489-1506] 3′UTR
805	AGAUGUAGUGAUCAGGGC	3381	GCCCUGAUCACUACAUCU	4416		[424-441] ORF
806	GAGGUAGGUGGCUUUGGU	3382	ACCAAAGCCACCUACCUC	4417	Rh	[2077-2094] 3′UTR
807	AAGCCGCUCAAAUACCUU	3383	AAGGUAUUUGAGCGGCUU	4418		[3219-3236] 3′UTR
808	UGAGCCUUGUAGAAAUGG	3384	CCAUUUCUACAAGGCUCA	4419	Rh	[1609-1626] 3′UTR
809	GACGCCAGCUAAGCAUAG	3385	CUAUGCUUAGCUGGCGUC	4420		[2026-2043] 3′UTR
810	GCAGCUUCCACGCCUCUG	3386	CAGAGGCGUGGAAGCUGC	4421	Rh	[1428-1445] 3′UTR
811	AGAAUUCCAGUGGGAGCC	3387	GGCUCCCACUGGAAUUCU	4422	Rh	[1585-1602] 3′UTR
812	GAACGCGUGGCCUAUGCA	3388	UGCAUAGGCCACGCGUUC	4423	Rh	[2977-2994] 3′UTR
813	ACAGAAAAAGCUGGGUCU	3389	AGACCCAGCUUUUUCUGU	4424	Rh	[1931-1948] 3′UTR
814	AAGGAAUAUCUCAUUGCA	3390	UGCAAUGAGAUAUUCCUU	4425		[623-640] ORF
815	CAAGAGGAUCCAGUAUGA	3391	UCAUACUGGAUCCUCUUG	4426	Rh, Rb	[499-516] ORF
816	AGCUGACAGAGGAAGCCG	3392	CGGCUUCCUCUGUCAGCU	4427		[3207-3224] 3′UTR
817	AUAAAACACUCAUCCCAU	3393	AUGGGAUGAGUGUUUUAU	4428		[1059-1076] 3′UTR
818	GAAUCUCUUGUUUCCUCC	3394	GGAGGAAACAAGAGAUUC	4429		[2360-2377] 3′UTR
819	GUUAUGUUCUAAGCACAG	3395	CUGUGCUUAGAACAUAAC	4430		[3305-3322] 3′UTR
820	ACACGUUGGUCUUUUAAC	3396	GUUAAAAGACCAACGUGU	4431		[3145-3162] 3′UTR
821	GGUGCACCCGCAACAGGC	3397	GCCUGUUGCGGGUGCACC	4432	Cw, Dg, Rt, Ms	[394-411] ORF
822	UCUGCAUCGUGGAAGCAU	3398	AUGCUUCCACGAUGCAGA	4433	Rh	[2946-2963] 3′UTR
823	CUGCCAGGCACUAUGUGU	3399	ACACAUAGUGCCUGGCAG	4434		[1177-1194] 3′UTR
824	GAAGUCUGAGACCUUCCG	3400	CGGAAGGUCUCAGACUUC	4435		[3515-3532] 3′UTR
825	CUGGUCAGCACAGAUCUU	3401	AAGAUCUGUGCUGACCAG	4436	Rh	[2584-2601] 3′UTR
826	GUGCAUUUUGCAGAAACU	3402	AGUUUCUGCAAAAUGCAC	4437	Rh, Rt, Ms	[1332-1349] 3′UTR
827	UCAUCUUGAGAGGGACAU	3403	AUGUCCCUCUCAAGAUGA	4438		[1396-1413] 3′UTR
828	CACUUAGGGAUCUCCCAG	3404	CUGGGAGAUCCCUAAGUG	4439	Rh	[1289-1306] 3′UTR
829	CACGCAAUGAAACCGAAG	3405	CUUCGGUUUCAUUGCGUG	4440		[2433-2450] 3′UTR
830	GACUGACAGCCAUCGUUC	3406	GAACGAUGGCUGUCAGUC	4441	Rh	[1987-2004] 3′UTR
831	AUUGCAAAGUAAAGGAUC	3407	GAUCCUUUACUUUGCAAU	4442		[3080-3097] 3′UTR
832	AGUGGAACGCGUGGCCUA	3408	UAGGCCACGCGUUCCACU	4443		[2973-2990] 3′UTR
833	GUUCGGUCUGAAAGGUGU	3409	ACACCUUUCAGACCGAAC	4444		[3107-3124] 3′UTR
834	UGCAGAUGUAGUGAUCAG	3410	CUGAUCACUACAUCUGCA	4445		[421-438] ORF
835	GUGUUCCCUCAGUGUGGU	3411	ACCACACUGAGGGAACAC	4446		[2282-2299] 3′UTR
836	UGCCGUAAUUUAAAGCUC	3412	GAGCUUUAAAUUACGGCA	4447		[3435-3452] 3′UTR
837	CUGCGGUUGCCAUUGCUU	3413	AAGCAAUGGCAACCGCAG	4448		[1809-1826] 3′UTR
838	CGGCUCCUGUGCGUGGUA	3414	UACCACGCACAGGAGCCG	4449	Rh	[895-912] ORF
839	GGGUUUCGACUGGUCCAG	3415	CUGGACCAGUCGAAACCC	4450	Rh	[1011-1028] 3′UTR
840	AGAGAAGAACAUCAACGG	3416	CCGUUGAUGUUCUUCUCU	4451	Rh, Rb, Cw	[838-855] ORF
841	AUGGACCAGUCCAUGUGA	3417	UCACAUGGACUGGUCCAU	4452	Rh	[2708-2725] 3′UTR
842	CCGUGCUACAUCUCCUCC	3418	GGAGGAGAUGUAGCACGG	4453	Rh	[788-805] ORF
843	CCAAAGCACCUGUUAAGA	3419	UCUUAACAGGUGCUUUGG	4454	Rh	[2522-2539] 3′UTR
844	CAACUGCAAAAAAAGCCU	3420	AGGCUUUUUUUGCAGUUG	4455		[989-1006] 3′UTR
845	CUUUCUCAGCCUCCAGGA	3421	UCCUGGAGGCUGAGAAAG	4456		[2108-2125] 3′UTR
846	UCUAAAGGUGAAUUCUCA	3422	UGAGAAUUCACCUUUAGA	4457	Ms	[2159-2176] 3′UTR
847	GCAGACUGGGAGGGUAUC	3423	GAUACCCUCCCAGUCUGC	4458	Rh	[2621-2638] 3′UTR
848	CUGGAACCAGUGGCUAGU	3424	ACUAGCCACUGGUUCCAG	4459		[1533-1550] 3′UTR
849	GACUGUGUAGCAGGCCUA	3425	UAGGCCUGCUACACAGUC	4460	Rh	[1367-1384] 3′UTR
850	GGCCAAGUUCUUCGCCUG	3426	CAGGCGAAGAACUUGGCC	4461	Rh, Rb, Cw, Dg, Ms	[862-879] ORF
851	GUUCGCUUCCUGUAUGGU	3427	ACCAUACAGGAAGCGAAC	4462		[2781-2798] 3′UTR
852	AAUUCCAGUGGGAGCCUC	3428	GAGGCUCCCACUGGAAUU	4463	Rh	[1587-1604] 3′UTR
853	UGCAAAAUGCUUCCAAAG	3429	CUUUGGAAGCAUUUUGCA	4464	Rh	[2473-2490] 3′UTR
854	CUGGAAUAUGAAGUCUGA	3430	UCAGACUUCAUAUUCCAG	4465	Ms	[3506-3523] 3′UTR
855	GCUGUGCCCUCCCAGGCU	3431	AGCCUGGGAGGGCACAGC	4466		[1950-1967] 3′UTR
856	CCAGAUGGGCUGCGAGUG	3432	CACUCGCAGCCCAUCUGG	4467	Rh, Ck, Rb, Rt	[745-762] ORF
857	GCGGUUGCCAUUGCUUCU	3433	AGAAGCAAUGGCAACCGC	4468		[1811-1828] 3′UTR
858	AGCUCUGUUGAUUUUGUU	3434	AACAAAAUCAACAGAGCU	4469		[3448-3465] 3′UTR
859	UAUCAUUCUUGAGCAAUC	3435	GAUUGCUCAAGAAUGAUA	4470		[3598-3615] 3′UTR
860	UGGAGGGAGACGUGGGUC	3436	GACCCACGUCUCCCUCCA	4471		[1135-1152] 3′UTR
861	AAGAAACUUCCUAGGGAA	3437	UUCCCUAGGAAGUUUCUU	4472		[2251-2268] 3′UTR
862	AAAGCUGGGUCUUGCUGU	3438	ACAGCAAGACCCAGCUUU	4473	Rh	[1937-1954] 3′UTR
863	AAUAUGAAGUCUGAGACC	3439	GGUCUCAGACUUCAUAUU	4474		[3510-3527] 3′UTR
864	UUCCUGAAGCCAGUGAUA	3440	UAUCACUGGCUUCAGGAA	4475		[2300-2317] 3′UTR
865	ACUCCUGUUUCUGCUGAU	3441	AUCAGCAGAAACAGGAGU	4476		[2818-2835] 3′UTR
866	CCAGGCUUAGUGUUCCCU	3442	AGGGAACACUAAGCCUGG	4477		[1961-1978] 3′UTR
867	CCAGAGUGGAACGCGUGG	3443	CCACGCGUUCCACUCUGG	4478		[2969-2986] 3′UTR
868	ACCAGGUCCCUUUCAUCU	3444	AGAUGAAAGGGACCUGGU	4479	Rh	[1384-1401] 3′UTR
869	CGAGUGCCUCUGGAUGGA	3445	UCCAUCCAGAGGCACUCG	4480	Rh, Rb, Cw, Dg, Rt, Ms	[811-828] ORF
870	UAUGUGUUCCCUCAGUGU	3446	ACACUGAGGGAACACAUA	4481		[2279-2296] 3′UTR
871	GUUUUCAUGCUGUACAGU	3447	ACUGUACAGCAUGAAAAC	4482	Rh	[2665-2682] 3′UTR
872	GACUGGGAGGGUAUCCAG	3448	CUGGAUACCCUCCCAGUC	4483	Rh	[2624-2641] 3′UTR
873	GUCAGCACAGAUCUUGAU	3449	AUCAAGAUCUGUGCUGAC	4484	Rh	[2587-2604] 3′UTR
874	CGGCCUGGGCGUGGUCUU	3450	AAGACCACGCCCAGGCCG	4485		[2456-2473] 3′UTR
875	CUGCGAGUGCAAGAUCAC	3451	GUGAUCUUGCACUCGCAG	4486	Rt	[754-771] ORF
876	UGAAAGGUGUGGCCUUUA	3452	UAAAGGCCACACCUUUCA	4487		[3115-3132] 3′UTR
877	UGUUCUGGCAUCAGGCAC	3453	GUGCCUGAUGCCAGAACA	4488		[1833-1850] 3′UTR
878	GGGCUUGUGUGCAGGGCC	3454	GGCCCUGCACACAAGCCC	4489	Rh	[1882-1899] 3′UTR
879	CCACCCAGAAGAAGAGCC	3455	GGCUCUUCUUCUGGGUGG	4490	Rh, Ck, Cw, Rt, Ms, Pg	[714-731] ORF
880	CAGCUGAGCUGCGUUCCA	3456	UGGAACGCAGCUCAGCUG	4491		[1640-1657] 3′UTR
881	UCUGGAUGGACUGGGUCA	3457	UGACCCAGUCCAUCCAGA	4492	Rh, Rb, Cw, Dg, Rt, Ms,	[819-836] ORF
					Pg
882	CCCAAGCAGGAGUUUCUC	3458	GAGAAACUCCUGCUUGGG	4493	Dg	[929-946] ORF
883	AAGGUGUGGCCUUUAUAU	3459	AUAUAAAGGCCACACCUU	4494		[3118-3135] 3′UTR
884	CCUCCCAGGCUUAGUGUU	3460	AACACUAAGCCUGGGAGG	4495		[1957-1974] 3′UTR
885	CCAACUGCAAAAAAAGCC	3461	GGCUUUUUUUGCAGUUGG	4496		[988-1005] 3′UTR
886	CUGGAUUGAGUUGCACAG	3462	CUGUGCAACUCAAUCCAG	4497		[1851-1868] 3′UTR
887	AUGGCCUGUUUUAAGAGA	3463	UCUCUUAAAACAGGCCAU	4498		[2130-2147] 3′UTR
888	UGUAUCAUUCUUGAGCAA	3464	UUGCUCAAGAAUGAUACA	4499		[3596-3613] 3′UTR
889	AGAGUUUAUCUACACGGC	3465	GCCGUGUAGAUAAACUCU	4500	Dg, Ms, Pg	[559-576] ORF
890	CGGGACCUGGUCAGCACA	3466	UGUGCUGACCAGGUCCCG	4501	Rh	[2578-2595] 3′UTR
891	AUGACAAAGAUUACCUAG	3467	CUAGGUAAUCUUUGUCAU	4502		[2231-2248] 3′UTR
892	UGAAGCCAGUGAUAUGGG	3468	CCCAUAUCACUGGCUUCA	4503		[2304-2321] 3′UTR
893	GUGGCCUUUAUAUUUGAU	3469	AUCAAAUAUAAAGGCCAC	4504		[3123-3140] 3′UTR
894	UAAGCAUAGUAAGAAGUC	3470	GACUUCUUACUAUGCUUA	4505		[2035-2052] 3′UTR
895	CUGCACAUCCUGAGGACA	3471	UGUCCUCAGGAUGUGCAG	4506	Rh	[1916-1933] 3′UTR
896	AGUUGACAAGCAGACUGC	3472	GCAGUCUGCUUGUCAACU	4507		[3561-3578] 3′UTR
897	UGAGCUCCCAGCACCUGA	3473	UCAGGUGCUGGGAGCUCA	4508		[1492-1509] 3′UTR
898	CUGUUAAGACUCCUGACC	3474	GGUCAGGAGUCUUAACAG	4509	Rh	[2531-2548] 3′UTR
899	CACAUCACCCUCUGUGAC	3475	GUCACAGAGGGUGAUGUG	4510	Rh	[668-685] ORF
900	AAAGUUGACAAGCAGACU	3476	AGUCUGCUUGUCAACUUU	4511		[3559-3576] 3′UTR
901	CCAAGUGGCAUGCAGCCC	3477	GGGCUGCAUGCCACUUGG	4512		[2550-2567] 3′UTR
902	GUACCAGAUGGGCUGCGA	3478	UCGCAGCCCAUCUGGUAC	4513	Rh, Ck, Rb, Rt	[742-759] ORF
903	UGUUUCCGUUUGGAUUUU	3479	AAAAUCCAAACGGAAACA	4514		[3462-3479] 3′UTR
904	AUCUUUGAGUAGGUUCGG	3480	CCGAACCUACUCAAAGAU	4515		[3095-3112] 3′UTR
905	UGAUCCCGUGCUACAUCU	3481	AGAUGUAGCACGGGAUCA	4516	Rh, Rb	[783-800] ORF
906	ACCUGGUCAGCACAGAUC	3482	GAUCUGUGCUGACCAGGU	4517	Rh	[2582-2599] 3′UTR
907	CACUUCUUUCUCAGCCUC	3483	GAGGCUGAGAAAGAAGUG	4518		[2103-2120] 3′UTR
908	GCUGCUGCGGUUGCCAUU	3484	AAUGGCAACCGCAGCAGC	4519		[1805-1822] 3′UTR
909	CAUUGCUUCUUGCCUGUU	3485	AACAGGCAAGAAGCAAUG	4520		[1819-1836] 3′UTR
910	CUGGAGGGAGACGUGGGU	3486	ACCCACGUCUCCCUCCAG	4521		[1134-1151] 3′UTR
911	UGGUGACACACUCACUUC	3487	GAAGUGAGUGUGUCACCA	4522		[2091-2108] 3′UTR
912	GGCAGGGCUGGGACACGC	3488	GCGUGUCCCAGCCCUGCC	4523		[1219-1236] 3′UTR
913	UGAACCACAGGUACCAGA	3489	UCUGGUACCUGUGGUUCA	4524	Rh, Rb, Cw, Ms, Pg	[732-749] ORF
914	GUUAGGAUAGGAAGAACU	3490	AGUUCUUCCUAUCCUAAC	4525		[2323-2340] 3′UTR
915	AGCUUUGCUUUAUCCGGG	3491	CCCGGAUAAAGCAAAGCU	4526		[1867-1884] 3′UTR
916	CUGUCCUGAGGCUGCUGU	3492	ACAGCAGCCUCAGGACAG	4527	Rh	[1751-1768] 3′UTR
917	AUUGCUUCUUGCCUGUUC	3493	GAACAGGCAAGAAGCAAU	4528		[1820-1837] 3′UTR
918	GAGCACCACCCAGAAGAA	3494	UUCUUCUGGGUGGUGCUC	4529	Rh, Pg	[709-726] ORF
919	GUAGUGAUCAGGGCCAAA	3495	UUUGGCCCUGAUCACUAC	4530	Cw, Rt, Pg	[428-445] ORF
920	CCUGUUAAGACUCCUGAC	3496	GUCAGGAGUCUUAACAGG	4531	Rh	[2530-2547] 3′UTR
921	AGGGUUUCGACUGGUCCA	3497	UGGACCAGUCGAAACCCU	4532	Rh	[1010-1027] 3′UTR
922	UCAUCCCAUGGGUCCAAA	3498	UUUGGACCCAUGGGAUGA	4533		[1068-1085] 3′UTR
923	GCCCUUGUUUUCUGCAGC	3499	GCUGCAGAAAACAAGGGC	4534	Rh	[1415-1432] 3′UTR
924	GUUGACAAGCAGACUGCG	3500	CGCAGUCUGCUUGUCAAC	4535		[3562-3579] 3′UTR
925	AGGGAACCUAUGUGUUCC	3501	GGAACACAUAGGUUCCCU	4536	Rh	[2271-2288] 3′UTR
926	CCCAGCUGGGUUAGGGCA	3502	UGCCCUAACCCAGCUGGG	4537		[1302-1319] 3′UTR
927	GUUGGUCUUUUAACCGUG	3503	CACGGUUAAAAGACCAAC	4538		[3149-3166] 3′UTR
928	UUAUGGCAACCCUAUCAA	3504	UUGAUAGGGUUGCCAUAA	4539		[484-501] ORF
929	CUAAAGUUGGUAAGAUGU	3505	ACAUCUUACCAACUUUAG	4540	Rh	[2686-2703] 3′UTR
930	UGAAUUCUCAGAUGAUAG	3506	CUAUCAUCUGAGAAUUCA	4541		[2167-2184] 3′UTR
931	UGCAGGUGGAUUCCUUCA	3507	UGAAGGAAUCCACCUGCA	4542	Rh	[2991-3008] 3′UTR
932	CUGCGCAUGUCUCUGAUG	3508	CAUCAGAGACAUGCGCAG	4543		[3575-3592] 3′UTR
933	GAAGAACAUCAACGGGCA	3509	UGCCCGUUGAUGUUCUUC	4544	Rh, Rb	[841-858] ORF
934	GGCGCUCGGCCUCCUGCU	3510	AGCAGGAGGCCGAGCGCC	4545	Dg, Rt, Ms	[331-348] ORF
935	CUGAGGACAGAAAAAGCU	3511	AGCUUUUUCUGUCCUCAG	4546	Rh	[1925-1942] 3′UTR
936	AUCUUGAUGACUUCCCUU	3512	AAGGGAAGUCAUCAAGAU	4547	Rh	[2597-2614] 3′UTR
937	UAGGUAUUAGACUUGCAC	3513	GUGCAAGUCUAAUACCUA	4548		[2911-2928] 3′UTR
938	UGAAGUCUGAGACCUUCC	3514	GGAAGGUCUCAGACUUCA	4549		[3514-3531] 3′UTR
939	CCGUAAUUUAAAGCUCUG	3515	CAGAGCUUUAAAUUACGG	4550		[3437-3454] 3′UTR
940	AAGGCUCUCCAUUUGGCA	3516	UGCCAAAUGGAGAGCCUU	4551		[3272-3289] 3′UTR
941	UAGGGAACCUAUGUGUUC	3517	GAACACAUAGGUUCCCUA	4552	Rh	[2270-2287] 3′UTR
942	GCUCCCAGCACCUGACUC	3518	GAGUCAGGUGCUGGGAGC	4553		[1495-1512] 3′UTR
943	UGGAUUGAGUUGCACAGC	3519	GCUGUGCAACUCAAUCCA	4554		[1852-1869] 3′UTR
944	CUGCUGGCGACGCUGCUU	3520	AAGCAGCGUCGCCAGCAG	4555		[347-364] ORF
945	CUGCGUUCCAGCCUCAGC	3521	GCUGAGGCUGGAACGCAG	4556		[1648-1665] 3′UTR
946	GUGACUUCAUCGUGCCCU	3522	AGGGCACGAUGAAGUCAC	4557	Rh, Rb, Cw, Dg, Pg	[681-698] ORF
947	GCCCUGGGACACCCUGAG	3523	CUCAGGGUGUCCCAGGGC	4558	Rh, Cw, Dg, Pg	[694-711] ORF
948	UAUACAACUCCACCAGAC	3524	GUCUGGUGGAGUUGUAUA	4559	Rh	[2734-2751] 3′UTR
949	ACCUUCCGGUGCUGGGAA	3525	UUCCCAGCACCGGAAGGU	4560		[3525-3542] 3′UTR
950	GCUUUCUGCAUGUGACGC	3526	GCGUCACAUGCAGAAAGC	4561		[2013-2030] 3′UTR
951	CCACAUCCAAGGGCAGCC	3527	GGCUGCCCUUGGAUGUGG	4562		[1516-1533] 3′UTR
952	GCAGCACUUAGGGAUCUC	3528	GAGAUCCCUAAGUGCUGC	4563	Rh	[1285-1302] 3′UTR
953	UGGGUCCAAGGUCCUCAU	3529	AUGAGGACCUUGGACCCA	4564		[1147-1164] 3′UTR
954	UCUAGGGCAGACUGGGAG	3530	CUCCCAGUCUGCCCUAGA	4565	Rh	[2615-2632] 3′UTR
955	GAAGGGAAGGAUUUUGGA	3531	UCCAAAAUCCUUCCCUUC	4566	Rh	[2061-2078] 3′UTR
956	GAGGAAUCGGUGAGGUCC	3532	GGACCUCACCGAUUCCUC	4567		[1734-1751] 3′UTR
957	AUUUGACCCAGAGUGGAA	3533	UUCCACUCUGGGUCAAAU	4568		[2962-2979] 3′UTR
958	GGCGACGCUGCUUCGCCC	3534	GGGCGAAGCAGCGUCGCC	4569		[352-369] ORF
959	UUAGCCUGUUCUAUUCAG	3535	CUGAAUAGAACAGGCUAA	4570	Rh	[2496-2513] 3′UTR
960	AGCUGAGCUGCGUUCCAG	3536	CUGGAACGCAGCUCAGCU	4571		[1641-1658] 3′UTR
961	AAGUUGACAAGCAGACUG	3537	CAGUCUGCUUGUCAACUU	4572		[3560-3577] 3′UTR
962	AGCACAGAUCUUGAUGAC	3538	GUCAUCAAGAUCUGUGCU	4573	Rh	[2590-2607] 3′UTR
963	GAGGGUAUCCAGGAAUCG	3539	CGAUUCCUGGAUACCCUC	4574		[2630-2647] 3′UTR
964	AGUGUGGUUUCCUGAAGC	3540	GCUUCAGGAAACCACACU	4575		[2292-2309] 3′UTR
965	UCCUUUUAGACAUGGUUG	3541	CAACCAUGUCUAAAAGGA	4576		[1111-1128] 3′UTR
966	GUUUCCUCCCACCUGUGU	3542	ACACAGGUGGGAGGAAAC	4577		[2369-2386] 3′UTR
967	CACUAUGGCCUGUUUUAA	3543	UUAAAACAGGCCAUAGUG	4578		[2126-2143] 3′UTR
968	CCAGCUGGGUUAGGGCAG	3544	CUGCCCUAACCCAGCUGG	4579		[1303-1320] 3′UTR
969	UGCGUUCCAGCCUCAGCU	3545	AGCUGAGGCUGGAACGCA	4580		[1649-1666] 3′UTR
970	CCAGCCUAGGAAGGGAAG	3546	CUUCCCUUCCUAGGCUGG	4581	Rh	[2052-2069] 3′UTR
971	GCUGGGUCUUGCUGUGCC	3547	GGCACAGCAAGACCCAGC	4582	Rh	[1940-1957] 3′UTR
972	GUUUCUCGACAUCGAGGA	3548	UCCUCGAUGUCGAGAAAC	4583	Ck, Dg	[940-957] ORF
973	GCUGGGACACGCGGCUUC	3549	GAAGCCGCGUGUCCCAGC	4584		[1225-1242] 3′UTR
974	UACCAACUUCUGCUUGUA	3550	UACAAGCAGAAGUUGGUA	4585	Rh	[2205-2222] 3′UTR
975	UCCAAGGGCAGCCUGGAA	3551	UUCCAGGCUGCCCUUGGA	4586		[1521-1538] 3′UTR
976	CAACCCUAUCAAGAGGAU	3552	AUCCUCUUGAUAGGGUUG	4587		[490-507] ORF
977	CAGCUGAGUCUUUUUGGU	3553	ACCAAAAAGACUCAGCUG	4588	Rh	[1662-1679] 3′UTR
978	UGUUAAGACUCCUGACCC	3554	GGGUCAGGAGUCUUAACA	4589	Rh	[2532-2549] 3′UTR
979	UAUCAAGAGGAUCCAGUA	3555	UACUGGAUCCUCUUGAUA	4590	Rh, Rb	[496-513] ORF
980	GCACCAGGCCAAGUUCUU	3556	AAGAACUUGGCCUGGUGC	4591	Rh, Rb, Cw, Rt, Ms	[856-873] ORF
981	GGGCUGGGACACGCGGCU	3557	AGCCGCGUGUCCCAGCCC	4592		[1223-1240] 3′UTR
982	GGUCCCUUCCCUAGCUGC	3558	GCAGCUAGGGAAGGGACC	4593		[1792-1809] 3′UTR
983	UGAUAGGUGAACCUGAGU	3559	ACUCAGGUUCACCUAUCA	4594		[2179-2196] 3′UTR
984	AUUCCUGUGCUGUGUUUU	3560	AAAACACAGCACAGGAAU	4595	Rh	[2880-2897] 3′UTR
985	GAUGCACAUCACCCUCUG	3561	CAGAGGGUGAUGUGCAUC	4596	Rh	[664-681] ORF
986	CCAGGCACUAUGUGUCUG	3562	CAGACACAUAGUGCCUGG	4597		[1180-1197] 3′UTR
987	GCUGCUGGCGACGCUGCU	3563	AGCAGCGUCGCCAGCAGC	4598		[346-363] ORF
988	UCCAGUGGGAGCCUCCCU	3564	AGGGAGGCUCCCACUGGA	4599	Rh	[1590-1607] 3′UTR
989	AGCUCUGACAUCCCUUCC	3565	GGAAGGGAUGUCAGAGCU	4600	Rh	[1027-1044] 3′UTR
990	ACAGCUUUGCUUUAUCCG	3566	CGGAUAAAGCAAAGCUGU	4601		[1865-1882] 3′UTR
991	GGGAACCUAUGUGUUCCC	3567	GGGAACACAUAGGUUCCC	4602	Rh	[2272-2289] 3′UTR
992	CAGGAGUUUCUCGACAUC	3568	GAUGUCGAGAAACUCCUG	4603	Ck, Dg	[935-952] ORF
993	GUCCCUUCCCUAGCUGCU	3569	AGCAGCUAGGGAAGGGAC	4604		[1793-1810] 3′UTR
994	AGGUUCGGUCUGAAAGGU	3570	ACCUUUCAGACCGAACCU	4605		[3105-3122] 3′UTR
995	UGACGAUAUACAGGCACA	3571	UGUGCCUGUAUAUCGUCA	4606		[2400-2417] 3′UTR
996	AGUCUUUUUGGUCUGCAC	3572	GUGCAGACCAAAAAGACU	4607		[1668-1685] 3′UTR
997	CACCCUGAGCACCACCCA	3573	UGGGUGGUGCUCAGGGUG	4608	Rh, Pg	[703-720] ORF
998	GAGAAGAACAUCAACGGG	3574	CCCGUUGAUGUUCUUCUC	4609	Rh, Rb	[839-856] ORF
999	GAGAAGUGACGGCUCCUG	3575	CAGGAGCCGUCACUUCUC	4610		[886-903] ORF
1000	UGCGAGUGCAAGAUCACG	3576	CGUGAUCUUGCACUCGCA	4611		[755-772] ORF
1001	AAGUAAAGGAUCUUUGAG	3577	CUCAAAGAUCCUUUACUU	4612		[3086-3103] 3′UTR
1002	AGGCACAUUAUGUAAACA	3578	UGUUUACAUAAUGUGCCU	4613	Rh	[2411-2428] 3′UTR
1003	CGCUCGGUCCGUGGACAA	3579	UUGUCCACGGACCGAGCG	4614		[3615-3632] 3′UTR
1004	GUUAAGAAGAGCCGGGUG	3580	CACCCGGCUCUUCUUAAC	4615		[3187-3204] 3′UTR
1005	GUGGAACGCGUGGCCUAU	3581	AUAGGCCACGCGUUCCAC	4616		[2974-2991] 3′UTR
1006	AAAGUUGGUAAGAUGUCA	3582	UGACAUCUUACCAACUUU	4617	Rh	[2688-2705] 3′UTR
1007	AGCUGCUGCGGUUGCCAU	3583	AUGGCAACCGCAGCAGCU	4618		[1804-1821] 3′UTR
1008	CUGCAUCGUGGAAGCAUU	3584	AAUGCUUCCACGAUGCAG	4619	Rh	[2947-2964] 3′UTR
1009	UACUCCUGUUUCUGCUGA	3585	UCAGCAGAAACAGGAGUA	4620		[2817-2834] 3′UTR
1010	CCUUGUAGAAAUGGGAGC	3586	GCUCCCAUUUCUACAAGG	4621	Rh	[1613-1630] 3′UTR
1011	AACCUAUGUGUUCCCUCA	3587	UGAGGGAACACAUAGGUU	4622		[2275-2292] 3′UTR
1012	UAGUUUAAGAAGGCUCUC	3588	GAGAGCCUUCUUAAACUA	4623		[3263-3280] 3′UTR
1013	UGCGCAUGUCUCUGAUGC	3589	GCAUCAGAGACAUGCGCA	4624		[3576-3593] 3′UTR
1014	AGAGAAGUGACGGCUCCU	3590	AGGAGCCGUCACUUCUCU	4625		[885-902] ORF
1015	CAAGGGUUUCGACUGGUC	3591	GACCAGUCGAAACCCUUG	4626	Rh	[1008-1025] 3′UTR
1016	UCUAAGCACAGCUCUCUU	3592	AAGAGAGCUGUGCUUAGA	4627		[3312-3329] 3′UTR
1017	AUUUGAUCCACACACGUU	3593	AACGUGUGUGGAUCAAAU	4628		[3134-3151] 3′UTR
1018	CUUCCCUCCCAGUCCCUG	3594	CAGGGACUGGGAGGGAAG	4629		[1239-1256] 3′UTR
1019	AAGAAGGCUCUCCAUUUG	3595	CAAAUGGAGAGCCUUCUU	4630		[3269-3286] 3′UTR
1020	CGGGUGGCAGCUGACAGA	3596	UCUGUCAGCUGCCACCCG	4631		[3199-3216] 3′UTR
1021	UGGGAGCCUCCCUCUGAG	3597	CUCAGAGGGAGGCUCCCA	4632	Rh	[1595-1612] 3′UTR
1022	UAUACCAACUUCUGCUUG	3598	CAAGCAGAAGUUGGUAUA	4633	Rh	[2203-2220] 3′UTR
1023	UGGAUGGACUGGGUCACA	3599	UGUGACCCAGUCCAUCCA	4634	Rh, Rt, Ms, Pg	[821-838] ORF
1024	CAGAGUGGAACGCGUGGC	3600	GCCACGCGUUCCACUCUG	4635		[2970-2987] 3′UTR
1025	UCUCUUGUUUCCUCCCAC	3601	GUGGGAGGAAACAAGAGA	4636		[2363-2380] 3′UTR
1026	CACCAUGAGCUCCCAGCA	3602	UGCUGGGAGCUCAUGGUG	4637		[1487-1504] 3′UTR
1027	AUCUGCACAUCCUGAGGA	3603	UCCUCAGGAUGUGCAGAU	4638	Rh	[1914-1931] 3′UTR
1028	CCCUUGUUUUCUGCAGCU	3604	AGCUGCAGAAAACAAGGG	4639	Rh	[1416-1433] 3′UTR
1029	CCCUUCCUGGAAACAGCA	3605	UGCUGUUUCCAGGAAGGG	4640	Rh, Rb, Rt, Ms	[1038-1055] 3′UTR
1030	ACCAUGAGCUCCCAGCAC	3606	GUGCUGGGAGCUCAUGGU	4641		[1488-1505] 3′UTR
1031	CACACGUUGGUCUUUUAA	3607	UUAAAAGACCAACGUGUG	4642		[3144-3161] 3′UTR
1032	CUGAGUCUUUUUGGUCUG	3608	CAGACCAAAAAGACUCAG	4643		[1665-1682] 3′UTR
1033	CCCUCCCAGUCCCUGCCU	3609	AGGCAGGGACUGGGAGGG	4644	Rh	[1242-1259] 3′UTR
1034	UCAGCCUCCAGGACACUA	3610	UAGUGUCCUGGAGGCUGA	4645		[2113-2130] 3′UTR
1035	UGCUUUAUCCGGGCUUGU	3611	ACAAGCCCGGAUAAAGCA	4646		[1872-1889] 3′UTR

TABLE B6
18 -mer siTIMP2 Cross-Species
		SEQ		SEQ
		ID		ID		human-73858577
No.	Sense (5′ > 3′)	NO:	Antisense (5′ > 3′)	NO:	Other Sp	ORF: 303-965
1	ACCAGAUGGGCUGCGAGU	4647	ACUCGCAGCCCAUCUGGU	4707	Rh, Ck, Rb, Rt	[744-761] ORF
2	ACAGGUACCAGAUGGGCU	4648	AGCCCAUCUGGUACCUGU	4708	Rh, Rb, Cw, Rt, Ms, Pg	[738-755] ORF
3	GAAGAGCCUGAACCACAG	4649	CUGUGGUUCAGGCUCUUC	4709	Rh, Rb, Cw, Ms, Pg	[724-741] ORF
4	UCUUCGCCUGCAUCAAGA	4650	UCUUGAUGCAGGCGAAGA	4710	Rh, Rb, Cw, Dg, Ms	[870-887] ORF
5	CGGGCACCAGGCCAAGUU	4651	AACUUGGCCUGGUGCCCG	4711	Rh, Rb, Rt, Ms	[853-870] ORF
6	CGCUCGGCCUCCUGCUGC	4652	GCAGCAGGAGGCCGAGCG	4712	Dg, Rt, Ms	[333-350] ORF
7	CAUCCCUUCCUGGAAACA	4653	UGUUUCCAGGAAGGGAUG	4713	Rh, Rb, Rt, Ms	[1035-1052] 3′UTR
8	CACCCGCAACAGGCGUUU	4654	AAACGCCUGUUGCGGGUG	4714	Cw, Rt, Ms	[398-415] ORF
9	GGCCGACGCCUGCAGCUG	4655	CAGCUGCAGGCGUCGGCC	4715	Cw, Dg, Rt, Ms	[370-387] ORF
10	GUGCCUCUGGAUGGACUG	4656	CAGUCCAUCCAGAGGCAC	4716	Rh, Rb, Cw, Dg, Rt, Ms	[814-831] ORF
11	CCUGAACCACAGGUACCA	4657	UGGUACCUGUGGUUCAGG	4717	Rh, Rb, Cw, Ms, Pg	[730-747] ORF
12	UCCUGGAAACAGCAUGAA	4658	UUCAUGCUGUUUCCAGGA	4718	Rh, Rb, Rt, Ms	[1042-1059] 3′UTR
13	GUCUCGCUGGACGUUGGA	4659	UCCAACGUCCAGCGAGAC	4719	Rt, Ms	[599-616] ORF
14	GCCGACGCCUGCAGCUGC	4660	GCAGCUGCAGGCGUCGGC	4720	Cw, Dg, Rt, Ms	[371-388] ORF
15	AACCACAGGUACCAGAUG	4661	CAUCUGGUACCUGUGGUU	4721	Rh, Rb, Cw, Rt, Ms, Pg	[734-751] ORF
16	CCCGGUGCACCCGCAACA	4662	UGUUGCGGGUGCACCGGG	4722	Cw, Dg, Rt, Ms	[391-408] ORF
17	CACAGGUACCAGAUGGGC	4663	GCCCAUCUGGUACCUGUG	4723	Rh, Rb, Cw, Rt, Ms, Pg	[737-754] ORF
18	CCCGCAACAGGCGUUUUG	4664	CAAAACGCCUGUUGCGGG	4724	Cw, Rt, Ms	[400-417] ORF
19	UCAAGCAGAUAAAGAUGU	4665	ACAUCUUUAUCUGCUUGA	4725	Cw, Dg, Rt, Ms, Pg	[519-536] ORF
20	CACCAGGCCAAGUUCUUC	4666	GAAGAACUUGGCCUGGUG	4726	Rh, Rb, Cw, Ms	[857-874] ORF
21	ACCACAGGUACCAGAUGG	4667	CCAUCUGGUACCUGUGGU	4727	Rh, Rb, Cw, Rt, Ms, Pg	[735-752] ORF
22	UCUCGCUGGACGUUGGAG	4668	CUCCAACGUCCAGCGAGA	4728	Rt, Ms	[600-617] ORF
23	CAAGCAGAUAAAGAUGUU	4669	AACAUCUUUAUCUGCUUG	4729	Cw, Dg, Rt, Ms, Pg	[520-537] ORF
24	GAUAAAGAUGUUCAAAGG	4670	CCUUUGAACAUCUUUAUC	4730	Dg, Rt, Ms	[526-543] ORF
25	GCACCCGCAACAGGCGUU	4671	AACGCCUGUUGCGGGUGC	4731	Cw, Dg, Rt, Ms	[397-414] ORF
26	CAGGCCAAGUUCUUCGCC	4672	GGCGAAGAACUUGGCCUG	4732	Rh, Rb, Cw, Dg, Ms	[860-877] ORF
27	UGCACCCGCAACAGGCGU	4673	ACGCCUGUUGCGGGUGCA	4733	Cw, Dg, Rt, Ms	[396-413] ORF
28	CAGGUACCAGAUGGGCUG	4674	CAGCCCAUCUGGUACCUG	4734	Rh, Rb, Cw, Dg, Rt, Ms, Pg	[739-756] ORF
29	GCUGGCGCUCGGCCUCCU	4675	AGGAGGCCGAGCGCCAGC	4735	Dg, Rt, Ms	[328-345] ORF
30	GCGCUCGGCCUCCUGCUG	4676	CAGCAGGAGGCCGAGCGC	4736	Dg, Rt, Ms	[332-349] ORF
31	GACGCCUGCAGCUGCUCC	4677	GGAGCAGCUGCAGGCGUC	4737	Cw, Dg, Rt, Ms	[374-391] ORF
32	UACCAGAUGGGCUGCGAG	4678	CUCGCAGCCCAUCUGGUA	4738	Rh, Ck, Rb, Rt	[743-760] ORF
33	GCUCGGCCUCCUGCUGCU	4679	AGCAGCAGGAGGCCGAGC	4739	Dg, Rt, Ms	[334-351] ORF
34	CGGUGCACCCGCAACAGG	4680	CCUGUUGCGGGUGCACCG	4740	Cw, Dg, Rt, Ms	[393-410] ORF
35	CCGGUGCACCCGCAACAG	4681	CUGUUGCGGGUGCACCGG	4741	Cw, Dg, Rt, Ms	[392-409] ORF
36	ACCCGCAACAGGCGUUUU	4682	AAAACGCCUGUUGCGGGU	4742	Cw, Rt, Ms	[399-416] ORF
37	AUCAAGCAGAUAAAGAUG	4683	CAUCUUUAUCUGCUUGAU	4743	Cw, Dg, Rt, Ms, Pg	[518-535] ORF
38	CCACAGGUACCAGAUGGG	4684	CCCAUCUGGUACCUGUGG	4744	Rh, Rb, Cw, Rt, Ms, Pg	[736-753] ORF
39	CCGACGCCUGCAGCUGCU	4685	AGCAGCUGCAGGCGUCGG	4745	Cw, Dg, Rt, Ms	[372-389] ORF
40	CUUCAUCGUGCCCUGGGA	4686	UCCCAGGGCACGAUGAAG	4746	Rh, Rb, Cw, Dg, Pg	[685-702] ORF
41	CGGCCGACGCCUGCAGCU	4687	AGCUGCAGGCGUCGGCCG	4747	Cw, Dg, Rt, Ms	[369-386] ORF
42	GUGCACCCGCAACAGGCG	4688	CGCCUGUUGCGGGUGCAC	4748	Cw, Dg, Rt, Ms	[395-412] ORF
43	CGACGCCUGCAGCUGCUC	4689	GAGCAGCUGCAGGCGUCG	4749	Cw, Dg, Rt, Ms	[373-390] ORF
44	ACCAGGCCAAGUUCUUCG	4690	CGAAGAACUUGGCCUGGU	4750	Rh, Rb, Cw, Ms	[858-875] ORF
45	UGCCUCUGGAUGGACUGG	4691	CCAGUCCAUCCAGAGGCA	4751	Rh, Rb, Cw, Dg, Rt, Ms	[815-832] ORF
46	AACAGGCGUUUUGCAAUG	4692	CAUUGCAAAACGCCUGUU	4752	Cw, Rt, Ms	[405-422] ORF
47	CUCGGCCUCCUGCUGCUG	4693	CAGCAGCAGGAGGCCGAG	4753	Dg, Rt	[335-352] ORF
48	CGGCCUCCUGCUGCUGGC	4694	GCCAGCAGCAGGAGGCCG	4754	Dg, Rt	[337-354] ORF
49	CCAGGCCAAGUUCUUCGC	4695	GCGAAGAACUUGGCCUGG	4755	Rh, Rb, Cw, Dg, Ms	[859-876] ORF
50	CUGGCGCUCGGCCUCCUG	4696	CAGGAGGCCGAGCGCCAG	4756	Dg, Rt, Ms	[329-346] ORF
51	UCGGCCUCCUGCUGCUGG	4697	CCAGCAGCAGGAGGCCGA	4757	Dg, Rt	[336-353] ORF
52	UGGCGCUCGGCCUCCUGC	4698	GCAGGAGGCCGAGCGCCA	4758	Dg, Rt, Ms	[330-347] ORF
53	AGGUACCAGAUGGGCUGC	4699	GCAGCCCAUCUGGUACCU	4759	Rh, Ck, Rb, Rt	[740-757] ORF
54	CUGUGACUUCAUCGUGCC	4700	GGCACGAUGAAGUCACAG	4760	Rh, Rb, Cw, Dg, Pg	[679-696] ORF
55	GACUUCAUCGUGCCCUGG	4701	CCAGGGCACGAUGAAGUC	4761	Rh, Rb, Cw, Dg, Pg	[683-700] ORF
56	ACGCCUGCAGCUGCUCCC	4702	GGGAGCAGCUGCAGGCGU	4762	Cw, Dg, Rt, Ms	[375-392] ORF
57	AAGAGCCUGAACCACAGG	4703	CCUGUGGUUCAGGCUCUU	4763	Rh, Rb, Cw, Ms, Pg	[725-742] ORF
58	CAGGGCCAAAGCGGUCAG	4704	CUGACCGCUUUGGCCCUG	4764	Rb, Dg	[436-453] ORF
59	UGACUUCAUCGUGCCCUG	4705	CAGGGCACGAUGAAGUCA	4765	Rh, Rb, Cw, Dg, Pg	[682-699] ORF
60	UGUGACUUCAUCGUGCCC	4706	GGGCACGAUGAAGUCACA	4766	Rh, Rb, Cw, Dg, Pg	[680-697] ORF

TABLE B7
Preferred 18 + 1 -mer siTIMP2
		SEQ		SEQ
		ID		ID
SiTIMP2_p#	Sense (5′ > 3′)	NO:	Antisense (5′ > 3′)	NO:	Length	Position
siTIMP2_p1	GGAGGAAAGAAGGAAUAUA	4767	UAUAUUCCUUCUUUCCUCC	4815	18 + 1	[614-631] ORF
siTIMP2_p2	GGACGUUGGAGGAAAGAAA	4768	UUUCUUUCCUCCAACGUCC	4816	18 + 1	[607-624] ORF
siTIMP2-p3	GGGUCUCGCUGGACGUUGA	4769	UCAACGUCCAGCGAGACCC	4817	18 + 1	[597-614] ORF
siTIMP2_p5	GGACUGGGUCACAGAGAAA	4770	UUUCUCUGUGACCCAGUCC	4818	18 + 1	[826-843] ORF
siTIMP2_p6	CUGCAUCAAGAGAAGUGAA	4771	UUCACUUCUCUUGAUGCAG	4819	18 + 1	[877-894] ORF
siTIMP2_p7	GAGGAAAGAAGGAAUAUCA	4772	UGAUAUUCCUUCUUUCCUC	4820	18 + 1	[615-632] ORF
siTIMP2_p8	GCUGGACGUUGGAGGAAAA	4773	UUUUCCUCCAACGUCCAGC	4821	18 + 1	[604-621] ORF
siTIMP2_p9	GGCGUUUUGCAAUGCAGAA	4774	UUCUGCAUUGCAAAACGCC	4822	18 + 1	[409-426] ORF
siTIMP2_p10	GCCUGCAUCAAGAGAAGUA	4775	UACUUCUCUUGAUGCAGGC	4823	18 + 1	[875-892] ORF
siTIMP2_p11	AGGAAAGAAGGAAUAUCUA	4776	UAGAUAUUCCUUCUUUCCU	4824	18 + 1	[616-633] ORF
siTIMP2_p12	AGAUCAAGCAGAUAAAGAA	4777	UUCUUUAUCUGCUUGAUCU	4825	18 + 1	[516-533] ORF
siTIMP2_p13	GUUGGAGGAAAGAAGGAAA	4778	UUUCCUUCUUUCCUCCAAC	4826	18 + 1	[611-628] ORF
siTIMP2_p14	GCUGCGAGUGCAAGAUCAA	4779	UUGAUCUUGCACUCGCAGC	4827	18 + 1	[753-770] ORF
siTIMP2_p15	GGGCUGCGAGUGCAAGAUA	4780	UAUCUUGCACUCGCAGCCC	4828	18 + 1	[751-768] ORF
siTIMP2_p19	GACAUCCCUUCCUGGAAAA	4781	UUUUCCAGGAAGGGAUGUC	4829	18 + 1	[1033-1050] 3′UTR
siTIMP2-p21	GAUGGACUGGGUCACAGAA	4782	UUCUGUGACCCAGUCCAUC	4830	18 + 1	[823-840] ORF
siTIMP2_p22	GCCUCUGGAUGGACUGGGA	4783	UCCCAGUCCAUCCAGAGGC	4831	18 + 1	[816-833] ORF
siTIMP2_p23	GAGUGCCUCUGGAUGGACA	4784	UGUCCAUCCAGAGGCACUC	4832	18 + 1	[812-829] ORF
siTIMP2_p26	GGCACCAGGCCAAGUUCUA	4785	UAGAACUUGGCCUGGUGCC	4833	18 + 1	[855-872] ORF
siTIMP2_p28	GCAACAGGCGUUUUGCAAA	4786	UUUGCAAAACGCCUGUUGC	4834	18 + 1	[403-420] ORF
siTIMP2_p31	GACGUUGGAGGAAAGAAGA	4787	UCUUCUUUCCUCCAACGUC	4835	18 + 1	[608-625] ORF
siTIMP2_p32	GAUCAAGCAGAUAAAGAUA	4788	UAUCUUUAUCUGCUUGAUC	4836	18 + 1	[517-534] ORF
siTIMP2_p34	UGAGAUCAAGCAGAUAAAA	4789	UUUUAUCUGCUUGAUCUCA	4837	18 + 1	[514-531] ORF
siTIMP2_p36	UGUGCAUUUUGCAGAAACA	4790	UGUUUCUGCAAAAUGCACA	4838	18 + 1	[1331-1348] 3′UTR
siTIMP2_p42	GAACCACAGGUACCAGAUA	4791	UAUCUGGUACCUGUGGUUC	4839	18 + 1	[733-750] ORF
siTIMP2_p43	CACCCAGAAGAAGAGCCUA	4792	UAGGCUCUUCUUCUGGGUG	4840	18 + 1	[715-732] ORF
siTIMP2_p45	CCUUCCUGGAAACAGCAUA	4793	UAUGCUGUUUCCAGGAAGG	4841	18 + 1	[1039-1056] 3′UTR
siTIMP2_p47	UGGGCUGCGAGUGCAAGAA	4794	UUCUUGCACUCGCAGCCCA	4842	18 + 1	[750-767] ORF
siTIMP2_p48	GAUGGGCUGCGAGUGCAAA	4795	UUUGCACUCGCAGCCCAUC	4843	18 + 1	[748-765] ORF
siTIMP2_p49	AUCCCUUCCUGGAAACAGA	4796	UCUGUUUCCAGGAAGGGAU	4844	18 + 1	[1036-1053] 3′UTR
siTIMP2_p50	AGUGCCUCUGGAUGGACUA	4797	UAGUCCAUCCAGAGGCACU	4845	18 + 1	[813-830] ORF
siTIMP2_p52	UGGAGGAAAGAAGGAAUAA	4798	UUAUUCCUUCUUUCCUCCA	4846	18 + 1	[613-630] ORF
siTIMP2_p53	GGGCACCAGGCCAAGUUCA	4799	UGAACUUGGCCUGGUGCCC	4847	18 + 1	[854-871] ORF
siTIMP2_p54	GUGCAUUUUGCAGAAACUA	4800	UAGUUUCUGCAAAAUGCAC	4848	18 + 1	[1332-1349] 3′UTR
siTIMP2_p56	CCAGAUGGGCUGCGAGUGA	4801	UCACUCGCAGCCCAUCUGG	4849	18 + 1	[745-762] ORF
siTIMP2_p57	CGAGUGCCUCUGGAUGGAA	4802	UUCCAUCCAGAGGCACUCG	4850	18 + 1	[811-828] ORF
siTIMP2_p58	CUGCGAGUGCAAGAUCACA	4803	UGUGAUCUUGCACUCGCAG	4851	18 + 1	[754-771] ORF
siTIMP2_p59	UCUGGAUGGACUGGGUCAA	4804	UUGACCCAGUCCAUCCAGA	4852	18 + 1	[819-836] ORF
siTIMP2_p60	GUACCAGAUGGGCUGCGAA	4805	UUCGCAGCCCAUCUGGUAC	4853	18 + 1	[742-759] ORF
siTIMP2_p63	GUAGUGAUCAGGGCCAAAA	4806	UUUUGGCCCUGAUCACUAC	4854	18 + 1	[428-445] ORF
siTIMP2_p66	GGCGCUCGGCCUCCUGCUA	4807	UAGCAGGAGGCCGAGCGCC	4855	18 + 1	[331-348] ORF
siTIMP2_p70	UGGAUGGACUGGGUCACAA	4808	UUGUGACCCAGUCCAUCCA	4856	18 + 1	[821-838] ORF
siTIMP2_p72	CCCUUCCUGGAAACAGCAA	4809	UUGCUGUUUCCAGGAAGGG	4857	18 + 1	[1038-1055] 3′UTR
siTIMP2_p73	ACCAGAUGGGCUGCGAGUA	4810	UACUCGCAGCCCAUCUGGU	4858	18 + 1	[744-761] ORF
siTIMP2_p74	ACAGGUACCAGAUGGGCUA	4811	UAGCCCAUCUGGUACCUGU	4859	18 + 1	[738-755] ORF
siTIMP2_p77	CGGGCACCAGGCCAAGUUA	4812	UAACUUGGCCUGGUGCCCG	4860	18 + 1	[853-870] ORF
siTIMP2_p80	CAUCCCUUCCUGGAAACAA	4813	UUGUUUCCAGGAAGGGAUG	4861	18 + 1	[1035-1052] 3′UTR
siTIMP2_p81	CACCCGCAACAGGCGUUUA	4814	UAAACGCCUGUUGCGGGUG	4862	18 + 1	[398-415] ORF

TABLE B8
18 + 1 -mer siTIMP2 with lowest predicted OT effect
			SEQ		SEQ
Cross			ID		ID	No. in
species:	Ranking	Sense (5′ > 3′)	NO:	Antisense (5′ > 3′)	NO:	Table B7
H/Rt	3	CUGCAUCAAGAGAAGUGAA	4771	UUCACUUCUCUUGAUGCAG	4819	siTIMP2_p6
H/Rt	3	GGCGUUUUGCAAUGCAGAA	4774	UUCUGCAUUGCAAAACGCC	4822	siTIMP2_p9
H/Rt	4	GGGCUGCGAGUGCAAGAUA	4780	UUCUGCAUUGCAAAACGCC	4828	siTIMP2_p15
H/Rt	4	GACAUCCCUUCCUGGAAAA	4781	UUCUGCAUUGCAAAACGCC	4829	siTIMP2_p19
H/Rt	4	GAUGGACUGGGUCACAGAA	4782	UUCUGCAUUGCAAAACGCC	4830	siTIMP2_p21
H/Rt	4	GCCUCUGGAUGGACUGGGA	4783	UUCUGCAUUGCAAAACGCC	4831	siTIMP2_p22
H/Rt	4	GAGUGCCUCUGGAUGGACA	4784	UUCUGCAUUGCAAAACGCC	4832	siTIMP2_p23
H/Rt	2	GCAACAGGCGUUUUGCAAA	4786	UUUGCAAAACGCCUGUUGC	4834	siTIMP2_p28
H/Rt	3	GACGUUGGAGGAAAGAAGA	4787	UCUUCUUUCCUCCAACGUC	4835	siTIMP2_p31
H/Rt	4	UGUGCAUUUUGCAGAAACA	4790	UGUUUCUGCAAAAUGCACA	4838	siTIMP2_p36
H/Rt	4	GAACCACAGGUACCAGAUA	4791	UAUCUGGUACCUGUGGUUC	4839	siTIMP2_p42
H/Rt	4	UGGGCUGCGAGUGCAAGAA	4794	UUCUUGCACUCGCAGCCCA	4842	siTIMP2_p47
H/Rt	4	AGUGCCUCUGGAUGGACUA	4797	UAGUCCAUCCAGAGGCACU	4845	siTIMP2_p50
H/Rt	4	CCAGAUGGGCUGCGAGUGA	4801	UCACUCGCAGCCCAUCUGG	4849	siTIMP2_p56
H/Rt	4	CGAGUGCCUCUGGAUGGAA	4802	UUCCAUCCAGAGGCACUCG	4850	siTIMP2_p57
H/Rt	2	CUGCGAGUGCAAGAUCACA	4803	UGUGAUCUUGCACUCGCAG	4851	siTIMP2_p58
H/Rt	3	GUACCAGAUGGGCUGCGAA	4805	UUCGCAGCCCAUCUGGUAC	4853	siTIMP2_p60
H/Rt	2	GUAGUGAUCAGGGCCAAAA	4806	UUUUGGCCCUGAUCACUAC	4854	siTIMP2_p63
H/Rt	3	UGGAUGGACUGGGUCACAA	4808	UUGUGACCCAGUCCAUCCA	4856	siTIMP2_p70
H/Rt	4	ACCAGAUGGGCUGCGAGUA	4810	UACUCGCAGCCCAUCUGGU	4858	siTIMP2_p73
H/Rt	4	ACAGGUACCAGAUGGGCUA	4811	UAGCCCAUCUGGUACCUGU	4859	siTIMP2_p74
H/Rt	2	CACCCGCAACAGGCGUUUA	4814	UAAACGCCUGUUGCGGGUG	4862	siTIMP2_p81

Example 6

In Vitro Testing of the siRNA Compounds for the Target Genes

Low-Throughput-Screen (LTS) for siRNA oligos directed to human and rat TIMP1 and TIMP2 gene.

About 2×10⁵ human cell lines (HeLa, LX2, hHSC or PC3) endogenously expressing TIMP1 or TIMP2 gene, are inoculated in 1.5 mL growth medium in order to reach 30-50% confluence after 24 hours. Cells are transfected with Lipofectamine-2000® reagent to a final concentration of 0.01-5 nM per transfected cells. Cells aere incubated at 37±1° C., 5% CO₂ for 48 hours. siRNA transfected cells are harvested and RNA is isolated using EZ-RNA® kit [Biological Industries (#20-410-100)].

Reverse transcription is performed as follows: Synthesis of cDNA is performed and human TIMP1 and TIMP2 mRNA levels are determined by Real Time qPCR and normalized to those of the Cyclophilin A (CYNA, PPIA) mRNA for each sample. siRNA activity is determined based on the ratio of the TIMP1 or TIMP2 mRNA quantity in siRNA-treated samples versus non-transfected control samples.

The most active sequences are selected from additional, assays.

IC50 Values for the LTS Selected TIMP1 or TIMP2 siRNA Oligos

Cells are grown as described above. The IC50 value of the tested RNAi activity is determined by constructing a dose-response curve using the activity results obtained with the various final siRNA concentrations. The dose response curve is constructed by plotting the relative amount of residual TIMP1 or TIMP2 mRNA versus the logarithm of transfected siRNA concentration. The curve is calculated by fitting the best sigmoid curve to the measured data. The method for the sigmoid fit is also known as a 3-point curve fit.

$Y+\mathrm{Bot}+\frac{100-\mathrm{Bot}}{1+{10}^{\left(\mathrm{LogIC}50-X\right)\times \mathrm{HillSlope}}}$

where Y is the residual TIMP1 or TIMP2 mRNA response, X is the logarithm of transfected siRNA concentration, Bot is the Y value at the bottom plateau, LogIC50 is the X value when Y is halfway between bottom and top plateaus and HillSlope is the steepness of the curve.

The percent of inhibition of gene expression using specific siRNAs was determined using qPCR analysis of target gene in cells expressing the endogenous gene. Other siRNA compounds according to Tables A1, A2, A3, A4, A5, A6, A7, A8, B1, B2, B3, B4, B5, B6, B7, B8 (Tables A1-B8) are tested in vitro where it is shown that these siRNA compounds inhibit gene expression. Activity is shown as percent residual mRNA; accordingly, a lower value reflects better activity.

In order to test the stability of the siRNA compounds in serum, specific siRNA molecules are incubated in four different batches of human serum (100% concentration) at 37° C. for up to 24 hours. Samples are collected at 0.5, 1, 3, 6, 8, 10, 16 and 24 hours. The migration patterns as an indication of are determined at each collection time by polyacrylamide gel electrophoresis (PAGE).

Example 7

Validation of siTIMP1 and siTIMP2 Knock Down Effect at the Protein Level

The inhibitory effect of different siTIMP1 and siTIMP2 siNA molecules on TIMP1 and TIMP2 mRNA expression are validated at the protein level by measuring TIMP1 and TIMP2 in hTERT cells transfected with different siTIMP1 and siTIMP2. Transfection of hTERT cells with different siTIMP1 and siTIMP2 are performed as described above. Transfected hTERT cells are lysed and the cell lysate are clarified by centrifugation. Proteins in the clarified cell lysate are resolved by SDS polyacrylamide gel electrophoresis. The level of TIMP1 and TIMP2 protein in the cell lysate are determined using anti-TIMP or anti-TIMP2 antibodies as the primary antibody HRP conjugated antibodies (Millipore) as the secondary antibody, and subsequently detection by Supersignal West Pico Chemiluminescence kit (Pierce). Anti-actin antibody (Abcam) is used as a protein loading control.

Example 8

Downregulation of Collagen I Expression by siTIMP1 and siTIMP2 siRNA Duplexes

To determine the effect of siTIMP1 and siTIMP2, alone or in combination on collagen I expression level, collagen I mRNA level in hTERT cells treated with different siTIMP1 and or siTIMP2. Briefly, hTERT cells are transfected with different siTIMP1, and or siTIMP2 as described in Example 2. The cells are lysed after 72 hours and mRNA were isolated using RNeasy mini kit according to the manual (Qiagen). The level of collagen 1 mRNA is determined by reverse transcription coupled with quantitative PCR using TaqMan® probes. Briefly, cDNA synthesis is carried out using High-Capacity cDNA Reverse Transcription Kit (ABI) according to the manual, and subjected to TaqMan Gene Expression Assay (ABI, COL1A1 assay ID Hs01076780_g1). The level of collagen I mRNA is normalized to the level of GAPDH mRNA according to the manufacturer's instruction (ABI). The signals are normalized to the signal obtained from cells transfected with scrambled siNA.

Example 9

Immunofluorescence Staining of siTIMP1 and or siTIMP2 treated hTERT Cells

To visualize the expression of two fibrosis markers, collagen I and alpha-smooth muscle actin (SMA), in hTERT cells transfected, the cells are stained with rabbit anti-collagen I antibody (Abcam) and mouse anti-alpha-SMA antibody (Sigma). Alexa Fluor 594 goat anti-mouse IgG and Alexa Fluor 488 goat anti-rabbit IgG (Invitrogen (Molecular Probes)) are used as secondary antibodies to visualize collagen I (green) and alpha-SMA (red). Hoescht is used to visualize nuleus (blue).

Example 10

Animal Models: Model Systems of Fibrotic Conditions

siRNAs provided herein may be tested in predictive animal models. Rat diabetic and aging models of kidney fibrosis include Zucker diabetic fatty (ZDF) rats, aged fa/fa (obese Zucker) rats, aged Sprague-Dawley (SD) rats, and Goto Kakizaki (GK) rats; GK rats are an inbred strain derived from Wistar rats, selected for spontaneous development of NIDDM (diabetes type II). Induced models of kidney fibrosis include the permanent unilateral ureteral obstruction (UUO) model which is a model of acute interstitial fibrosis occurring in healthy non-diabetic animals; renal fibrosis develops within days following the obstruction. Another induced model of kidney fibrosis is 5/6 nephrectomy model.

Two models of liver fibrosis in rats are the Bile Duct Ligation (BDL) with sham operation as controls, and CCl4 poisoning, with olive oil fed animals as controls, as described in the following references: Lotersztajn S, et al Hepatic Fibrosis: Molecular Mechanisms and Drug Targets. Annu Rev Pharmacol Toxicol. 2004 Oct. 7; Uchio K, et al., Down-regulation of connective tissue growth factor and type I collagen mRNA expression by connective tissue growth factor antisense oligonucleotide during experimental liver fibrosis. Wound Repair Regen. 2004 January-February; 12(1):60-6; Xu X Q, et al., Molecular classification of liver cirrhosis in a rat model by proteomics and bioinformatics Proteomics. 2004 October; 4(10):3235-45.

Models for ocular scarring are well known in the art e.g. Sherwood M B et al., J Glaucoma. 2004 October; 13(5):407-12. A new model of glaucoma filtering surgery in the rat; Miller M H et al., Ophthalmic Surg. 1989 May; 20(5):350-7. Wound healing in an animal model of glaucoma fistulizing surgery in the Rb; vanBockxmeer F M et al., Retina. 1985 Fall-Winter; 5(4): 239-52. Models for assessing scar tissue inhibitors; Wiedemann P et al., J Pharmacol Methods. 1984 August; 12(1): 69-78. Proliferative vitreoretinopathy: the Rb cell injection model for screening of antiproliferative drugs.

Models of cataract are described in the following publications: The role of Src family kinases in cortical cataract formation. Zhou J, Menko A S. Invest Ophthalmol V is Sci. 2002 July; 43(7):2293-300; Bioavailability and anticataract effects of a topical ocular drug delivery system containing disulfuram and hydroxypropyl-beta-cyclodextrin on selenite-treated rats. Wang S, et al. Curr Eye Res. 2004 July; 29(1):51-8; and Long-term organ culture system to study the effects of UV-A irradiation on lens transglutaminase. Weinreb O, Dovrat A.; Curr Eye Res. 2004 July; 29(1):51-8.

The compounds disclosed herein are tested in these models of fibrotic conditions, in which it is found that they are effective in treating liver fibrosis and other fibrotic conditions. The compounds as described herein are tested in this animal model and the results show that these siRNA compounds are useful in treating and/or preventing ischemia reperfusion injury following lung transplantation.

The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

Applicants reserve the right to physically incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.

It will be readily apparent to one skilled in the art that varying substitutions and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims. The present disclosure teaches one skilled in the art to test various combinations and/or substitutions of chemical modifications described herein toward generating nucleic acid constructs with improved activity for mediating RNAi activity. Such improved activity can include improved stability, improved bioavailability, and/or improved activation of cellular responses mediating RNAi. Therefore, the specific embodiments described herein are not limiting and one skilled in the art can readily appreciate that specific combinations of the modifications described herein can be tested without undue experimentation toward identifying nucleic acid molecules with improved RNAi activity.

The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising”, “having,” “including,” containing”, etc. shall be read expansively and without limitation (e.g., meaning “including, but not limited to,”). Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. Other embodiments are within the following claims. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

Claims

1. A nucleic acid molecule, wherein: (a) the nucleic acid molecule comprises a sense strand and an antisense strand;(b) each strand of the nucleic acid molecule is independently 15 to 49 nucleotides in length;(c) a 15 to 49 nucleotide sequence of the antisense strand is complementary to a sequence of an mRNA encoding TIMP1 (SEQ ID NO:1) or TIMP2 (SEQ ID NO:2); and(d) a 15 to 49 nucleotide sequence of the sense strand is complementary to the antisense strand thereby generating a duplex region and includes a 15 to 49 nucleotide sequence of an mRNA encoding TIMP1 (SEQ ID NO:1) or TIMP2 (SEQ ID NO:2).

2. The nucleic acid molecule of claim 1 wherein the sequence of the antisense strand is complementary to a sequence of an mRNA encoding human TIMP1 (SEQ ID NO:1), and wherein the antisense strand and the sense strand comprise a sequence pair selected from the group consisting of siTIMP1_p2 (SEQ ID NOS:267 and 299); siTIMP1_p6 (SEQ ID NOS:268 and 300); siTIMP1_p14 (SEQ ID NOS:269 and 301); siTIMP1_p16 (SEQ ID NOS:270 and 302); siTIMP1_p17 (SEQ ID NOS:271 and 303); siTIMP1_p19 (SEQ ID NOS:272 and 304); siTIMP1_p20 (SEQ ID NOS:273 and 305); siTIMP1_p21 (SEQ ID NOS:274 and 306); siTIMP1_p23 (SEQ ID NOS:275 and 307; siTIMP1_p29 (278 and 310); siTIMP1_p33 (280 and 312); siTIMP1_p38 (SEQ ID NOS:281 and 313); siTIMP1_p42 (282 and 314); siTIMP1_p43 (SEQ ID NOS:283 and 315); siTIMP1_p45 (284 and 316); siTIMP1_p60 (SEQ ID NOS:286 and 318); siTIMP1_p71 (SEQ ID NOS:287 and 319); siTIMP1_p73 (SEQ ID NOS:288 and 320); siTIMP1_p78 (290 and 322); siTIMP1_p79 (SEQ ID NOS:291 and 323); siTIMP1_p85 (SEQ ID NOS:292 and 324); siTIMP1_p89 (SEQ ID NOS:293 and 325); siTIMP1_p91 (SEQ ID NOS:294 and 326); siTIMP1_p96 (SEQ ID NOS:295 and 327); siTIMP1_p98 (SEQ ID NOS:296 and 328); siTIMP1_p99 (SEQ ID NOS:297 and 329) and siTIMP1_p108 (SEQ ID NOS:298 and 330).

3. The nucleic acid molecule of claim 1, wherein the sequence of the antisense strand is complementary to a sequence of an mRNA encoding human TIMP1, and wherein the sense strand and the antisense strand are selected from the sequence pairs shown in Table C set forth as TIMP1-A (SEQ ID NOS:5 and 6); TIMP1-B (SEQ ID NOS:7 and 8) and TIMP1-C (SEQ ID NO:9 and 10).

4. The nucleic acid molecule of claim 1, wherein the sequence of the antisense strand that is complementary to a sequence of an mRNA encoding human TIMP1 comprises a sequence complimentary to a sequence between nucleotides 300-400 of SEQ ID NO: 1, 355-373 of SEQ ID NO: 1, 600-750 of SEQ ID NO: 1, 620-638 of SEQ ID NO: 1 or 640-658 of SEQ ID NO: 1.

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. The nucleic acid molecule of claim 1, wherein the sequence of the antisense strand is complementary to a sequence of an mRNA encoding human TIMP2, and wherein the sense strand and the antisense strand are selected from the sequence pairs shown in Table D.

10. The nucleic acid molecule of claim 1, wherein the sequence of the antisense strand is complementary to a sequence of an mRNA encoding human TIMP2 and comprises a sequence complimentary to a sequence between nucleotides 400-500 of SEQ ID NO: 2, 500-600 of SEQ ID NO: 2, 600-700 of SEQ ID NO: 2, and 698-716 of SEQ ID NO: 2.

11. (canceled)

12. (canceled)

13. (canceled)

14. (canceled)

15. (canceled)

16. (canceled)

17. (canceled)

18. The nucleic acid molecule of claim 1, wherein the antisense strand and the sense strand are independently 17 to 49 nucleotides in length.

19. (canceled)

20. (canceled)

21. (canceled)

22. (canceled)

23. (canceled)

24. The nucleic acid molecule of claim 1, wherein the antisense strand and the sense strand are each 19 nucleotides in length.

25. (canceled)

26. (canceled)

27. (canceled)

28. (canceled)

29. (canceled)

30. (canceled)

31. (canceled)

32. The nucleic acid molecule of claim 1, wherein the duplex region is 19 nucleotides in length.

33. The nucleic acid molecule of claim 1, wherein the antisense strand and the sense strand are separate polynucleotide strands.

34. (canceled)

35. (canceled)

36. The nucleic acid molecule of claim 1, wherein the sense strand and the antisense strands are part of a single polynucleotide strand having both a sense region and an antisense region.

37. (canceled)

38. (canceled)

39. (canceled)

40. (canceled)

41. (canceled)

42. (canceled)

43. (canceled)

44. (canceled)

45. (canceled)

46. (canceled)

47. (canceled)

48. (canceled)

49. (canceled)

50. (canceled)

51. (canceled)

52. (canceled)

53. (canceled)

54. (canceled)

55. (canceled)

56. (canceled)

57. The nucleic acid molecule of claim 1, wherein the nucleic acid molecule comprises one or more modifications or modified nucleotides.

58. (canceled)

59. (canceled)

60. (canceled)

61. (canceled)

62. (canceled)

63. (canceled)

64. (canceled)

65. (canceled)

66. (canceled)

67. (canceled)

68. (canceled)

69. (canceled)

70. (canceled)

71. (canceled)

72. (canceled)

73. (canceled)

74. (canceled)

75. (canceled)

76. (canceled)

77. (canceled)

78. (canceled)

79. (canceled)

80. (canceled)

81. (canceled)

82. (canceled)

83. (canceled)

84. (canceled)

85. (canceled)

86. A method for treating an individual suffering from a disease associated with TIMP1 or TIMP2, wherein (a) when the disease is associated with TIMP1, the method comprises administering to said individual a nucleic acid molecule of claim 1 comprising a sequence of the antisense strand complementary to a sequence of a mRNA encoding human TIMP1, in an amount sufficient to reduce expression of TIMP1; and(b) when the disease is associated with TIMP2, the method comprises administering to said individual a nucleic acid molecule of claim 1—comprising a sequence of the antisense strand complementary to a sequence of a mRNA encoding human TIMP2, in an amount sufficient to reduce expression of TIMP2.

87. (canceled)

88. The method of claim 86, wherein said disease associated with TIMP1 or TIMP2 is fibrosis.

89. A composition comprising a nucleic acid molecule of any of claim 1-4, 9, 10, 24, 32, 33, 36, 57, 98, 99, 105, 125-128 or 133 and a pharmaceutically acceptable carrier.

90. (canceled)

91. (canceled)

92. (canceled)

93. (canceled)

94. (canceled)

95. (canceled)

96. (canceled)

97. (canceled)

98. A double stranded nucleic acid molecule having the structure (A 1):

99. The nucleic acid molecule of claim 98 having the structure (A1), wherein (N)x comprises an antisense sequence to an mRNA set forth in SEQ ID NO:1 and wherein (N)x comprises an antisense oligonucleotide present in any one of Tables A 1, A2, A3 or A4; or wherein (N)x comprises an antisense sequence to an mRNA set forth in SEQ ID NO:2 and wherein (N)x comprises an antisense oligonucleotide present in any one of Tables B1, B2, B3 or B4.

100. (canceled)

101. (canceled)

102. (canceled)

103. (canceled)

104. (canceled)

105. The nucleic acid molecule of claim 98, wherein x=y=19.

106. (canceled)

107. (canceled)

108. (canceled)

109. (canceled)

110. (canceled)

111. (canceled)

112. (canceled)

113. (canceled)

114. (canceled)

115. (canceled)

116. (canceled)

117. (canceled)

118. (canceled)

119. (canceled)

120. (canceled)

121. (canceled)

122. (canceled)

123. (canceled)

124. (canceled)

125. A double stranded nucleic acid molecule having a structure (A2) set forth below:

126. The nucleic acid molecule of claim 125 wherein x=y=18.

127. The nucleic acid molecule of claim 125, wherein (N)x comprises an antisense sequence to an mRNA set forth in SEQ ID NO:1 or SEQ ID NO:2.

128. The nucleic acid molecule of claim 127, having the structure (A2), wherein (N)x comprises an antisense sequence to an mRNA set forth in SEQ ID NO:1, comprising an antisense oligonucleotide present in any one of Tables A5, A6, A7, A8; orwherein (N)x comprises an antisense sequence to an mRNA set forth in SEQ ID NO:2, comprising an antisense oligonucleotide present in any one of Tables B5, B6, B7, or B8.

129. (canceled)

130. (canceled)

131. (canceled)

132. (canceled)

133. A nucleic acid molecule consisting of four ribonucleotide strands forming three siRNA duplexes having the general structure:

134. (canceled)

135. (canceled)

136. (canceled)

137. (canceled)

138. (canceled)

139. (canceled)

140. (canceled)

141. (canceled)

142. (canceled)

143. (canceled)

144. (canceled)

145. (canceled)