COMPOSITIONS AND METHODS FOR INHIBITING MAPT EXPRESSION

Abstract
Oligonucleotides are provided herein that inhibit MAPT gene expression, including oligonucleotides conjugated to a targeting ligand (e.g., lipid moiety). Also provided are compositions including the same and uses thereof, particularly uses relating to treating diseases, disorders, and/or conditions associated with MAPT gene expression.
Description
TECHNICAL FIELD

The disclosure relates generally to biology and medicine, and more particularly it relates to oligonucleotides and compositions including the same for inhibiting or reducing (i.e., modulating) microtubule-associated protein tau (MAPT) gene expression, as well as their use for treating diseases and disorders associated with MAPT gene expression.


BACKGROUND

Microtubules perform several essential roles within cells throughout the body. Within the central nervous system (CNS), microtubules provide structural support and assist in transporting substances throughout cells. Changes in microtubule mass, structure, and pattern are known factors leading to the development of many neurodegenerative diseases. Tau is an essential protein for forming microtubules, whose abnormal expression leads to neurodegenerative diseases. Tau proteins combine with tubulin to form microtubules. Alternative splicing of MAPT generates different Tau proteins used in microtubule assembly. Mutations (e.g., insertions and mismatches) in MAPT that alter Tau function and expression are known causes of several diseases and disorders impacting the CNS (e.g., Alzheimer's disease (AD), Parkinson's disease (PD), and tauopathies). Strategies for targeting MAPT gene expression to prevent such diseases and disorders are needed.


The mammalian CNS is a complex system of tissues, including cells, fluids, and chemicals that interact in concert to enable a wide variety of functions, including movement, navigation, cognition, speech, vision, and emotion. Unfortunately, a variety of diseases and disorders of the CNS are known (e.g., neurological disorders) and affect or disrupt some or all of these functions. Typically, treatments for diseases and disorders of the CNS have been limited to small molecule drugs, antibodies, and/or to adaptive or behavioral therapies. There exists an ongoing need to develop treatments for diseases and disorders of the CNS associated with inappropriate MAPT gene expression.


BRIEF SUMMARY

To address this need, the disclosure describes compositions for and methods of treating a disease, disorder, or condition associated with MAPT gene expression. The disclosure is based, at least in part, on discovering and developing double-stranded (ds) oligonucleotides such as RNAi oligonucleotides that effectively target and reduce MAPT gene expression in tissues of the CNS. Specifically, target sequences within MAPT mRNA were identified, and oligonucleotides that bind to these target sequences and inhibit MAPT mRNA expression were generated. As demonstrated herein, the oligonucleotides inhibit human and non-human primate (NIP) MAPT gene expression in CNS tissue. Further, MAPT mRNA expression was reduced in CNS tissue associated with AD or progressive supranuclear palsy (PSP) with both N-acetylgalactosamine (GalNAc)-conjugated and lipid-conjugated MAPT mRNA-targeting oligonucleotides. Without being bound by theory, the oligonucleotides described herein are useful for treating a disease, disorder, or condition associated with MAPT gene expression.


Accordingly, and in some aspects, the disclosure provides a RNAi oligonucleotide for reducing MAPT gene expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a MAPT mRNA target sequence of any one of SEQ ID NOs: 912-1295, and wherein the region of complementarity is at least about 15 contiguous nucleotides in length.


In any of the foregoing or related aspects, the sense strand is about 15 to about 50 nucleotides in length. In some aspects, the sense strand is 18 to 36 nucleotides in length. In some aspects, the antisense strand is about 15 to about 30 nucleotides in length. In some aspects, the antisense strand is 22 nucleotides in length, wherein the antisense strand and the sense strand form a duplex region of at least about 19 nucleotides in length, optionally at least 20 nucleotides in length. In some aspects, the region of complementarity is at least about 19 contiguous nucleotides in length. In some aspects, the region of complementarity is at least about 20 contiguous nucleotides in length.


In other aspects, the disclosure provides a ds RNAi oligonucleotide for reducing MAPT gene expression, the oligonucleotide comprising:

    • (i) an antisense strand of about 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is selected from SEQ ID NOs: 1296-1679, and
    • (ii) a sense strand of about 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some aspects, the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length. In some aspects, L is a triloop (triL) or a tetraloop (tetraL). In some aspects, L is a tetraL. In some aspects, the tetraL comprises the sequence 5′-GAAA-3′. In some aspects, S1 and S2 are about 1 to about 10 nucleotides in length and have the same length. In some aspects, S1 and S2 are 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, or 10 nucleotides in length. In some aspects, S1 and S2 are 6 nucleotides in length. In some aspects, the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1680).


In other aspects, the oligonucleotide comprises a blunt end. In some aspects, the blunt end comprises the 3′ end of the sense strand. In some aspects, the sense strand is about 20-22 nucleotides. In some aspects, the sense strand is 20 nucleotides.


In any of the foregoing or related aspects, the antisense strand comprises a 3′ overhang sequence of one or more nucleotides in length. In some aspects, the overhang comprises purine nucleotides. In some aspects, the 3′ overhang sequence is 2 nucleotides in length. In some aspects, the 3′ overhang is selected from AA, GG, AG, and GA. In some aspects, the overhang is GG or AA. In some aspects, the overhang is GG.


In any of the foregoing or related aspects, the oligonucleotide comprises at least one modified nucleotide. In some aspects, the modified nucleotide comprises a 2-modification. In some aspects, the 2-modification is a modification selected from 2′-aminoethyl (EA), 2′-fluoro (2′-F), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-OME), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA). In some aspects, the modification is a 2′-modification selected from 2′-F and 2′-OMe. In some aspects, about 18% to about 23%, or 18%, 19%, 20%, 21%, 22%, or 23% of the nucleotides of the sense strand comprise a 2′-F modification. In other aspects, about 38% to about 43%, or 38%, 39%, 40%, 41%, 42%, or 43% of the nucleotides of the sense strand comprise a 2′-F modification. In some aspects, about 25% to about 35%, or 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the antisense strand comprise a 2′-F modification. In some aspects, about 25% to about 35%, or 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the oligonucleotide comprise a 2′-F modification. In some aspects, about 35-45%, 35%, 36%, 37%, 38%, 39% 40%, 41%, 42%, 43%, 44% or 45% of the nucleotides of the oligonucleotide comprise a 2′-F modification. In some aspects, the sense strand comprises 20 nucleotides with positions 1-20 from 5′ to 3′, wherein each of positions 3, 5, 8, 10, 12, 13, 15, and 17 comprise a 2′-F modification. In other aspects, the sense strand comprises 36 nucleotides with positions 1-36 from 5′ to 3′, wherein each of positions 3, 5, 8, 10, 12, 13, 15, and 17 comprise a 2′-F modification. In some aspects, the antisense strand comprises 22 nucleotides with positions 1-22 from 5′ to 3′, and wherein each of positions 2, 3, 4, 5, 7, 10 14, 16, and 19 comprise a 2′-F modification. In some aspects, the remaining nucleotides comprise a 2′-OMe modification.


In any of the foregoing or related aspects, the oligonucleotide comprises at least one modified internucleotide linkage. In some aspects, the at least one modified internucleotide linkage is a phosphorothioate linkage. In some aspects, the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5′ to 3′. In some aspects, the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5′ to 3′. In some aspects, the sense strand comprises a phosphorothioate linkage between positions 1 and 2, wherein positions are numbered 1-2 from 5′ to 3′. In some aspects, the sense strand is 20 nucleotides in length, and wherein the sense strand comprises a phosphorothioate linkage between positions between positions 1 and 2, between positions 18 and 19 and between positions 19 and 20, wherein positions are numbered 1-20 from 5′ to 3′.


In any of the foregoing or related aspects, the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog. In some aspects, the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate, optionally wherein the phosphate analog is a 4′-phosphate analog comprising 4′-oxymethylphosphonate.


In any of the foregoing or related aspects, at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands. In some aspects, each targeting ligand comprises a carbohydrate, amino sugar, lipid, cholesterol, or polypeptide. In some aspects, the stem-loop comprises one or more targeting ligands conjugated to one or more nucleotides of the stem-loop. In some aspects, the one or more targeting ligands is conjugated to one or more nucleotides of the loop. In some aspects, the loop comprises 4 nucleotides numbered 1-4 from 5′ to 3′, wherein nucleotides at positions 2, 3, and 4 each comprise one or more targeting ligands, wherein the targeting ligands are the same or different. In some aspects, each targeting ligand comprises a GalNAc moiety. In some aspects, the GalNac moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety, or a tetravalent GalNAc moiety. In some aspects, up to 4 nucleotides of L of the stem-loop are each conjugated to a monovalent GalNAc moiety.


In other aspects, the one or more targeting ligands is a lipid moiety. In some aspects, the lipid moiety is conjugated to the 5′ terminal nucleotide of the sense strand. In some aspects, the lipid moiety is a hydrocarbon chain. In some aspects, the hydrocarbon chain is a C8-C30 hydrocarbon chain. In some aspects, the hydrocarbon chain is a C16 hydrocarbon chain. In some aspects, the C16 hydrocarbon chain is represented by:




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In some aspects, the lipid moiety is conjugated to the 2′ carbon of the ribose ring of the 5′ terminal nucleotide.


In any of the foregoing or related aspects, the region of complementarity is fully complementary to the MAPT mRNA target sequence at nucleotide positions 2-8 of the antisense strand, wherein nucleotide positions are numbered 5′ to 3′. In some aspects, the region of complementarity is fully complementary to the MAPT mRNA target sequence at nucleotide positions 2-11 of the antisense strand, wherein nucleotide positions are numbered 5′ to 3′.


In any of the foregoing or related aspects, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 769-803 and 1681. In some aspects, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 804-838.


In some aspects, the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

    • a) SEQ ID NOs: 769 and 804, respectively;
    • b) SEQ ID NOs: 770 and 805, respectively;
    • c) SEQ ID NOs: 771 and 806, respectively;
    • d) SEQ ID NOs: 772 and 807, respectively;
    • e) SEQ ID NOs: 773 and 808, respectively;
    • f) SEQ ID NOs: 774 and 809, respectively;
    • g) SEQ ID NOs: 775 and 810, respectively;
    • h) SEQ ID NOs: 776 and 811, respectively;
    • i) SEQ ID NOs: 777 and 812, respectively;
    • j) SEQ ID NOs: 778 and 813, respectively;
    • k) SEQ ID NOs: 779 and 814, respectively;
    • l) SEQ ID NOs: 780 and 815, respectively;
    • m) SEQ ID NOs: 781 and 816, respectively;
    • n) SEQ ID NOs: 782 and 817, respectively;
    • o) SEQ ID NOs: 783 and 818, respectively;
    • p) SEQ ID NOs: 784 and 819, respectively;
    • q) SEQ ID NOs: 785 and 820, respectively;
    • r) SEQ ID NOs: 786 and 821, respectively;
    • s) SEQ ID NOs: 787 and 822, respectively;
    • t) SEQ ID NOs: 788 and 823, respectively;
    • u) SEQ ID NOs: 789 and 824, respectively;
    • v) SEQ ID NOs: 790 and 825, respectively;
    • w) SEQ ID NOs: 791 and 826, respectively;
    • x) SEQ ID NOs: 792 and 827, respectively;
    • y) SEQ ID NOs: 793 and 828, respectively;
    • z) SEQ ID NOs: 794 and 829, respectively;
    • aa) SEQ ID NOs: 795 and 830, respectively;
    • bb) SEQ ID NOs: 796 and 831, respectively;
    • cc) SEQ ID NOs: 797 and 832, respectively;
    • dd) SEQ ID NOs: 798 and 833, respectively;
    • ee) SEQ ID NOs: 799 and 834, respectively;
    • ff) SEQ ID NOs: 800 and 835, respectively;
    • gg) SEQ ID NOs: 801 and 836, respectively;
    • hh) SEQ ID NOs: 802 and 837, respectively;
    • ii) SEQ ID NOs: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively.


In some aspects, the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively;
    • j) SEQ ID NOs: 803 and 838, respectively;
    • k) SEQ ID NOs: 1681 and 815, respectively.


In some aspects, the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 780 and 815, respectively;
    • c) SEQ ID NOs: 781 and 816, respectively;
    • d) SEQ ID NOs: 798 and 833, respectively;
    • e) SEQ ID NOs: 799 and 834, respectively;
    • f) SEQ ID NOs: 803 and 838, respectively; and
    • g) SEQ ID NOs: 1681 and 815, respectively.


In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 771, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 806. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 780, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 815. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 781, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 816. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 798, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 833. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 799, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 834. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 803, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 838. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 1681, and the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 815.


In any of the foregoing or related aspects, the antisense strand is 22 nucleotides in length. In some aspects, the antisense strand comprises a nucleotide sequence selected from SEQ ID NOs: 806, 815, 816, 833, 834, and 838. In some aspects, the sense strand is 36 nucleotides in length. In some aspects, the sense strand comprises a nucleotide sequence selected from SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124. In some aspects, the sense strand comprises a nucleotide sequence selected from SEQ ID NOs: 771, 780, 781, 798, 799, and 803.


In any of the foregoing or related aspects, the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 839-873 and 1682. In some aspects, the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 874-908.


In some aspects, the sense strand and antisense strands comprise nucleotide sequences selected from:

    • a) SEQ ID NOs: 839 and 874, respectively;
    • b) SEQ ID NOs: 840 and 875, respectively;
    • c) SEQ ID NOs: 841 and 876, respectively;
    • d) SEQ ID NOs: 842 and 877, respectively;
    • e) SEQ ID NOs: 843 and 878, respectively;
    • f) SEQ ID NOs: 844 and 879, respectively;
    • g) SEQ ID NOs: 845 and 880, respectively;
    • h) SEQ ID NOs: 846 and 881, respectively;
    • i) SEQ ID NOs: 847 and 882, respectively;
    • j) SEQ ID NOs: 848 and 883, respectively;
    • k) SEQ ID NOs: 849 and 884, respectively;
    • l) SEQ ID NOs: 850 and 885, respectively;
    • m) SEQ ID NOs: 851 and 886, respectively;
    • n) SEQ ID NOs: 852 and 887, respectively;
    • o) SEQ ID NOs: 853 and 888, respectively;
    • p) SEQ ID NOs: 854 and 889, respectively;
    • q) SEQ ID NOs: 855 and 890, respectively;
    • r) SEQ ID NOs: 856 and 891, respectively;
    • s) SEQ ID NOs: 857 and 892, respectively;
    • t) SEQ ID NOs: 858 and 893, respectively;
    • u) SEQ ID NOs: 859 and 894, respectively;
    • v) SEQ ID NOs: 860 and 895, respectively;
    • w) SEQ ID NOs: 861 and 896, respectively;
    • x) SEQ ID NOs: 862 and 897, respectively;
    • y) SEQ ID NOs: 863 and 898, respectively;
    • z) SEQ ID NOs: 864 and 899, respectively;
    • aa) SEQ ID NOs: 865 and 900, respectively;
    • bb) SEQ ID NOs: 866 and 901, respectively;
    • cc) SEQ ID NOs: 867 and 902, respectively;
    • dd) SEQ ID NOs: 868 and 903, respectively;
    • ee) SEQ ID NOs: 869 and 904, respectively;
    • ff) SEQ ID NOs: 870 and 905, respectively;
    • gg) SEQ ID NOs: 871 and 906, respectively;
    • hh) SEQ ID NOs: 872 and 907, respectively;
    • ii) SEQ ID NOs: 873 and 908, respectively; and
    • jj) SEQ ID NOs: 1682 and 885, respectively.


In other aspects, the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

    • a) SEQ ID NOs: 860 and 895, respectively;
    • b) SEQ ID NOs: 865 and 900, respectively;
    • c) SEQ ID NOs: 868 and 903, respectively;
    • d) SEQ ID NOs: 869 and 904, respectively;
    • e) SEQ ID NOs: 873 and 908, respectively;
    • f) SEQ ID NOs: 841 and 876, respectively;
    • g) SEQ ID NOs: 846 and 881, respectively;
    • h) SEQ ID NOs: 850 and 885, respectively;
    • i) SEQ ID NOs: 851 and 886, respectively;
    • j) SEQ ID NOs: 852 and 887, respectively; and
    • k) SEQ ID NOs: 1682 and 885, respectively.


In certain aspects, the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

    • a) SEQ ID NOs: 841 and 876, respectively;
    • b) SEQ ID NOs: 850 and 885, respectively;
    • c) SEQ ID NOs: 851 and 886, respectively;
    • d) SEQ ID NOs: 868 and 903, respectively;
    • e) SEQ ID NOs: 869 and 904, respectively;
    • f) SEQ ID NOs: 873 and 908, respectively; and
    • g) SEQ ID NOs: 1682 and 885, respectively.


In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 841, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 876. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 850, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 885. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 851, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 886. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 868, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 903. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 869, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 904. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 873, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 908. In some aspects, the sense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 1682, and the antisense strand comprises the nucleotide sequence as set forth in SEQ ID NO: 885.


In some aspects, the sense strand comprises the sequence and all of the modifications of 5′-[mAs][mG][fA][mG][fJ][mG][mU][fG][mG][fA][mA][fA][fA][mA][fA][mA][fA][mA][mG][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademAGalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 841), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fCs][fU][fU][fU][mU][fU][mU][mU][fU][mU][mC][mC][fA][mC][fA][mC][mU][fC][mUs][mGs][mG]-3′ (SEQ ID NO: 876), wherein mC, mA, mG, mU=2′-OMe ribonucleosides; fA, fC, fG, fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=




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In some aspects, the sense strand comprises the sequence and all of the modifications of 5′-[mCs][mA][fG][mG][fU][mG][mG][fA][mA][fG][mU][fA][fA][mA][fA][mU][fC][mU][mG][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 850), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fCs][fA][fG][fA][mU][fU][mU][mU][fA][mC][mU][mU][fC][mC][fA][mC][mC][fU][mGs][mGs][mG]-3′ (SEQ ID NO: 885), wherein mC, mA, mG, mU=2′-OMe ribonucleosides; fA, fC, fG, fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=




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In some aspects, the sense strand comprises the sequence and all of the modifications of 5′-[mAs][mG][fG][mU][fG][mG][mA][fA][mG][fJ][mA][fA][fA][mA][fU][mC][fJ][mG][mA][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 851), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fUs][fC][fA][fG][mA][fU][mU][mU][fU][mA][mC][mU][fU][mC][fC][mA][mC][fC][m Us][mGs][mG]-3′ (SEQ ID NO: 886), wherein mC, mA, mG, mU=2′-OMe ribonucleosides; fA, fC, fG, fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=




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In some aspects, the sense strand comprises the sequence and all of the modifications of 5′-[mAs][mG][fG][mA][fA][mA][mU][fA][mA][fA][mA][fA][fG][mA][fU][mU][fG][mA][mA][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 868), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fUs][fJ][fC][fA][mA][fU][mC][mU][fU][mU][mU][mU][fA][mU][fJ][mU][mC][fC][m Us][mGs][mG]-3′ (SEQ ID NO: 903), wherein mC, mA, mG, mU=2′-OMe ribonucleosides; fA, fC, fG, fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=




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In some aspects, the sense strand comprises the sequence and all of the modifications of 5′-[mGs][mG][fA][mA][fA][mU][mA][fA][mA][fA][mA][fG][fA][mU][fU][mG][fA][mA][mA][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 869), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fUs][fU][fU][fC][mA][fA][mU][mC][fU][mU][mU][mU][fU][mA][fJ][mU][mU][fC][m Cs][mGs][mG]-3′ (SEQ ID NO: 904), wherein mC, mA, mG, mU=2′-OMe ribonucleosides; fA, fC, fG, fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=




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In some aspects, the sense strand comprises the sequence and all of the modifications of 5′-[mAs][mU][fA][mA][fA][mA][mA][fG][mA][fJ][mU][fG][fA][mA][fA][mC][fC][mC][mA][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 873), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fUs][fG][fG][fG][mU][fU][mU][mC][fA][mA][mU][mC][fU][mU][fU][mU][mU][fA][m Us][mGs][mG]-3′ (SEQ ID NO: 908), wherein mC, mA, mG, mU=2′-OMe ribonucleosides; fA, fC, fG, fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=




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In some aspects, the sense strand comprises the sequence and all of the modifications of 5′-[ademCs-C16][mA][fG][mG][fU][mG][mG][fA][mA][fG][mU][fA][fA][mA][fA][mU][fC][mUs][mGs][mA]-3′ (SEQ ID NO: 1682), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fCs][fA][fG][fA][mU][fU][mU][mU][fA][mC][mU][mU][fC][mC][fA][mC][mC][fU][mGs][mGs][mG]-3′ (SEQ ID NO: 885), wherein mC, mA, mG, mU=2′-OMe ribonucleosides; fA, fC, fG, fU=2′-F ribonucleosides; s=phosphorothioate, and [ademCs-C16]=cytosine conjugated to C16 hydrocarbon chain:




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In some aspects, the disclosure provides a pharmaceutical composition comprising a RNAi oligonucleotide described herein, and a pharmaceutically acceptable carrier, delivery agent or excipient.


In other aspects, the disclosure provides a method for treating a subject having a disease, disorder or condition associated with MAPT gene expression, the method comprising administering to the subject a therapeutically effective amount of a RNAi oligonucleotide described herein, or pharmaceutical composition thereof, thereby treating the subject.


In further aspects, the disclosure provides a method of delivering an oligonucleotide to a subject, the method comprising administering a pharmaceutical composition described herein to the subject.


In yet further aspects, the disclosure provides, a method for reducing MAPT gene expression in a cell, a population of cells or a subject, the method comprising the step of:

    • i. contacting the cell or the population of cells with a RNAi oligonucleotide or pharmaceutical composition described herein; or
    • ii. administering to the subject a RNAi oligonucleotide or pharmaceutical composition described herein.


In some aspects, reducing MAPT gene expression comprises reducing an amount or level of MAPT mRNA, an amount or level of Tau protein, or both. In some aspects, a RNAi oligonucleotide or pharmaceutical composition described herein the subject has a disease, disorder, or condition associated with MAPT gene expression. In some aspects, the disease, disorder, or condition associated with MAPT gene expression is AD, frontotemporal dementia (FTD), PSP, PD, Tau protein-associated diseases, primary age-related tauopathy, chronic traumatic encephalopathy, corticobasal degeneration, Lytico-bodig disease, ganglioglioma, meningioangiomatosis, postencephalitic parkinsonism, or subacute sclerosing panencephalitis.


In any of the foregoing or related aspects, MAPT gene expression is reduced in tissue of one or more regions of the CNS, wherein the tissue is associated with AD. In some aspects, tissue associated with AD is selected from: prefrontal cortex, motor cortex, temporal cortex, parietal cortex, and hippocampus. In some aspects, MAPT gene expression is reduced in tissue of one or more regions of the CNS, wherein the tissue is associated with PSP. In some aspects, tissue associated with PSPy is selected from: caudate nucleus, globus pallidus, thalamus, midbrain tegmentum, substantia nigra, pons, cerebellar white matter, cerebellar dentate nucleus, medulla, cervical spinal cord, thoracic spinal cord, and lumbar spinal cord. In some aspects, MAPT gene expression is reduced in one or more regions of the CNS selected from: cervical spinal cord, thoracic spinal cord, lumbar spinal cord, frontal cortex, temporal cortex, cerebellum, midbrain, occipital cortex, parietal cortex, hippocampus, caudate nucleus, thalamus, brainstem, motor cortex, globus pallidus, midbrain tegmentum, substantia nigra, pons, cerebellar white matter, and cerebellar dentate nucleus.


In any of the foregoing or related aspects, the RNAi oligonucleotide, or pharmaceutical composition is administered in combination with a second composition or therapeutic agent.


In other aspects, the disclosure provides use of a RNAi oligonucleotide or pharmaceutical composition described herein in the manufacture of a medicament for the treatment of a disease, disorder, or condition associated with MAPT gene expression.


In further aspects, the disclosure provides a RNAi oligonucleotide or pharmaceutical composition described herein for use, or adaptable for use, in the treatment of a disease, disorder, or condition associated with MAPT gene expression.


In some aspects, the disclosure provides a kit comprising the a RNAi oligonucleotide described herein, an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administration to a subject having a disease, disorder, or condition associated with MAPT gene expression.


In any of the foregoing or related aspects, the disease, disorder, or condition associated withMAPT gene expression is AD, FTD, PD, PSP, Tau protein-associated diseases, primary age-related tauopathy, chronic traumatic encephalopathy, corticobasal degeneration, Lytico-bodig disease, ganglioglioma, meningioangiomatosis, postencephalitic parkinsonism, or subacute sclerosing panencephalitis.





BRIEF DESCRIPTION OF THE FIGURES

The advantages, effects, features, and objects other than those set forth above will become more readily apparent when consideration is given to the detailed description below. Such detailed description refers to the following drawings, where:



FIGS. 1A and 1B provide graphs depicting the percent (%) of human MAPT mRNA remaining in the liver of mice exogenously expressing human MAPT (hydrodynamic injection model) after treatment with GalNAc-conjugated MAPT oligonucleotides specific for human (Hs) MAPT or human and NHP (Hs-Mf; “double-common”) MAPT. CD-1 mice were dosed subcutaneously with 3 mg/kg of the indicated GalNAc-conjugated MAPT-targeting oligonucleotide formulated in PBS. Four days post-dose, mice were hydrodynamically injected (HDI) with a DNA plasmid encoding human MAPT The level of human MAPT mRNA was determined from livers collected 18 hours later.



FIGS. 2A and 2B provide graphs depicting the dose response of GalNAc-conjugated MAPT-targeting oligonucleotides selected based on inhibitory efficacy shown in FIGS. 1A-1B in addition to GalNAc-conjugated MAPT-targeting oliognucleotides specific for human (Hs), NHP (Mf), and murine (Mm) MAPT The percent (%) of MAPT mRNA remaining in liver tissue was measured in CD-1 HDI mice as described in FIGS. 1A-1B. Following injection with 0.3 mg/kg, 1.0 mg/kg, or 3.0 mg/kg of the indicated GalNAc-conjugated MAPT-targeting oligonucleotide, percent (%) mRNA remaining was determined in two cohorts, FIG. 2A (Set I) and FIG. 2B (Set II). Hs=construct is human MAPT specific; Hs-Mf=construct is human and monkey MAPT specific.



FIGS. 3A-3M provide graphs depicting the percent (%) of human MAPT mRNA remaining in the CNS of NHP after treatment with GalNAc-conjugated MAPT-targeting oligonucleotides. NHPs were dosed by intra cisterna magna (i.c.m) injection with 50 mg of the indicated GalNAc-conjugated MAPT-targeting oligonucleotide formulated in artificial cerebrospinal fluid (aCSF) on study days 0 and 7. The level of MAPT mRNA was determined relative to the percent (%) of MAPT mRNA remaining in aCSF-treated animals. CNS tissues measured included cervical spinal cord (FIG. 3A), thoracic spinal cord (FIG. 3B), lumbar spinal cord (FIG. 3C), frontal cortex (FIG. 3D), temporal cortex (FIG. 3E), cerebellum (FIG. 3F), midbrain (FIG. 3G), occipital cortex (FIG. 3H), parietal cortex (FIG. 3I), hippocampus (FIG. 3J), caudate nucleus (FIG. 3K), thalamus (FIG. 3L), and brainstem (FIG. 3M).



FIGS. 4A-4B provide schematics of a lipid-conjugated RNAi oligonucleotide (FIG. 4A) and a GalNAc-conjugated RNAi oligonucleotide (FIG. 4B).



FIGS. 5A-5B provide graphs depicting the percent (%) of NHP (Mf) MAPT mRNA remaining (FIG. 5A) and concentration of oligonucleotide (FIG. 5B) in CNS tissue associated with AD. NHPs were intrathecally administered MAPT-2357 conjugated to a C16 lipid or GalNAc, as shown in the modification patterns of FIGS. 4A-4B. Tissue was collected and analyzed 28 days after administration of the indicated oligonucleotide.



FIGS. 6A-6B provide graphs depicting the percent (%) of NHP (Mf) MAPT mRNA remaining (FIG. 6A) and concentration of oligonucleotide (FIG. 6B) in CNS tissue associated with PSP. NHPs were intrathecally administered MAPT-2357 conjugated to a C16 lipid or GalNAc, as shown in the modification patterns of FIGS. 4A-4B. Tissue was collected and analyzed 28 days after administration of the indicated oligonucleotide.





DETAILED DESCRIPTION

According to some aspects, the disclosure provides oligonucleotides such as RNAi oligonucleotides that reduce MAPT gene expression in the CNS. In some embodiments, the oligonucleotides provided herein are designed to treat diseases associated with MAPT gene expression in the CNS. In some respects, the disclosure provides methods of treating a disease associated with MAPT by reducing MAPT gene expression in cells (e.g., cells of the CNS).


Oligonucleotide Inhibitors of MAPT Gene Expression


The disclosure provides, inter alia, oligonucleotides that inhibit MAPT gene expression (e.g., RNAi oligonucleotides). In some embodiments, the oligonucleotide that inhibits MAPT gene expression is targeted to a MAPT mRNA.


MAPT Target Sequences


In some embodiments, an oligonucleotide herein (e.g., a RNAi oligonucleotide) is targeted to a target sequence comprising a MAPT mRNA. In some embodiments, the oligonucleotide is targeted to a target sequence within a MAPT mRNA sequence.


In some embodiments, the oligonucleotide corresponds to a target sequence within a MAPT mRNA sequence. In some embodiments, the oligonucleotide, or a portion, fragment, or strand thereof (e.g., an antisense strand or a guide strand of a RNAi oligonucleotide) binds or anneals to a target sequence comprising MAPT mRNA, thereby inhibiting MAPT gene expression.


In some embodiments, the oligonucleotide is targeted to a MAPT target sequence for the purpose of inhibiting MAPT gene expression in vivo. In some embodiments, the amount or extent of inhibition of MAPT gene expression by the oligonucleotide targeted to a MAPT target sequence correlates with the potency of the oligonucleotide. In some embodiments, the amount or extent of MAPT gene expression inhibition by the oligonucleotide targeted to a MAPT target sequence correlates with the amount or extent of therapeutic benefit in a subject or patient having a disease, disorder, or condition associated with MAPT gene expression treated with the oligonucleotide.


In some embodiments, a sense strand of the oligonucleotide comprises a MAPT target sequence. In some embodiments, a portion or region of the sense strand of the oligonucleotide (e.g., a RNAi oligonucleotide) comprises a MAPT target sequence. In some embodiments, the MAPT target sequence comprises, or consists of, a nucleotide sequence of any one of SEQ ID NOs: 912-1295. In some embodiments, the MAPT target sequence comprises, or consists of, a nucleotide sequence of any one of SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, 1124, and 924. In some embodiments, the MAPT target sequence comprises, or consists of, a nucleotide sequence of any one of SEQ ID NOs: 1061, 1108, 1119, 1120, 1124, 1130, 1065, 1095, 1096, and 1102. In some embodiments, the MAPT target sequence comprises, or consists of, a nucleotide sequence of any one of SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124. In some embodiments, the MAPT target sequence comprises the nucleotide sequence set forth in SEQ ID NO: 1130. In some embodiments, the MAPT target sequence comprises the nucleotide sequence set forth in SEQ ID NO: 1095. In some embodiments, the MAPT target sequence comprises the nucleotide sequence set forth in SEQ ID NO: 1096. In some embodiments, the MAPT target sequence comprises the nucleotide sequence set forth in SEQ ID NO: 1119. In some embodiments, the MAPT target sequence comprises the nucleotide sequence set forth in SEQ ID NO: 1120. In some embodiments, the MAPT target sequence comprises the nucleotide sequence set forth in SEQ ID NO: 1124.


MAPT mRNA Targeting Sequences


In some embodiments, an oligonucleotide herein (e.g., a RNAi oligonucleotide) has a region of complementarity to MAPT mRNA (e.g., within a target sequence of MAPT mRNA) for purposes of targeting the mRNA in cells and inhibiting its expression. In some embodiments, the oligonucleotide comprises a MAPT mRNA target sequence (e.g., an antisense strand or a guide strand of a ds oligonucleotide such as a RNAi oligonucleotide) having a region of complementarity that binds or anneals to a MAPT target sequence by complementary (Watson-Crick) base pairing. The targeting sequence or region of complementarity is generally of suitable length and base content to enable binding or annealing of the oligonucleotide (or a strand thereof) to a MAPT mRNA for purposes of inhibiting its expression. In some embodiments, the targeting sequence or region of complementarity is at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29 or at least about 30 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 nucleotides. In some embodiments, the targeting sequence or region of complementarity is about 12 to about 30 (e.g., 12 to 30, 12 to 22, 15 to 25, 17 to 21, 18 to 27, 19 to 27, or 15 to 30) nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 18 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 19 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 20 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 21 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 22 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 23 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 24 nucleotides in length. In some embodiments, the oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 912-1295, and the targeting sequence or region of complementarity is 18 nucleotides in length. In some embodiments, the oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 912-1295, and the targeting sequence or region of complementarity is 19 nucleotides in length. In some embodiments, the oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1-384, and the targeting sequence or region of complementarity is 20 nucleotides in length. In some embodiments, the oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1-384, and the targeting sequence or region of complementarity is 21 nucleotides in length. In some embodiments, the oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1-384, and the targeting sequence or region of complementarity is 22 nucleotides in length. In some embodiments, the oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1-384, and the targeting sequence or region of complementarity is 23 nucleotides in length. In some embodiments, the oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1-384, and the targeting sequence or region of complementarity is 24 nucleotides in length.


In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementarity (e.g., an antisense strand or a guide strand of a ds oligonucleotide) that is fully complementary to a MAPT mRNA target sequence. In some embodiments, the targeting sequence or region of complementarity is partially complementary to a MAPT mRNA target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to a sequence of any one of SEQ ID NOs: 912-1295. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a sequence of any one of SEQ ID NOs: 912-1295. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to a sequence of any one of SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, 1124, or 924. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a sequence of any one of SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, 1124, or 924. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to a sequence of any one of SEQ ID NOs: 1061, 1108, 1119, 1120, 1124, 1130, 1065, 1095, 1096, or 1102. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a sequence of any one of SEQ ID NOs: 1061, 1108, 1119, 1120, 1124, 1130, 1065, 1095, 1096, or 1102. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to a sequence of any one of SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a sequence of any one of SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to the sequence set forth in SEQ ID NO: 1130. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to the sequence set forth in SEQ ID NO: 1095. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to the sequence set forth in SEQ ID NO: 1096. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to the sequence set forth in SEQ ID NO: 1119. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to the sequence set forth in SEQ ID NO: 1120. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to the sequence set forth in SEQ ID NO: 1124. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a sequence of any one of SEQ ID NOs: 1130. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to the sequence of SEQ ID NO: 1095. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to the sequence of SEQ ID NO: 1096. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to the sequence of SEQ ID NO: 1119. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to the sequence of SEQ ID NO: 1120. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to the sequence of SEQ ID NO: 1124.


In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a MAPT mRNA, wherein the contiguous sequence of nucleotides is about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 20, 12 to 18, 12 to 16, 14 to 22, 16 to 20, 18 to 20, or 18 to 19 nucleotides in length). In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a MAPT mRNA, wherein the contiguous sequence of nucleotides is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a MAPT mRNA, wherein the contiguous sequence of nucleotides is 19 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a MAPT mRNA, wherein the contiguous sequence of nucleotides is 20 nucleotides in length.


In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementarity that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 912-1295, optionally where the contiguous sequence of nucleotides is 19 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementarity that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, 1124, and 924, optionally wherein the contiguous sequence of nucleotides is 19 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementarity that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1061, 1108, 1119, 1120, 1124, 1130, 1065, 1095, 1096, and 1102, optionally where the contiguous sequence of nucleotides is 19 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementarity that is complementary to a contiguous sequence of nucleotides of SEQ ID NO: 1130, 1095, 1096, 1119, 1120, and 1124, optionally where the contiguous sequence of nucleotides is 19 nucleotides in length.


In some embodiments, the targeting sequence or region of complementarity of the oligonucleotide is complementary to contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 912-1295 and spans the entire length of the antisense strand. In some embodiments, the targeting sequence or region of complementarity of the oligonucleotide is complementary to contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 912-1295 and spans a portion of the entire length of an antisense strand. In some embodiments, the oligonucleotide comprises a region of complementarity (e.g., on an antisense strand of a ds oligonucleotide) that is at least partially (e.g., fully) complementary to a contiguous stretch of nucleotides spanning nucleotides 1-20 of a sequence as set forth in any one of SEQ ID NOs: 912-1295. In some embodiments, the targeting sequence or region of complementarity of the oligonucleotide is complementary to contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 1-384 and spans the entire length of an antisense strand. In some embodiments, the region of complementarity of the oligonucleotide is complementary to contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 1-384 and spans a portion of the entire length of an antisense strand. In some embodiments, the oligonucleotide comprises the region of complementarity (e.g., on an antisense strand of a ds oligonucleotide) that is at least partially (e.g., fully) complementary to a contiguous stretch of nucleotides spanning nucleotides 1-19 of a sequence as set forth in any one of SEQ ID NOs: 1-384.


In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having one or more base pair (bp) mismatches with the corresponding MAPT mRNA target sequence. In some embodiments, the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding MAPT mRNA target sequence provided that the ability of the targeting sequence or region of complementarity to bind or anneal to MAPT mRNA under appropriate hybridization conditions and/or the ability of the oligonucleotide to inhibit MAPT gene expression is maintained. Alternatively, in some embodiments, the targeting sequence or region of complementarity comprises no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding MAPT mRNA target sequence provided that the ability of the targeting sequence or region of complementarity to bind or anneal to MAPT mRNA under appropriate hybridization conditions and/or the ability of the oligonucleotide to inhibit MAPT gene expression is maintained. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 1 mismatch with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 2 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 3 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 4 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 5 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity more than one mismatch (e.g., 2, 3, 4, 5, or more mismatches) with the corresponding target sequence, wherein at least 2 (e.g., all) of the mismatches are positioned consecutively (e.g., 2, 3, 4, 5, or more mismatches in a row), or wherein the mismatches are interspersed in any position throughout the targeting sequence or region of complementarity. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity more than one mismatch (e.g., 2, 3, 4, 5, or more mismatches) with the corresponding target sequence, wherein at least 2 (e.g., all) of the mismatches are positioned consecutively (e.g., 2, 3, 4, 5, or more mismatches in a row), or wherein at least one or more non-mismatched base pair is located between the mismatches, or a combination thereof.


In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 912-1295, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding MAPT mRNA target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 912-1295, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding MAPT mRNA target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, 1124, and 924, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding MAPT mRNA target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, 1124, and 924, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding MAPT mRNA target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1061, 1108, 1119, 1120, 1124, 1130, 1065, 1095, 1096, and 1102, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding MAPT mRNA target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1061, 1108, 1119, 1120, 1124, 1130, 1065, 1095, 1096, and 1102, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding MAPT mRNA target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding MAPT mRNA target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding MAPT mRNA target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of SEQ ID NO: 1095, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding MAPT mRNA target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of SEQ ID NO: 1095, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding MAPT mRNA target sequence.


Types of Oligonucleotides


A variety of oligonucleotide types and/or structures are useful for targeting MAPT mRNA in the methods herein including, but not limited to, RNAi oligonucleotides. Any of the oligonucleotide types described herein or elsewhere are contemplated for use as a framework to incorporate a MAPT mRNA targeting sequence herein for the purposes of inhibiting MAPT gene expression.


In some embodiments, the oligonucleotides herein inhibit MAPT gene expression by engaging with RNA interference (RNAi) pathways upstream or downstream of Dicer involvement (e.g., a RNAi oligonucleotide). For example, RNAi oligonucleotides have been developed with each strand having sizes of about 19-25 nucleotides with at least one 3′ overhang of about 1 to about 5 nucleotides (see, e.g., U.S. Pat. No. 8,372,968). Longer oligonucleotides also have been developed that are processed by Dicer to generate active RNAi products (see, e.g., U.S. Pat. No. 8,883,996). Further work produced extended ds oligonucleotides where at least one end of at least one strand is extended beyond a duplex targeting region, including structures where one of the strands includes a thermodynamically-stabilizing tetraL structure (see, e.g., U.S. Pat. Nos. 8,513,207 and 8,927,705, as well as Intl. Patent Application Publication No. WO 2010/033225). Such structures may include single-stranded (ss) extensions (on one or both sides of the molecule) as well as ds extensions.


In some embodiments, the oligonucleotide engages with the RNAi pathway downstream of the involvement of Dicer (e.g., Dicer cleavage). In some embodiments, the oligonucleotide has an overhang (e.g., of 1, 2, or 3 nucleotides in length) in the 3′ end of the sense strand. In some embodiments, the oligonucleotide comprises a 21-nucleotide antisense strand that is antisense to a target mRNA (e.g., MAPT mRNA) and a complementary sense strand, in which both strands anneal to form a 19-bp duplex and 2 nucleotide overhangs at either or both 3′ ends. Longer oligonucleotide designs also are contemplated including oligonucleotides having an antisense strand of 23 nucleotides and a sense strand of 21 nucleotides, where there is a blunt end on the right side of the oligonucleotide (3′ end of sense strand/5′ end of antisense strand) and a two nucleotide 3′ guide strand overhang on the left side of the oligonucleotide (5′ end of the sense strand/3′ end of the antisense strand). In such molecules, there is a 21 bp duplex region. See, e.g., U.S. Pat. Nos. 9,012,138; 9,012,621; and 9,193,753.


In some embodiments, the oligonucleotide comprises sense and antisense strands that are both in the range of about 17 to about 36 (e.g., 17 to 26, 20 to 25, or 21-23) nucleotides in length. In some embodiments, the oligonucleotide comprises an antisense strand of 19-30 nucleotides in length and a sense strand of 19-50 nucleotides in length, where the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand. In some embodiments, the oligonucleotide comprises sense and antisense strands that are both in the range of about 19-22 nucleotides in length. In some embodiments, the sense and antisense strands are of equal length. In some embodiments, the oligonucleotide comprises sense and antisense strands, such that there is a 3′ overhang on either the sense strand or the antisense strand, or both the sense and antisense strand. In some embodiments, for oligonucleotides that have sense and antisense strands that are both in the range of about 21-23 nucleotides in length, a 3′ overhang on the sense, antisense, or both is/are 1 or 2 nucleotides in length. In some embodiments, the oligonucleotide has a guide strand of 22 nucleotides and a passenger strand of 20 nucleotides, where there is a blunt end on the right side of the molecule (3′ end of passenger strand/5′ end of guide strand) and a 2 nucleotide 3′ guide strand overhang on the left side of the molecule (5′ end of the passenger strand/3′ end of the guide strand). In such molecules, there is a 20 bp duplex region.


Other oligonucleotide designs for use with the compositions and methods herein include: 16-mer siRNAs (see, e.g., NUCLEIC ACIDS IN CHEMISTRY AND BIOLOGY, Blackburn (ed.), Royal Society of Chemistry, 2006), shRNAs (e.g., having 19 bp or shorter stems; see, e.g., Moore et al. (2010) METHODS MOL. BIOL. 629:141-58), blunt siRNAs (e.g., of 19 bps in length; see, e.g., Kraynack & Baker (2006) RNA 12:163-76), asymmetrical siRNAs (aiRNA; see, e.g., Sun et al. (2008) NAT. BIOTECHNOL. 26:1379-82), asymmetric shorter-duplex siRNA (see, e.g., Chang et al. (2009) MOL. THER. 17:725-732), fork siRNAs (see, e.g., Hohjoh (2004) FEBS LETT. 557:193-98), single-stranded siRNAs (Elsner (2012) NAT. BIOTECHNOL. 30:1063), dumbbell-shaped circular siRNAs (see, e.g., Abe et al. (2007) J. AM. CHEM. SOC. 129:15108-09), and small internally segmented interfering RNA (siRNA; see, e.g., Bramsen et al. (2007) NUCLEIC ACIDS RES. 35:5886-97). Further non-limiting examples of an oligonucleotide structure that may be used in some embodiments to reduce or inhibit the expression of MAPT are microRNA (miRNA), short hairpin RNA (shRNA), and short siRNA (see, e.g., Hamilton et al. (2002) EMBO J. 21:4671-79; see also, US Patent Application Publication No. 2009/0099115).


Still, in some embodiments, the oligonucleotide for reducing or inhibiting MAPT gene expression herein is ss. Such structures may include, but are not limited to, ss RNAi molecules. Recent efforts have demonstrated the activity of ss RNAi molecules (see, e.g., Matsui et al. (2016) Mol. Ther. 24:946-955). However, in some embodiments, the oligonucleotide is an antisense oligonucleotide (ASO). An ASO is a ss oligonucleotide that has a nucleobase sequence which, when written or depicted in the 5′ to 3′ direction, comprises the reverse complement of a targeted segment of a particular nucleic acid and is suitably modified (e.g., as a gapmer) so as to induce RNaseH-mediated cleavage of its target RNA in cells or (e.g., as a mixmer) so as to inhibit translation of the target mRNA in cells. ASOs for use herein may be modified in any suitable manner known in the art including, for example, as shown in U.S. Pat. No. 9,567,587 (including, e.g., length, sugar moieties of the nucleobase (pyrimidine, purine), and alterations of the heterocyclic portion of the nucleobase). Further, ASOs have been used for decades to reduce expression of specific target genes (see, e.g., Bennett et al. (2017) Annu. Rev. Pharmacol. 57:81-105).


In some embodiments, the ASO shares a region of complementarity with MAPT mRNA. In some embodiments, the ASO targets various areas of the human MAPT identified as NM_001123066.3. In some embodiments, the ASO is about 15-50 nucleotides in length. In some embodiments, the ASO is about 15-25 nucleotides in length. In some embodiments, the ASO is 22 nucleotides in length. In some embodiments, the ASO is complementary to any one of SEQ ID NOs: 912-1295. In some embodiments, the ASO is at least 15 contiguous nucleotides in length. In some embodiments, the ASO is at least 19 contiguous nucleotides in length. In some embodiments, the ASO is at least 20 contiguous nucleotides in length. In some embodiments, the ASO differs by 1, 2, or 3 nucleotides from the target sequence.


Double-Stranded RNAi Oligonucleotides


In some aspects, the disclosure provides ds RNAi oligonucleotides for targeting MAPT mRNA and inhibiting MAPT gene expression (e.g., via the RNAi pathway) comprising a sense strand (also referred to herein as a passenger strand) and an antisense strand (also referred to herein as a guide strand). In some embodiments, the sense strand and antisense strand are separate strands and are not covalently linked. In some embodiments, the sense strand and the antisense strand are covalently linked. In some embodiments, the sense strand and the antisense strand form a duplex region, wherein the sense strand and the antisense strand, or a portion thereof, binds with one another in a complementary fashion (e.g., by Watson-Crick base pairing).


In some embodiments, the sense strand has a first region (R1) and a second region (R2), wherein R2 comprises a first subregion (S1), a L (e.g., tetraL or triL), and a second subregion (S2), wherein L is located between S1 and S2, and wherein S1 and S2 form a second duplex (D2). D2 may have various lengths. In some embodiments, D2 is about 1 to about 6 bp in length. In some embodiments, D2 is 2-6, 3-6, 4-6, 5-6, 1-5, 2-5, 3-5, or 4-5 bp in length. In some embodiments, D2 is 1, 2, 3, 4, 5, or 6 bp in length. In some embodiments, D2 is 6 bp in length.


In some embodiments, R1 of the sense strand and the antisense strand form a first duplex (D1). In some embodiments, D1 is at least about 15 (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21) nucleotides in length. In some embodiments, D1 is in the range of about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 27, 15 to 22, 18 to 22, 18 to 25, 18 to 27, 18 to 30, or 21 to 30 nucleotides in length). In some embodiments, D1 is at least 12 nucleotides in length (e.g., at least 12, at least 15, at least 20, at least 25, or at least 30 nucleotides in length). In some embodiments, D1 is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, D1 is 19 nucleotides in length. In some embodiments, D1 is 20 nucleotides in length. In some embodiments, D1 comprising the sense strand and the antisense strand does not span the entire length of the sense strand and/or the antisense strand. In some embodiments, D1 comprising the sense strand and the antisense strand spans the entire length of either the sense strand or the antisense strand or both. In certain embodiments, D1 comprising the sense strand and the antisense strand spans the entire length of both the sense strand and the antisense strand.


In some embodiments, a sense strand described here is 36 nucleotides in length and positions are numbered 1-36 from 5′ to 3′. In some embodiments, an antisense strand described herein is 22 nucleotides in length and positions are numbered 1-22 from 5′ to 3′. In some embodiments, position numbers described herein adhere to this numbering format.


In some embodiments, the RNAi oligonucleotide comprises a sense strand having a sequence of any one of SEQ ID NOs: 1-384 and an antisense strand comprising a complementary sequence of any one of SEQ ID NOs: 385-768. In some embodiments, the RNAi oligonucleotide comprises a sense strand having a sequence of SEQ ID NOs: 912-1295 and an antisense strand comprising a complementary sequence of any one of SEQ ID NOs: 1296-1679.


In some embodiments, the RNAi oligonucleotide comprises a sense strand having a sequence of any one of SEQ ID NOs: 769-803 and an antisense strand comprising a complementary sequence of any one of SEQ ID NOs: 804-838. In some embodiments, the RNAi oligonucleotide comprises a sense strand having a sequence of any one of SEQ ID NOs: 769-803 and 1681 and an antisense strand comprising a complementary sequence of any one of SEQ ID NOs: 804-838.


In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

    • a) SEQ ID NOs: 769 and 804, respectively;
    • b) SEQ ID NOs: 770 and 805, respectively;
    • c) SEQ ID NOs: 771 and 806, respectively;
    • d) SEQ ID NOs: 772 and 807, respectively;
    • e) SEQ ID NOs: 773 and 808, respectively;
    • f) SEQ ID NOs: 774 and 809, respectively;
    • g) SEQ ID NOs: 775 and 810, respectively;
    • h) SEQ ID NOs: 776 and 811, respectively;
    • i) SEQ ID NOs: 777 and 812, respectively;
    • j) SEQ ID NOs: 778 and 813, respectively;
    • k) SEQ ID NOs: 779 and 814, respectively;
    • l) SEQ ID NOs: 780 and 815, respectively;
    • m) SEQ ID NOs: 781 and 816, respectively;
    • n) SEQ ID NOs: 782 and 817, respectively;
    • o) SEQ ID NOs: 783 and 818, respectively;
    • p) SEQ ID NOs: 784 and 819, respectively;
    • q) SEQ ID NOs: 785 and 820, respectively;
    • r) SEQ ID NOs: 786 and 821, respectively;
    • s) SEQ ID NOs: 787 and 822, respectively;
    • t) SEQ ID NOs: 788 and 823, respectively;
    • u) SEQ ID NOs: 789 and 824, respectively;
    • v) SEQ ID NOs: 790 and 825, respectively;
    • w) SEQ ID NOs: 791 and 826, respectively;
    • x) SEQ ID NOs: 792 and 827, respectively;
    • y) SEQ ID NOs: 793 and 828, respectively;
    • z) SEQ ID NOs: 794 and 829, respectively;
    • aa) SEQ ID NOs: 795 and 830, respectively;
    • bb) SEQ ID NOs: 796 and 831, respectively;
    • cc) SEQ ID NOs: 797 and 832, respectively;
    • dd) SEQ ID NOs: 798 and 833, respectively;
    • ee) SEQ ID NOs: 799 and 834, respectively;
    • ff) SEQ ID NOs: 800 and 835, respectively;
    • gg) SEQ ID NOs: 801 and 836, respectively;
    • hh) SEQ ID NOs: 802 and 837, respectively;
    • ii) SEQ ID NOs: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively.


In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively;
    • j) SEQ ID NOs: 803 and 838, respectively; and
    • k) SEQ ID NOs: 1681 and 815, respectively.


In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 780 and 815, respectively;
    • c) SEQ ID NOs: 781 and 816, respectively;
    • d) SEQ ID NOs: 798 and 833, respectively;
    • e) SEQ ID NOs: 799 and 834, respectively;
    • f) SEQ ID NOs: 803 and 838, respectively; and
    • g) SEQ ID NOs: 1681 and 815, respectively.


In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 771, and the antisense strand comprises the sequence of SEQ ID NO: 806. In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 780, and the antisense strand comprises the sequence of SEQ ID NO: 815. In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 781, and the antisense strand comprises the sequence of SEQ ID NO: 816. In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 798, and the antisense strand comprises the sequence of SEQ ID NO: 833. In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 799, and the antisense strand comprises the sequence of SEQ ID NO: 834. In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 803, and the antisense strand comprises the sequence of SEQ ID NO: 838. In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 1681, and the antisense strand comprises the sequence of SEQ ID NO: 815.


It should be appreciated that, in some embodiments, sequences presented in the Sequence Listing may be referred to in describing the structure of the oligonucleotide (e.g., a RNAi oligonucleotide) or other nucleic acid. In such embodiments, the actual oligonucleotide or other nucleic acid may have one or more alternative nucleotides (e.g., a RNA counterpart of a DNA nucleotide or a DNA counterpart of an RNA nucleotide) and/or one or more modified nucleotides and/or one or more modified internucleotide linkages and/or one or more other modification when compared with the specified sequence while retaining essentially same or similar complementary properties as the specified sequence.


In some embodiments, a RNAi oligonucleotide herein comprises a 25-nucleotide sense strand and a 27-nucleotide antisense strand that when acted upon by a Dicer enzyme results in an antisense strand that is incorporated into the mature RNA-induced silencing complex (RISC). In some embodiments, the 25-nucleotide sense strand comprises a sequence selected from SEQ ID NOs: 1-384. In some embodiments, the 27-nucleotide antisense strand comprises a sequence selected from SEQ ID NOs: 385-768. In some embodiments, the sense strand of the RNAi oligonucleotide is longer than 27 nucleotides (e.g., 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides). In some embodiments, the sense strand of the RNAi oligonucleotide is longer than 25 nucleotides (e.g., 26, 27, 28, 29 or 30 nucleotides). In some embodiments, the sense strand of the RNAi oligonucleotide comprises a nucleotide sequence selected from SEQ ID NOs: 912-1295, wherein the nucleotide sequence is longer than 27 nucleotides (e.g., 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides). In some embodiments, the sense strand of the RNAi oligonucleotide comprises a nucleotide sequence selected from SEQ ID NOs: 912-1295, wherein the nucleotide sequence is longer than 25 nucleotides (e.g., 26, 27, 28, 29, or 30 nucleotides).


In some embodiments, the RNAi oligonucleotide has one 5′ end that is thermodynamically less stable when compared to the other 5′ end. In some embodiments, an asymmetric RNAi oligonucleotide is provided that comprises a blunt end at the 3′ end of a sense strand and a 3′ overhang at the 3′ end of an antisense strand. In some embodiments, the 3′ overhang on the antisense strand is about 1-8 nucleotides in length (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 nucleotides in length). Typically, the RNAi oligonucleotide has a two-nucleotide overhang on the 3′ end of the antisense (guide) strand; however, other overhangs are possible. In some embodiments, the overhang is a 3′ overhang comprising a length of between about 1 to about 6 nucleotides, optionally 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, 5 to 6 nucleotides, or 1, 2, 3, 4, 5 or 6 nucleotides. However, in some embodiments, the overhang is a 5′ overhang comprising a length of between about 1 to about 6 nucleotides, optionally 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, 5 to 6 nucleotides, or 1, 2, 3, 4, 5, or 6 nucleotides. In some embodiments, the RNAi oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 912-1295, and a 5′ overhang comprising a length of between about 1 and about 6 nucleotides. In some embodiments, the RNAi oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 912-1295, wherein the RNAi oligonucleotide comprises a 5′ overhang comprising a length of between about 1 and about 6 nucleotides. In some embodiments, the RNAi oligonucleotide comprises an antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1296-1679, wherein the RNAi oligonucleotide comprises a 5′ overhang comprising a length of between about 1 and about 6 nucleotides. In some embodiments, the RNAi oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 912-1295 and antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1296-1679, wherein the RNAi oligonucleotide comprises a 5′ overhang comprising a length of between about 1 and about 6 nucleotides.


In some embodiments, two terminal nucleotides on the 3′ end of an antisense strand are modified. In some embodiments, the two terminal nucleotides on the 3′ end of the antisense strand are complementary with the target mRNA (e.g., MAPT mRNA). In some embodiments, the two terminal nucleotides on the 3′ end of the antisense strand are not complementary with the target mRNA. In some embodiments, the two terminal nucleotides on the 3′ end of the antisense strand of a RNAi oligonucleotide herein are unpaired. In some embodiments, the two terminal nucleotides on the 3′ end of the antisense strand of the RNAi oligonucleotide herein comprise an unpaired GG. In some embodiments, the two terminal nucleotides on the 3′ end of the antisense strand of the RNAi oligonucleotide herein are not complementary to the target mRNA. In some embodiments, two terminal nucleotides on each 3′ end of the RNAi oligonucleotide are GG. Typically, one or both of the two terminal GG nucleotides on each 3′ end of the RNAi oligonucleotide is not complementary with the target mRNA. In some embodiments, two terminal nucleotides on each 3′ end of the oligonucleotide are GG. In some embodiments, one or both of the two terminal GG nucleotides on each 3′ end of the RNAi oligonucleotide is not complementary with the target mRNA. In some embodiments, the RNAi oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 912-1295, wherein the two terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide herein comprises an unpaired GG. In some embodiments, the RNAi oligonucleotide comprises an antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1296-1679, wherein the two terminal nucleotides on the 3′ end of the antisense strand of the RNAi oligonucleotide comprises an unpaired GG. In some embodiments, the RNAi oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 912-1295 and antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1296-1679, wherein the two terminal nucleotides on the 3′ end of the antisense strand of the RNAi oligonucleotide comprises an unpaired GG.


In some embodiments, there is one or more (e.g., 1, 2, 3, 4, or 5) mismatch(s) between a sense strand and an antisense strand comprising the RNAi oligonucleotide. If there is more than one mismatch between the sense and antisense strands, they may be positioned consecutively (e.g., 2, 3, or more in a row), or interspersed throughout the region of complementarity. In some embodiments, the 3′ end of the sense strand contains one or more mismatches. In one embodiment, two mismatches are incorporated at the 3′ end of the sense strand. In some embodiments, base mismatches, or destabilization of segments at the 3′ end of the sense strand of the RNAi oligonucleotide improves or increases the potency of the oligonucleotide.


In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

    • a) SEQ ID NOs: 769 and 804, respectively;
    • b) SEQ ID NOs: 770 and 805, respectively;
    • c) SEQ ID NOs: 771 and 806, respectively;
    • d) SEQ ID NOs: 772 and 807, respectively;
    • e) SEQ ID NOs: 773 and 808, respectively;
    • f) SEQ ID NOs: 774 and 809, respectively;
    • g) SEQ ID NOs: 775 and 810, respectively;
    • h) SEQ ID NOs: 776 and 811, respectively;
    • i) SEQ ID NOs: 777 and 812, respectively;
    • j) SEQ ID NOs: 778 and 813, respectively;
    • k) SEQ ID NOs: 779 and 814, respectively;
    • l) SEQ ID NOs: 780 and 815, respectively;
    • m) SEQ ID NOs: 781 and 816, respectively;
    • n) SEQ ID NOs: 782 and 817, respectively;
    • o) SEQ ID NOs: 783 and 818, respectively;
    • p) SEQ ID NOs: 784 and 819, respectively;
    • q) SEQ ID NOs: 785 and 820, respectively;
    • r) SEQ ID NOs: 786 and 821, respectively;
    • s) SEQ ID NOs: 787 and 822, respectively;
    • t) SEQ ID NOs: 788 and 823, respectively;
    • u) SEQ ID NOs: 789 and 824, respectively;
    • v) SEQ ID NOs: 790 and 825, respectively;
    • w) SEQ ID NOs: 791 and 826, respectively;
    • x) SEQ ID NOs: 792 and 827, respectively;
    • y) SEQ ID NOs: 793 and 828, respectively;
    • z) SEQ ID NOs: 794 and 829, respectively;
    • aa) SEQ ID NOs: 795 and 830, respectively;
    • bb) SEQ ID NOs: 796 and 831, respectively;
    • cc) SEQ ID NOs: 797 and 832, respectively;
    • dd) SEQ ID NOs: 798 and 833, respectively;
    • ee) SEQ ID NOs: 799 and 834, respectively;
    • ff) SEQ ID NOs: 800 and 835, respectively;
    • gg) SEQ ID NOs: 801 and 836, respectively;
    • hh) SEQ ID NOs: 802 and 837, respectively;
    • ii) SEQ ID NOs: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively, wherein there is one or more (e.g., 1, 2, 3, 4, or 5) mismatch(s) between the sense and antisense strands.


In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively;
    • j) SEQ ID NOs: 803 and 838, respectively; and
    • k) SEQ ID NOs: 1681 and 815, respectively, wherein there is one or more (e.g., 1, 2, 3, 4, or 5) mismatch(s) between the sense and antisense strands.


In some embodiments, the RNAi oligonucleotide comprises a sense strand and an antisense strand comprising sequence selected from:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 780 and 815, respectively;
    • c) SEQ ID NOs: 781 and 816, respectively;
    • d) SEQ ID NOs: 798 and 833, respectively;
    • e) SEQ ID NOs: 799 and 834, respectively;
    • f) SEQ ID NOs: 803 and 838, respectively; and
    • g) SEQ ID NOs: 1681 and 815, respectively, wherein there is one or more (e.g., 1, 2, 3, 4, or 5) mismatch(s) between the sense and antisense strands.


Antisense Strands


In some embodiments, an antisense strand of an oligonucleotide herein (e.g., a RNAi oligonucleotide) is referred to as a “guide strand.” The antisense strand engages with RISC and binds to an Argonaute protein such as Ago2, or engages with or binds to one or more similar factors, and directs silencing of a target gene. In some embodiments, a sense strand complementary to a guide strand is referred to as a “passenger strand.”


In some embodiments, an oligonucleotide comprises an antisense strand of up to about 50 nucleotides in length (e.g., up to 50, up to 40, up to 35, up to 30, up to 27, up to 25, up to 21, up to 19, up to 17, up to 15, or up to 12 nucleotides in length). In some embodiments, the oligonucleotide comprises an antisense strand of at least about 12 nucleotides in length (e.g., at least 12, at least 15, at least 19, at least 21, at least 22, at least 25, at least 27, at least 30, at least 35, or at least 38 nucleotides in length). In some embodiments, the oligonucleotide comprises an antisense strand in a range of about 12 to about 40 (e.g., 12 to 40, 12 to 36, 12 to 32, 12 to 28, 15 to 40, 15 to 36, 15 to 32, 15 to 30, 15 to 28, 17 to 22, 17 to 25, 19 to 27, 19 to 30, 20 to 40, 22 to 40, 25 to 40, or 32 to 40) nucleotides in length. In some embodiments, the oligonucleotide comprises an antisense of about 15 to about 30 nucleotides in length. In some embodiments, an antisense strand of any one of the oligonucleotides disclosed herein is 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, or 40 nucleotides in length. In some embodiments, the oligonucleotide comprises an antisense strand of 22 nucleotides in length.


In some embodiments, an oligonucleotide for targeting MAPT comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 1296-1679. In some embodiments, the oligonucleotide comprises an antisense strand comprising at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 1296-1679. In some embodiments, the oligonucleotide for targeting MAPT comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 385-768. In some embodiments, the oligonucleotide comprises an antisense strand comprising at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 385-768. In some embodiments, the oligonucleotide for targeting MAPT comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 804-838. In some embodiments, the oligonucleotide comprises an antisense strand comprising at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 804-838. In some embodiments, the oligonucleotide for targeting MAPT comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 1509, 1511, 1514, 1403, 1415, 1428, 1448, 1449, 1451, 1467, 1299, 1479, 1480, 1486, 1494, 1307, 1309, 1409, 1423, 1433, 1445, 1454, 1456, 1459, 1465, 1492, 1495, 1498, 1503, 1504, 1505, 1506, 1507, 1508, and 1308. In some embodiments, the oligonucleotide comprises an antisense strand comprising at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 1509, 1511, 1514, 1403, 1415, 1428, 1448, 1449, 1451, 1467, 1299, 1479, 1480, 1486, 1494, 1307, 1309, 1409, 1423, 1433, 1445, 1454, 1456, 1459, 1465, 1492, 1495, 1498, 1503, 1504, 1505, 1506, 1507, 1508, and 1308. In some embodiments, the oligonucleotide for targeting MAPT comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 806, 811, 815, 816, 817, 825, 830, 833, 834, and 838. In some embodiments, the oligonucleotide comprises an antisense strand comprising at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 806, 811, 815, 816, 817, 825, 830, 833, 834, and 838. In some embodiments, the oligonucleotide for targeting MAPT comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 806, 815, 816, 833, 834, and 838. In some embodiments, the oligonucleotide comprises an antisense strand comprising at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 806, 815, 816, 833, 834, and 838.


Sense Strands

In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for targeting MAPT mRNA comprises a sense strand comprising or consisting of a sequence as set forth in in any one of SEQ ID NOs: 912-1295. In some embodiments, the oligonucleotide has a sense strand that comprise at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in in any one of SEQ ID NOs: 912-1295. In some embodiments, the oligonucleotide comprises a sense strand sequence a set forth in any one of SEQ ID NOs: 1-384. In some embodiments, the oligonucleotide has a sense strand that comprise at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in in any one of SEQ ID NOs: 1-384. In some embodiments, the oligonucleotide comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 769-803. In some embodiments, the oligonucleotide comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 769-803 and 1681. In some embodiments, the oligonucleotide comprises the sense strand sequence as set forth in SEQ ID NO: 1681. In some embodiments, the oligonucleotide has a sense strand comprised of least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 769-803. In some embodiments, the oligonucleotide comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, 1124, and 924. In some embodiments, the oligonucleotide has a sense strand comprised of least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, 1124, and 924. In some embodiments, the oligonucleotide comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 771, 776, 780, 781, 782, 790, 795, 798, 799, and 803. In some embodiments, the oligonucleotide has a sense strand that comprise at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 771, 776, 780, 781, 782, 790, 795, 798, 799, and 803. In some embodiments, the oligonucleotide comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 771, 780, 781, 798, 799, and 803. In some embodiments, the oligonucleotide has a sense strand that comprise at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 771, 780, 781, 798, 799, and 803.


In some embodiments, the oligonucleotide comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 771, 776, 780, 781, 782, 790, 795, 798, 799, 803, and 1681. In some embodiments, the oligonucleotide has a sense strand that comprises at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 771, 776, 780, 781, 782, 790, 795, 798, 799, 803, and 1681. In some embodiments, the oligonucleotide comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 771, 780, 781, 798, 799, 803, and 1681. In some embodiments, the oligonucleotide has a sense strand that comprise at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 771, 780, 781, 798, 799, 803, and 1681.


In some embodiments, the oligonucleotide comprises a sense strand of up to about 50 nucleotides in length (e.g., up to 50, up to 40, up to 36, up to 30, up to 27, up to 25, up to 21, up to 19, up to 17, or up to 12 nucleotides in length). In some embodiments, the oligonucleotide may have a sense strand of at least about 12 nucleotides in length (e.g., at least 12, at least 15, at least 19, at least 21, at least 25, at least 27, at least 30, at least 36, or at least 38 nucleotides in length). In some embodiments, the oligonucleotide may have a sense strand in a range of about 12 to about 50 (e.g., 12 to 50, 12 to 40, 12 to 36, 12 to 32, 12 to 28, 15 to 40, 15 to 36, 15 to 32, 15 to 28, 17 to 21, 17 to 25, 19 to 27, 19 to 30, 20 to 40, 22 to 40, 25 to 40, or 32 to 40) nucleotides in length. In some embodiments, the oligonucleotide comprises a sense strand about 15 to about 50 nucleotides in length. In some embodiments, the oligonucleotide comprises a sense strand 18 to 36 nucleotides in length. In some embodiments, the oligonucleotide may have a sense strand of 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, 49, or 50 nucleotides in length. In some embodiments, the oligonucleotide comprises a sense strand of 36 nucleotides in length.


In some embodiments, the oligonucleotide comprises a sense strand comprising a stem-loop structure at the 3′ end of the sense strand. In some embodiments, the stem-loop is formed by intrastrand base pairing. In some embodiments, the sense strand comprises a stem-loop structure at its 5′ end. In some embodiments, the stem of the stem-loop comprises a duplex of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 2 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 3 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 4 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 5 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 6 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 7 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 8 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 9 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 10 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 11 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 12 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 13 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 14 nucleotides in length.


In some embodiments, a stem-loop provides oligonucleotide protection against degradation (e.g., enzymatic degradation), facilitates or improves targeting and/or delivery to a target cell, tissue, or organ (e.g., the liver or brain), or both. For example, in some embodiments, the loop of a stem-loop provides nucleotides comprising one or more modifications that facilitate, improve, or increase targeting to a target mRNA (e.g., a MAPT mRNA), inhibition of target gene expression (e.g., MAPT gene expression), and/or delivery to a target cell, tissue, or organ (e.g., the CNS), or a combination thereof. In some embodiments, the stem-loop itself or modification(s) to the stem-loop do not substantially affect the inherent gene expression inhibition activity of the oligonucleotide, but facilitates, improves, or increases stability (e.g., provides protection against degradation) and/or delivery of the oligonucleotide to a target cell, tissue, or organ (e.g., the CNS). In certain embodiments, the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which loop (L) forms a ss loop between S1 and S2 of up to about 10 nucleotides in length (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length). In some embodiments, the L is 3 nucleotides in length. In some embodiments, the L is 4 nucleotides in length. In some embodiments, the L is 5 nucleotides in length. In some embodiments, the L is 6 nucleotides in length. In some embodiments, the L is 7 nucleotides in length. In some embodiments, the L is 8 nucleotides in length. In some embodiments, the L is 9 nucleotides in length. In some embodiments, the L is 10 nucleotides in length.


In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 912-1295, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a ss loop between S1 and S2 of up to about 10 nucleotides in length (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length). In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 912-1295, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a ss loop between S1 and S2 of 4 nucleotides in length (i.e., a tetraL).


In some embodiments, the tetraL comprises the sequence 5′-GAAA-3′. In some embodiments, the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1680).


In some embodiments, the L of a stem-loop having the structure S1-L-S2 as described above is a triL. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 912-1295 and a triL. In some embodiments, the triL comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, delivery ligands, and combinations thereof.


In some embodiments, the L of a stem-loop having the structure S1-L-S2 as described above is a tetraL as described in U.S. Pat. No. 10,131,912, incorporated herein by reference (e.g., within a nicked tetraL structure). In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 912-1295 and a tetraL. In some embodiments, the tetraL comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, delivery ligands, and combinations thereof.


Duplex Length


In some embodiments, a duplex is formed between a sense and antisense strand and is at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21) nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is in the range of about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30, or 21 to 30 nucleotides in length). In some embodiments, the duplex formed between the sense and antisense strands is 12, 13, 14, 15, 16, 17, 18, 19, 29, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 12 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 13 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 14 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 15 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 16 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 17 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 18 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 19 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 20 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 21 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 22 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 23 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 24 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 25 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 26 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 27 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 28 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 29 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands is 30 nucleotides in length. In some embodiments, the duplex formed between the sense and antisense strands does not span the entire length of the sense strand and/or antisense strand. In some embodiments, the duplex between the sense and antisense strand spans the entire length of either the sense or antisense strands. In some embodiments, the duplex between the sense and antisense strands spans the entire length of both the sense strand and the antisense strand.


In some embodiments, the duplex between the sense and antisense strands spans the entire length of both the sense strand and the antisense strand. In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 769 and 804, respectively;
    • b) SEQ ID NO: 770 and 805, respectively;
    • c) SEQ ID NO: 771 and 806, respectively;
    • d) SEQ ID NO: 772 and 807, respectively;
    • e) SEQ ID NO: 773 and 808, respectively;
    • f) SEQ ID NO: 774 and 809, respectively;
    • g) SEQ ID NO: 775 and 810, respectively;
    • h) SEQ ID NO: 776 and 811, respectively;
    • i) SEQ ID NO: 777 and 812, respectively;
    • j) SEQ ID NO: 778 and 813, respectively;
    • k) SEQ ID NO: 779 and 814, respectively;
    • l) SEQ ID NO: 780 and 815, respectively;
    • m) SEQ ID NO: 781 and 816, respectively;
    • n) SEQ ID NO: 782 and 817, respectively;
    • o) SEQ ID NO: 783 and 818, respectively;
    • p) SEQ ID NO: 784 and 819, respectively;
    • q) SEQ ID NO: 785 and 820, respectively;
    • r) SEQ ID NO: 786 and 821, respectively;
    • s) SEQ ID NO: 787 and 822, respectively;
    • t) SEQ ID NO: 788 and 823, respectively;
    • u) SEQ ID NO: 789 and 824, respectively;
    • v) SEQ ID NO: 790 and 825, respectively;
    • w) SEQ ID NO: 791 and 826, respectively;
    • x) SEQ ID NO: 792 and 827, respectively;
    • y) SEQ ID NO: 793 and 828, respectively;
    • z) SEQ ID NO: 794 and 829, respectively;
    • aa) SEQ ID NO: 795 and 830, respectively;
    • bb) SEQ ID NO: 796 and 831, respectively;
    • cc) SEQ ID NO: 797 and 832, respectively;
    • dd) SEQ ID NO: 798 and 833, respectively;
    • ee) SEQ ID NO: 799 and 834, respectively;
    • ff) SEQ ID NO: 800 and 835, respectively;
    • gg) SEQ ID NO: 801 and 836, respectively;
    • hh) SEQ ID NO: 802 and 837, respectively;
    • ii) SEQ ID NO: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively, wherein the duplex formed between the sense and antisense strand is in the range of about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30, or 21 to 30 nucleotides in length).


In some embodiments, the duplex between the sense and antisense strands spans the entire length of both the sense strand and the antisense strand. In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 771 and 806, respectively;
    • b) SEQ ID NO: 776 and 811, respectively;
    • c) SEQ ID NO: 780 and 815, respectively;
    • d) SEQ ID NO: 781 and 816, respectively;
    • e) SEQ ID NO: 782 and 817, respectively;
    • f) SEQ ID NO: 790 and 825, respectively;
    • g) SEQ ID NO: 795 and 830, respectively;
    • h) SEQ ID NO: 798 and 833, respectively;
    • i) SEQ ID NO: 799 and 834, respectively;
    • j) SEQ ID NO: 803 and 838, respectively; and
    • k) SEQ ID NOs: 1681 and 815, respectively, wherein the duplex formed between the sense and antisense strand is in the range of about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30, or 21 to 30 nucleotides in length).


In some embodiments, the duplex between the sense and antisense strands spans the entire length of both the sense strand and the antisense strand. In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 771 and 806, respectively;
    • b) SEQ ID NO: 780 and 815, respectively;
    • c) SEQ ID NO: 781 and 816, respectively;
    • d) SEQ ID NO: 798 and 833, respectively;
    • e) SEQ ID NO: 799 and 834, respectively;
    • f) SEQ ID NO: 803 and 838, respectively; and
    • g) SEQ ID NOs: 1681 and 815, respectively, wherein the duplex formed between the sense and antisense strand is in the range of about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30, or 21 to 30 nucleotides in length).


Oligonucleotide Termini


In some embodiments, an oligonucleotide herein (e.g., a RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein termini of either or both strands comprise a blunt end. In some embodiments, the oligonucleotide comprises sense and antisense strands that are separate strands that form an asymmetric duplex region having an overhang at the 3′ terminus of the antisense strand. In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein termini of either or both strands comprise an overhang comprising one or more nucleotides. In some embodiments, the one or more nucleotides comprising the overhang are unpaired nucleotides. In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein a 3′ terminus of the sense strand and a 5′ terminus of the antisense strand comprise a blunt end. In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein a 5′ terminus of the sense strand and a 3′ terminus of the antisense strand comprise a blunt end.


In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein a 3′ terminus of either or both strands comprises a 3′ overhang comprising one or more nucleotides. In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises a 3′ overhang comprising one or more nucleotides. In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 3′ overhang comprising one or more nucleotides. In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein both the sense strand and the antisense strand comprise a 3′ overhang comprising one or more nucleotides.


In some embodiments, the 3′ overhang is about 1 to about 20 nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length). In some embodiments, the 3′ overhang is 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 nucleotides in length). In some embodiments, the 3′ overhang is 1 nucleotide in length. In some embodiments, the 3′ overhang is 2 nucleotides in length. In some embodiments, the 3′ overhang is 3 nucleotides in length. In some embodiments, the 3′ overhang is 4 nucleotides in length. In some embodiments, the 3′ overhang is 5 nucleotides in length. In some embodiments, the 3′ overhang is 6 nucleotides in length. In some embodiments, the 3′ overhang is 7 nucleotides in length. In some embodiments, the 3′-overhang is 8 nucleotides in length. In some embodiments, the 3′ overhang is 9 nucleotides in length. In some embodiments, the 3′ overhang is 10 nucleotides in length. In some embodiments, the 3′ overhang is 11 nucleotides in length. In some embodiments, the 3′ overhang is 12 nucleotides in length. In some embodiments, the 3′ overhang is 13 nucleotides in length. In some embodiments, the 3′ overhang is 14 nucleotides in length. In some embodiments, the 3′ overhang is 15 nucleotides in length. In some embodiments, the 3′ overhang is 16 nucleotides in length. In some embodiments, the 3′ overhang is 17 nucleotides in length. In some embodiments, the 3′ overhang is 18 nucleotides in length. In some embodiments, the 3′ overhang is 19 nucleotides in length. In some embodiments, the 3′ overhang is 20 nucleotides in length.


In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 3′ overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 769 and 804, respectively;
    • b) SEQ ID NO: 770 and 805, respectively;
    • c) SEQ ID NO: 771 and 806, respectively;
    • d) SEQ ID NO: 772 and 807, respectively;
    • e) SEQ ID NO: 773 and 808, respectively;
    • f) SEQ ID NO: 774 and 809, respectively;
    • g) SEQ ID NO: 775 and 810, respectively;
    • h) SEQ ID NO: 776 and 811, respectively;
    • i) SEQ ID NO: 777 and 812, respectively;
    • j) SEQ ID NO: 778 and 813, respectively;
    • k) SEQ ID NO: 779 and 814, respectively;
    • l) SEQ ID NO: 780 and 815, respectively;
    • m) SEQ ID NO: 781 and 816, respectively;
    • n) SEQ ID NO: 782 and 817, respectively;
    • o) SEQ ID NO: 783 and 818, respectively;
    • p) SEQ ID NO: 784 and 819, respectively;
    • q) SEQ ID NO: 785 and 820, respectively;
    • r) SEQ ID NO: 786 and 821, respectively;
    • s) SEQ ID NO: 787 and 822, respectively;
    • t) SEQ ID NO: 788 and 823, respectively;
    • u) SEQ ID NO: 789 and 824, respectively;
    • v) SEQ ID NO: 790 and 825, respectively;
    • w) SEQ ID NO: 791 and 826, respectively;
    • x) SEQ ID NO: 792 and 827, respectively;
    • y) SEQ ID NO: 793 and 828, respectively;
    • z) SEQ ID NO: 794 and 829, respectively;
    • aa) SEQ ID NO: 795 and 830, respectively;
    • bb) SEQ ID NO: 796 and 831, respectively;
    • cc) SEQ ID NO: 797 and 832, respectively;
    • dd) SEQ ID NO: 798 and 833, respectively;
    • ee) SEQ ID NO: 799 and 834, respectively;
    • ff) SEQ ID NO: 800 and 835, respectively;
    • gg) SEQ ID NO: 801 and 836, respectively;
    • hh) SEQ ID NO: 802 and 837, respectively;
    • ii) SEQ ID NO: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively, wherein the antisense strand comprises the 3′ overhang about 1 to about 20 nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length), optionally wherein the 3′ overhang is 2 nucleotides in length.


In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the antisense strand comprises the 3′ overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 771 and 806, respectively;
    • b) SEQ ID NO: 776 and 811, respectively;
    • c) SEQ ID NO: 780 and 815, respectively;
    • d) SEQ ID NO: 781 and 816, respectively;
    • e) SEQ ID NO: 782 and 817, respectively;
    • f) SEQ ID NO: 790 and 825, respectively;
    • g) SEQ ID NO: 795 and 830, respectively;
    • h) SEQ ID NO: 798 and 833, respectively;
    • i) SEQ ID NO: 799 and 834, respectively;
    • j) SEQ ID NO: 803 and 838, respectively; and
    • k) SEQ ID NOs: 1681 and 815, respectively, wherein the antisense strand comprises the 3′ overhang about 1 to about 20 nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length), optionally wherein the 3′ overhang is 2 nucleotides in length.


In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the antisense strand comprises the 3′ overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 771 and 806, respectively;
    • b) SEQ ID NO: 780 and 815, respectively;
    • c) SEQ ID NO: 781 and 816, respectively;
    • d) SEQ ID NO: 798 and 833, respectively;
    • e) SEQ ID NO: 799 and 834, respectively;
    • f) SEQ ID NO: 803 and 838, respectively; and
    • g) SEQ ID NOs: 1681 and 815, respectively, wherein the antisense strand comprises a 3′ overhang about 1 to about 20 nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length), optionally wherein the 3′ overhang is 2 nucleotides in length.


In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand comprises a 5′ overhang comprising one or more nucleotides.


In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 769 and 804, respectively;
    • b) SEQ ID NOs: 770 and 805, respectively;
    • c) SEQ ID NOs: 771 and 806, respectively;
    • d) SEQ ID NOs: 772 and 807, respectively;
    • e) SEQ ID NOs: 773 and 808, respectively;
    • f) SEQ ID NOs: 774 and 809, respectively;
    • g) SEQ ID NOs: 775 and 810, respectively;
    • h) SEQ ID NOs: 776 and 811, respectively;
    • i) SEQ ID NOs: 777 and 812, respectively;
    • j) SEQ ID NOs: 778 and 813, respectively;
    • k) SEQ ID NOs: 779 and 814, respectively;
    • l) SEQ ID NOs: 780 and 815, respectively;
    • m) SEQ ID NOs: 781 and 816, respectively;
    • n) SEQ ID NOs: 782 and 817, respectively;
    • o) SEQ ID NOs: 783 and 818, respectively;
    • p) SEQ ID NOs: 784 and 819, respectively;
    • q) SEQ ID NOs: 785 and 820, respectively;
    • r) SEQ ID NOs: 786 and 821, respectively;
    • s) SEQ ID NOs: 787 and 822, respectively;
    • t) SEQ ID NOs: 788 and 823, respectively;
    • u) SEQ ID NOs: 789 and 824, respectively;
    • v) SEQ ID NOs: 790 and 825, respectively;
    • w) SEQ ID NOs: 791 and 826, respectively;
    • x) SEQ ID NOs: 792 and 827, respectively;
    • y) SEQ ID NOs: 793 and 828, respectively;
    • z) SEQ ID NOs: 794 and 829, respectively;
    • aa) SEQ ID NOs: 795 and 830, respectively;
    • bb) SEQ ID NOs: 796 and 831, respectively;
    • cc) SEQ ID NOs: 797 and 832, respectively;
    • dd) SEQ ID NOs: 798 and 833, respectively;
    • ee) SEQ ID NOs: 799 and 834, respectively;
    • ff) SEQ ID NOs: 800 and 835, respectively;
    • gg) SEQ ID NOs: 801 and 836, respectively;
    • hh) SEQ ID NOs: 802 and 837, respectively;
    • ii) SEQ ID NOs: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively, wherein the antisense strand comprises a 3′ overhang about 1 to about 20 nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 3′ overhang is 2 nucleotides in length.


In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively;
    • j) SEQ ID NOs: 803 and 838, respectively; and
    • k) SEQ ID NOs: 1681 and 815, respectively, wherein the antisense strand comprises the 3′ overhang about 1 to about 20 nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 3′ overhang is 2 nucleotides in length.


In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 771 and 806, respectively;
    • b) SEQ ID NO: 780 and 815, respectively;
    • c) SEQ ID NO: 781 and 816, respectively;
    • d) SEQ ID NO: 798 and 833, respectively;
    • e) SEQ ID NO: 799 and 834, respectively;
    • f) SEQ ID NO: 803 and 838, respectively; and
    • g) SEQ ID NOs: 1681 and 815, respectively, wherein the antisense strand comprises the 3′ overhang about 1 to about 20 nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 3′ overhang is 2 nucleotides in length.


In some embodiments, one or more (e.g., 2, 3, 4, 5, or more) nucleotides comprising the 3′ terminus or 5′ terminus of the sense and/or antisense strand are modified. For example, in some embodiments, one or two terminal nucleotides of the 3′ terminus of the antisense strand are modified. In some embodiments, the last nucleotide at the 3′ terminus of an antisense strand is modified, for example, comprises 2′ modification (e.g., a 2′-OMe). In some embodiments, the last one or two terminal nucleotides at the 3′ terminus of an antisense strand are complementary with the target. In some embodiments, the last one or two nucleotides at the 3′ terminus of the antisense strand are not complementary with the target.


In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the 3′ terminus of the sense strand comprises a step-loop and the 3′ terminus of the antisense strand comprises the 3′ overhang. In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand that form a nicked tetraL structure, wherein the 3′ terminus of the sense strand comprises the stem-loop, wherein the loop is a tetraL, and wherein the 3′ terminus of the antisense strand comprises the 3′ overhang described herein. In some embodiments, the 3′ overhang is 2 nucleotides in length. In some embodiments, the 2 nucleotides comprising the 3′ overhang both comprise guanine (G) nucleobases. Typically, one or both of the nucleotides comprising the 3′ overhang of the antisense strand are not complementary with the target mRNA.


Oligonucleotide Modifications


In some embodiments, the oligonucleotide (e.g., a RNAi oligonucleotide) comprises a modification. Oligonucleotides may be modified in various ways to improve or control specificity, stability, delivery, bioavailability, resistance from nuclease degradation, immunogenicity, base-pairing properties, RNA distribution and cellular uptake, and other features relevant to therapeutic research use.


In some embodiments, the modification is a modified sugar. In some embodiments, the modification is a 5′ terminal phosphate group. In some embodiments, the modification is a modified internucleoside linkage. In some embodiments, the modification is a modified base. In some embodiments, the modification is a reversible modification. In some embodiments, the oligonucleotide may comprise any one of the modifications described herein or any combination thereof. For example, in some embodiments, the oligonucleotide comprises at least one modified sugar, a 5′ terminal phosphate group, at least one modified internucleoside linkage, at least one modified base, and at least one reversible modification.


In some embodiments, the oligonucleotide comprises at least one modified sugar, a 5′ terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base. In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 769 and 804, respectively;
    • b) SEQ ID NO: 770 and 805, respectively;
    • c) SEQ ID NO: 771 and 806, respectively;
    • d) SEQ ID NO: 772 and 807, respectively;
    • e) SEQ ID NO: 773 and 808, respectively;
    • f) SEQ ID NO: 774 and 809, respectively;
    • g) SEQ ID NO: 775 and 810, respectively;
    • h) SEQ ID NO: 776 and 811, respectively;
    • i) SEQ ID NO: 777 and 812, respectively;
    • j) SEQ ID NO: 778 and 813, respectively;
    • k) SEQ ID NO: 779 and 814, respectively;
    • l) SEQ ID NO: 780 and 815, respectively;
    • m) SEQ ID NO: 781 and 816, respectively;
    • n) SEQ ID NO: 782 and 817, respectively;
    • o) SEQ ID NO: 783 and 818, respectively;
    • p) SEQ ID NO: 784 and 819, respectively;
    • q) SEQ ID NO: 785 and 820, respectively;
    • r) SEQ ID NO: 786 and 821, respectively;
    • s) SEQ ID NO: 787 and 822, respectively;
    • t) SEQ ID NO: 788 and 823, respectively;
    • u) SEQ ID NO: 789 and 824, respectively;
    • v) SEQ ID NO: 790 and 825, respectively;
    • w) SEQ ID NO: 791 and 826, respectively;
    • x) SEQ ID NO: 792 and 827, respectively;
    • y) SEQ ID NO: 793 and 828, respectively;
    • z) SEQ ID NO: 794 and 829, respectively;
    • aa) SEQ ID NO: 795 and 830, respectively;
    • bb) SEQ ID NO: 796 and 831, respectively;
    • cc) SEQ ID NO: 797 and 832, respectively;
    • dd) SEQ ID NO: 798 and 833, respectively;
    • ee) SEQ ID NO: 799 and 834, respectively;
    • ff) SEQ ID NO: 800 and 835, respectively;
    • gg) SEQ ID NO: 801 and 836, respectively;
    • hh) SEQ ID NO: 802 and 837, respectively;
    • ii) SEQ ID NO: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises at least one modified sugar, a 5′ terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 771 and 806, respectively;
    • b) SEQ ID NO: 776 and 811, respectively;
    • c) SEQ ID NO: 780 and 815, respectively;
    • d) SEQ ID NO: 781 and 816, respectively;
    • e) SEQ ID NO: 782 and 817, respectively;
    • f) SEQ ID NO: 790 and 825, respectively;
    • g) SEQ ID NO: 795 and 830, respectively;
    • h) SEQ ID NO: 798 and 833, respectively;
    • i) SEQ ID NO: 799 and 834, respectively;
    • j) SEQ ID NO: 803 and 838, respectively; and
    • k) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises at least one modified sugar, a 5′ terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 771 and 806, respectively;
    • b) SEQ ID NO: 780 and 815, respectively;
    • c) SEQ ID NO: 781 and 816, respectively;
    • d) SEQ ID NO: 798 and 833, respectively;
    • e) SEQ ID NO: 799 and 834, respectively;
    • f) SEQ ID NO: 803 and 838, respectively; and
    • g) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises at least one modified sugar, a 5′ terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base.


The number of modifications on the oligonucleotide and the position of those nucleotide modifications may influence the properties of an oligonucleotide. For example, oligonucleotides may be delivered in vivo by conjugating them to encompassing them in a lipid nanoparticle (LNP) or similar carrier. However, when an oligonucleotide is not protected by an LNP or similar carrier, it may be advantageous for at least some of the nucleotides to be modified. Accordingly, in some embodiments, all or substantially all of the nucleotides of the oligonucleotides are modified. In some embodiments, more than half of the nucleotides are modified. In some embodiments, less than half of the nucleotides are modified. In some embodiments, the sugar moiety of all nucleotides comprising the oligonucleotide is modified at the 2′ position. The modifications may be reversible or irreversible. In some embodiments, an oligonucleotide as disclosed herein has a number and type of modified nucleotides sufficient to cause the desired characteristics (e.g., protection from enzymatic degradation, capacity to target a desired cell after in vivo administration, and/or thermodynamic stability).


Sugar Modifications


In some embodiments, the oligonucleotide comprises a modified sugar. In some embodiments, the modified sugar (also referred herein to a sugar analog) includes a modified deoxyribose or ribose moiety in which, for example, one or more modifications occur at the 2′, 3′, 4′, and/or 5′ carbon position of the sugar. In some embodiments, the modified sugar may also include non-natural alternative carbon structures such as those present in locked nucleic acids (“LNA”; see, e.g., Koshkin et al. (1998) TETRAHEDON 54:3607-30), unlocked nucleic acids (“UNA”; see, e.g., Snead et al. (2013) MOL. THER-NUCL. ACIDS 2:e103), and bridged nucleic acids (“BNA”; see, e.g., Imanishi & Obika (2002) CHEM COMMUN. (CAMB) 21:1653-59).


In some embodiments, a nucleotide modification in a sugar comprises a 2′-modification. In some embodiments, the 2′-modification may be 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-F, EA, 2′-OMe, 2′-MOE, 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA) or 2′-FANA. In some embodiments, the modification is 2′-F, 2′-OMe or 2′-MOE. In some embodiments, the modification in a sugar comprises a modification of the sugar ring, which may comprise modification of one or more carbons of the sugar ring. For example, the modification of a sugar of a nucleotide may comprise a 2′-oxygen of a sugar is linked to a 1-carbon or 4′-carbon of the sugar, or a 2′-oxygen is linked to the 1-carbon or 4′-carbon via an ethylene or methylene bridge. In some embodiments, the modified nucleotide has an acyclic sugar that lacks a 2′-carbon to 3′-carbon bond. In some embodiments, the modified nucleotide has a thiol group, for example, in the 4′ position of the sugar.


In some embodiments, the oligonucleotide described herein comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, or more). In some embodiments, the sense strand of the RNAi oligonucleotide comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, or more). In some embodiments, the antisense strand of the oligonucleotide comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, or more).


In some embodiments, all the nucleotides of the sense strand of the oligonucleotide are modified. In some embodiments, all the nucleotides of the antisense strand of the oligonucleotide are modified. In some embodiments, all the nucleotides of the oligonucleotide (i.e., both the sense strand and the antisense strand) are modified. In some embodiments, the modified nucleotide comprises a 2′-modification (e.g., a 2′-F or 2′-OMe, 2′-MOE, and 2′-FANA). In some embodiments, the modified nucleotide comprises a 2′-modification (e.g., a 2′-F or 2′-OMe)


In some embodiments, the disclosure provides oligonucleotides having different modification patterns. In some embodiments, the modified oligonucleotides comprise a sense strand sequence having a modification pattern as set forth in the Examples and Sequence Listing and an antisense strand having a modification pattern as set forth in the Examples and Sequence Listing.


In some embodiments, the oligonucleotide comprises an antisense strand having nucleotides that are modified with 2′-F. In some embodiments, the oligonucleotide comprises an antisense strand comprises nucleotides that are modified with 2′-F and 2′-OMe. In some embodiments, the oligonucleotide comprises a sense strand having nucleotides that are modified with 2′-F. In some embodiments, the oligonucleotide comprises a sense strand comprising nucleotides that are modified with 2′-F and 2′-OMe.


In some embodiments, the oligonucleotide comprises a sense strand with about 10-15%, 10%, 11%, 12%, 13%, 14%, or 15% of the nucleotides of the sense strand comprising a 2′-F modification. In some embodiments, the oligonucleotide comprises a sense strand with about 18-23% (e.g., 18%, 19%, 20%, 21%, 22%, or 23%) of the nucleotides of the sense strand comprising a 2′-F modification. In some embodiments, the oligonucleotide comprises a sense strand with about 38-43% (e.g., 38%, 39%, 40%, 41%, 42%, or 43%) of the nucleotides of the sense strand comprising a 2′-F modification. In some embodiments, about 11% of the nucleotides of the sense strand comprise a 2′-F modification. In some embodiments, about 22% of the nucleotides of the sense strand comprise a 2′-F modification. In some embodiments, about 40% of the nucleotides of the sense strand comprise a 2′-F modification. In some embodiments, the oligonucleotide comprises an antisense strand with about 25% to about 35% (e.g., 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35%) of the nucleotides of the antisense strand comprising a 2′-F modification. In some embodiments, about 32% of the nucleotides of the antisense strand comprise a 2′-F modification. In some embodiments, the oligonucleotide has about 15% to about 25% (e.g., 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%) of its nucleotides comprising a 2′-F modification. In some embodiments, the oligonucleotide has about 35-45% (e.g., 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44% or 45%) of its nucleotides comprising a 2′-F modification. In some embodiments, about 19% of the nucleotides in the oligonucleotide comprise a 2′-F modification. In some embodiments, about 29% of the nucleotides in the oligonucleotide comprise a 2′-F modification. In some embodiments, about 40% of the nucleotides in the oligonucleotide comprise a 2′-F modification.


In some embodiments, one or more of positions 8, 9, 10, or 11 of a 36-nucleotide sense strand are modified with a 2′-F group. In some embodiments, one or more of positions 8, 9, 10, or 11 of a sense strand comprising a stem-loop are modified with a 2′-F group. In some embodiments, the sugar moiety at each of nucleotides at positions 1-7 and 12-20 of a 36-nucleotide sense strand is modified with a 2′-OMe. In some embodiments, the sugar moiety at each of nucleotides at positions 1-7 and 12-20 of a sense strand comprising a stem-loop is modified with a 2′-OMe. In some embodiments, the sugar moiety at each of nucleotides at positions 1-7 and 12-36 in the sense strand is modified with a 2′-OMe.


In some embodiments, one or more of positions 3, 5, 8, 10, 12, 13, 15, and 17 of the sense strand are modified with a 2′-F.


In some embodiments, the antisense strand has 3 nucleotides that are modified at the 2′-position of the sugar moiety with a 2′-F. In some embodiments, the sugar moiety at positions 2, 5 and 14 and optionally up to 3 of the nucleotides at positions 1, 3, 7, and 10 of the antisense strand are modified with a 2′-F. In some embodiments, the sugar moiety at positions 2, 5, and 14 and optionally up to 3 of the nucleotides at positions 3, 4, 7, and 10 of the antisense strand are modified with a 2′-F. In other embodiments, the sugar moiety at each of the positions at positions 2, 5, and 14 of the antisense strand is modified with the 2′-F. In other embodiments, the sugar moiety at each of the positions at positions 1, 2, 5, and 14 of the antisense strand is modified with the 2′-F. In other embodiments, the sugar moiety at each of the positions at positions 2, 4, 5, and 14 of the antisense strand is modified with the 2′-F. In still other embodiments, the sugar moiety at each of the positions at positions 1, 2, 3, 5, 7, and 14 of the antisense strand is modified with the 2′-F. In other embodiments, the sugar moiety at each of the positions at positions 2, 3, 4, 5, 7, and 14 of the antisense strand is modified with the 2′-F. In yet another embodiment, the sugar moiety at each of the positions at positions 1, 2, 3, 5, 10, and 14 of the antisense strand is modified with the 2′-F. In other embodiments, the sugar moiety at each of the positions at positions 2, 3, 4, 5, 10, and 14 of the antisense strand is modified with the 2′-F. In another embodiment, the sugar moiety at each of the positions at positions 2, 3, 5, 7, 10, and 14 of the antisense strand is modified with the 2′-F. In other embodiments, the sugar moiety at each of the positions at positions 2, 3, 4, 5, 7, 10, and 14 of an antisense strand duplexed with a 36-nucleotide sense strand is modified with the 2′-F. In other embodiments, the sugar moiety at each of the positions at positions 2, 3, 4, 5, 7, 10, and 14 of an antisense strand duplexed with a sense strand comprising a stem-loop is modified with the 2′-F.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at positions 2 and 14 modified with 2′-F. In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at positions 2, 5, and 14 modified with 2′-F. In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at positions 1, 2, 5, and 14 modified with 2′-F. In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at positions 2, 4, 5, and 14 modified with 2′-F. In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at positions 1, 2, 3, 5, 7, and 14 modified with 2′-F. In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at positions 2, 3, 4, 5, 7, and 14 modified with 2′-F. In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at positions 1, 2, 3, 5, 10, and 14 modified with 2′-F. In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at positions 2, 3, 4, 5, 10, and 14 modified with 2′-F. In some embodiments, the oligonucleotide comprises a 36-nucleotide sense strand and an antisense strand, wherein the antisense strand comprises a sugar moiety at positions 2, 3, 4, 5, 7, 10, and 14 modified with 2′-F. In some embodiments, the oligonucleotide comprises a sense strand comprising a stem-loop and an antisense strand, wherein the antisense strand comprises a sugar moiety at positions 2, 3, 4, 5, 7, 10, and 14 modified with 2′-F. In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at positions 2, 3, 4, 5, 7, 10, 14, 16, and 19 modified with 2′-F.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 5, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 1, 2, 5, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 4, 5, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 1, 2, 3, 5, 7, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 1, 2, 3, 5, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 5, 7, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises a 36-nucleotide sense strand and an antisense strand, wherein the antisense strand comprising a sugar moiety at positions 2, 3, 4, 5, 7, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA. In some embodiments, the oligonucleotide comprises a sense strand comprising a stem-loop and an antisense strand, wherein the antisense strand comprising a sugar moiety at positions 2, 3, 4, 5, 7, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, 10, 14, 16, and 19 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with 2′-F.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with 2′-OMe.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises a 36-nucleotide sense strand having the sugar moiety at positions 8-11 modified with 2′-F. In some embodiments, the oligonucleotide comprises a sense strand comprising a stem-loop and the sugar moiety at positions 8-11 modified with 2′-F. In some embodiments, the oligonucleotide comprises a 36-nucleotide sense strand having the sugar moiety at positions 1-7 and 12-17 or 12-20 modified with 2′-OMe. In some embodiments, the oligonucleotide comprises a sense strand comprising a stem loop and the sugar moiety at positions 1-7 and 12-17 or 12-20 modified with 2′-OMe. In some embodiments, the oligonucleotide comprises a 36-nucleotide sense strand having the sugar moiety at positions 1-7 and 12-17, 12-20 or 12-22 modified with 2′-OMe. In some embodiments, the oligonucleotide comprises a sense strand comprising a stem-loop and the sugar moiety at positions 1-7 and 12-17, 12-20, or 12-22 modified with 2′-OMe. In some embodiments, the oligonucleotide comprises a 36-nucleotide sense strand having the sugar moiety of each of the nucleotides at positions 1-7 and 12-17 or 12-20 of the sense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA. In some embodiments, the oligonucleotide comprises a sense strand comprising and stem-loop and having the sugar moiety of each of the nucleotides at positions 1-7 and 12-17 or 12-20 of the sense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA. In some embodiments, the oligonucleotide comprises a 36-nucleotide sense strand having the sugar moiety of each of the nucleotides at positions 1-7 and 12-17, 12-20, or 12-22 of the sense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA. In some embodiments, the oligonucleotide comprises a sense strand comprising a stem-loop and the sugar moiety of each of the nucleotides at positions 1-7 and 12-17, 12-20, or 12-22 of the sense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises a sense strand having the sugar moiety at positions 3, 5, 8, 10, 12, 13, 15, and 17 modified with 2′-F. In some embodiments, the oligonucleotide comprises a sense strand having the sugar moiety at positions 1, 2, 4, 6, 7, 9, 11, 14, 16, and 18-20 modified with 2′-OMe. In some embodiments, the oligonucleotide comprises a sense strand having the sugar moiety of each of the nucleotides at positions 1, 2, 4, 6, 7, 9, 11, 14, 16, and 18-20 of the sense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA. In some embodiments, the oligonucleotide comprises a sense strand having the sugar moiety of each of the nucleotides at positions 1-7 and 12-17, 12-20, or 12-22 of the sense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with 2′-F.


In some embodiments, the oligonucleotide comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with 2′-OMe.


In some embodiments, the oligonucleotide comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, 10, and 14 of the antisense strand modified with 2′-F, and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA); and a 36-nucleotide sense strand having the sugar moiety at each of the nucleotides at positions 8-11 of the sense strand modified with 2′-F, and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA). In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, 10, and 14 of the antisense strand modified with 2′-F, and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA; and a sense strand comprising a stem-loop and the sugar moiety at each of the nucleotides at positions 8-11 of the sense strand modified with 2′-F, and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the oligonucleotide comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, 10, 14, 16, and 19 of the antisense strand modified with 2′-F, and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA; and a sense strand having the sugar moiety at each of the nucleotides at positions 3, 5, 8, 10, 12, 13, 15, and 17 of the sense strand modified with 2′-F, and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, EA, 2′-OMe, 2′-MOE, 2′-O-NMA, and 2′-FANA.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NO: 769 and 804, respectively;
    • b) SEQ ID NO: 770 and 805, respectively;
    • c) SEQ ID NO: 771 and 806, respectively;
    • d) SEQ ID NO: 772 and 807, respectively;
    • e) SEQ ID NO: 773 and 808, respectively;
    • f) SEQ ID NO: 774 and 809, respectively;
    • g) SEQ ID NO: 775 and 810, respectively;
    • h) SEQ ID NO: 776 and 811, respectively;
    • i) SEQ ID NO: 777 and 812, respectively;
    • j) SEQ ID NO: 778 and 813, respectively;
    • k) SEQ ID NO: 779 and 814, respectively;
    • l) SEQ ID NO: 780 and 815, respectively;
    • m) SEQ ID NO: 781 and 816, respectively;
    • n) SEQ ID NO: 782 and 817, respectively;
    • o) SEQ ID NO: 783 and 818, respectively;
    • p) SEQ ID NO: 784 and 819, respectively;
    • q) SEQ ID NO: 785 and 820, respectively;
    • r) SEQ ID NO: 786 and 821, respectively;
    • s) SEQ ID NO: 787 and 822, respectively;
    • t) SEQ ID NO: 788 and 823, respectively;
    • u) SEQ ID NO: 789 and 824, respectively;
    • v) SEQ ID NO: 790 and 825, respectively;
    • w) SEQ ID NO: 791 and 826, respectively;
    • x) SEQ ID NO: 792 and 827, respectively;
    • y) SEQ ID NO: 793 and 828, respectively;
    • z) SEQ ID NO: 794 and 829, respectively;
    • aa) SEQ ID NO: 795 and 830, respectively;
    • bb) SEQ ID NO: 796 and 831, respectively;
    • cc) SEQ ID NO: 797 and 832, respectively;
    • dd) SEQ ID NO: 798 and 833, respectively;
    • ee) SEQ ID NO: 799 and 834, respectively;
    • ff) SEQ ID NO: 800 and 835, respectively;
    • gg) SEQ ID NO: 801 and 836, respectively;
    • hh) SEQ ID NO: 802 and 837, respectively;
    • ii) SEQ ID NO: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively, wherein one or more of positions 3, 5, 8, 10, 12, 13, 15, or 17 of the sense strand are modified with a 2′-F group.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively;
    • j) SEQ ID NOs: 803 and 838, respectively; and
    • k) SEQ ID NOs: 1681 and 815, respectively, wherein one or more of positions 3, 5, 8, 10, 12, 13, 15, or 17 of the sense strand is modified with a 2′-F group.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 780 and 815, respectively;
    • c) SEQ ID NOs: 781 and 816, respectively;
    • d) SEQ ID NOs: 798 and 833, respectively;
    • e) SEQ ID NOs: 799 and 834, respectively;
    • f) SEQ ID NOs: 803 and 838, respectively; and
    • g) SEQ ID NOs: 1681 and 815, respectively, wherein one or more of positions 3, 5, 8, 10, 12, 13, 15, or 17 of the sense strand is modified with a 2′-F group.


5′ Terminal Phosphate


In some embodiments, the oligonucleotide comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5′ terminal phosphate. In some embodiments, 5′ terminal phosphate groups of the oligonucleotide enhance the interaction with Ago2. However, oligonucleotides comprising a 5′-phosphate group may be susceptible to degradation via phosphatases or other enzymes, which can limit their bioavailability in vivo. In some embodiments, the oligonucleotide includes analogs of 5′ phosphates that are resistant to such degradation. In some embodiments, the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate, or a combination thereof. In certain embodiments, the 5′ end of the oligonucleotide strand is attached to chemical moiety that mimics the electrostatic and steric properties of a natural 5′-phosphate group (“phosphate mimic”).


In some embodiments, the oligonucleotide has a phosphate analog at a 4′-carbon position of the sugar (referred to as a “4′-phosphate analog”). See, e.g., Intl. Patent Application Publication No. WO 2018/045317. In some embodiments, the oligonucleotide comprises a 4′-phosphate analog at a 5′ terminal nucleotide. In some embodiments, the phosphate analog is an oxymethyl phosphonate, in which the oxygen atom of the oxymethyl group is bound to the sugar moiety (e.g., at its 4′-carbon) or analog thereof. In other embodiments, the 4′-phosphate analog is a thiomethylphosphonate or an aminomethylphosphonate, in which the sulfur atom of the thiomethyl group or the nitrogen atom of the amino methyl group is bound to the 4′-carbon of the sugar moiety or analog thereof. In certain embodiments, the 4′-phosphate analog is an oxymethyl phosphonate. In some embodiments, the oxymethyl phosphonate is represented by the formula —O—CH2—PO(OH)2, —O—CH2—PO(OR)2, or —O—CH2-POOH(R), in which R is independently selected from H, CH3, an alkyl group, CH2CH2CN, CH2OCOC(CH3)3, CH2OCH2CH2Si (CH3)3 or a protecting group. In certain embodiments, the alkyl group is CH2CH3. More typically, R is independently selected from H, CH3 or CH2CH3. In some embodiment, R is CH3. In some embodiments, the 4′-phosphate analog is 4′-oxymethylphosphonate. In some embodiments, the modified nucleotide having the 4′-phosphonate analog is a uridine. In some embodiments, the modified nucleotide is 4′-O-monomethylphosphonate-2′-O-methyl uridine.


In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 769 and 804, respectively;
    • b) SEQ ID NOs: 770 and 805, respectively;
    • c) SEQ ID NOs: 771 and 806, respectively;
    • d) SEQ ID NOs: 772 and 807, respectively;
    • e) SEQ ID NOs: 773 and 808, respectively;
    • f) SEQ ID NOs: 774 and 809, respectively;
    • g) SEQ ID NOs: 775 and 810, respectively;
    • h) SEQ ID NOs: 776 and 811, respectively;
    • i) SEQ ID NOs: 777 and 812, respectively;
    • j) SEQ ID NOs: 778 and 813, respectively;
    • k) SEQ ID NOs: 779 and 814, respectively;
    • l) SEQ ID NOs: 780 and 815, respectively;
    • m) SEQ ID NOs: 781 and 816, respectively;
    • n) SEQ ID NOs: 782 and 817, respectively;
    • o) SEQ ID NOs: 783 and 818, respectively;
    • p) SEQ ID NOs: 784 and 819, respectively;
    • q) SEQ ID NOs: 785 and 820, respectively;
    • r) SEQ ID NOs: 786 and 821, respectively;
    • s) SEQ ID NOs: 787 and 822, respectively;
    • t) SEQ ID NOs: 788 and 823, respectively;
    • u) SEQ ID NOs: 789 and 824, respectively;
    • v) SEQ ID NOs: 790 and 825, respectively;
    • w) SEQ ID NOs: 791 and 826, respectively;
    • x) SEQ ID NOs: 792 and 827, respectively;
    • y) SEQ ID NOs: 793 and 828, respectively;
    • z) SEQ ID NOs: 794 and 829, respectively;
    • aa) SEQ ID NOs: 795 and 830, respectively;
    • bb) SEQ ID NOs: 796 and 831, respectively;
    • cc) SEQ ID NOs: 797 and 832, respectively;
    • dd) SEQ ID NOs: 798 and 833, respectively;
    • ee) SEQ ID NOs: 799 and 834, respectively;
    • ff) SEQ ID NOs: 800 and 835, respectively;
    • gg) SEQ ID NOs: 801 and 836, respectively;
    • hh) SEQ ID NOs: 802 and 837, respectively;
    • ii) SEQ ID NOs: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises a 5′ terminal phosphate, optionally a 5′ terminal phosphate analog.


In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively;
    • j) SEQ ID NOs: 803 and 838, respectively; and
    • k) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises a 5′ terminal phosphate, optionally a 5′ terminal phosphate analog.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 780 and 815, respectively;
    • c) SEQ ID NOs: 781 and 816, respectively;
    • d) SEQ ID NOs: 798 and 833, respectively;
    • e) SEQ ID NOs: 799 and 834, respectively;
    • f) SEQ ID NOs: 803 and 838, respectively; and
    • g) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises a 5′ terminal phosphate, optionally a 5′ terminal phosphate analog.


In some embodiments, the oligonucleotide comprises an antisense strand comprising a 4′-phosphate analog at the 5′ terminal nucleotide, wherein 5′ terminal nucleotide comprises the following structure:




embedded image


4′-O-monomethylphosphonate-2′-O-methyl uridine phosphorothioate [MePhosphonate-4O-mUs].


Modified Internucleotide Linkage


In some embodiments, an oligonucleotide herein (e.g., a RNAi oligonucleotide) comprises a modified internucleotide linkage. In some embodiments, phosphate modifications or substitutions result in an oligonucleotide that comprises at least about 1 (e.g., at least 1, at least 2, at least 3, or at least 5) modified internucleotide linkage. In some embodiments, the oligonucleotide comprises about 1 to about 10 (e.g., 1 to 10, 2 to 8, 4 to 6, 3 to 10, 5 to 10, 1 to 5, 1 to 3, or 1 to 2) modified internucleotide linkages. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 modified internucleotide linkages.


A modified internucleotide linkage may be a phosphorodithioate linkage, a phosphorothioate linkage, a phosphotriester linkage, a thionoalkylphosphonate linkage, a thionalkylphosphotriester linkage, a phosphoramidite linkage, a phosphonate linkage or a boranophosphate linkage. In some embodiments, at least one modified internucleotide linkage of the oligonucleotide is a phosphorothioate linkage.


In some embodiments, the oligonucleotide has a phosphorothioate linkage between one or more of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 3 and 4 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the oligonucleotide described herein has a phosphorothioate linkage between each of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the oligonucleotide described herein has a phosphorothioate linkage between each of (i) positions 1 and 2 of the sense strand; and (ii) positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 20 and 21, and positions 21 and 22 of the antisense strand.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 769 and 804, respectively;
    • b) SEQ ID NOs: 770 and 805, respectively;
    • c) SEQ ID NOs: 771 and 806, respectively;
    • d) SEQ ID NOs: 772 and 807, respectively;
    • e) SEQ ID NOs: 773 and 808, respectively;
    • f) SEQ ID NOs: 774 and 809, respectively;
    • g) SEQ ID NOs: 775 and 810, respectively;
    • h) SEQ ID NOs: 776 and 811, respectively;
    • i) SEQ ID NOs: 777 and 812, respectively;
    • j) SEQ ID NOs: 778 and 813, respectively;
    • k) SEQ ID NOs: 779 and 814, respectively;
    • l) SEQ ID NOs: 780 and 815, respectively;
    • m) SEQ ID NOs: 781 and 816, respectively;
    • n) SEQ ID NOs: 782 and 817, respectively;
    • o) SEQ ID NOs: 783 and 818, respectively;
    • p) SEQ ID NOs: 784 and 819, respectively;
    • q) SEQ ID NOs: 785 and 820, respectively;
    • r) SEQ ID NOs: 786 and 821, respectively;
    • s) SEQ ID NOs: 787 and 822, respectively;
    • t) SEQ ID NOs: 788 and 823, respectively;
    • u) SEQ ID NOs: 789 and 824, respectively;
    • v) SEQ ID NOs: 790 and 825, respectively;
    • w) SEQ ID NOs: 791 and 826, respectively;
    • x) SEQ ID NOs: 792 and 827, respectively;
    • y) SEQ ID NOs: 793 and 828, respectively;
    • z) SEQ ID NOs: 794 and 829, respectively;
    • aa) SEQ ID NOs: 795 and 830, respectively;
    • bb) SEQ ID NOs: 796 and 831, respectively;
    • cc) SEQ ID NOs: 797 and 832, respectively;
    • dd) SEQ ID NOs: 798 and 833, respectively;
    • ee) SEQ ID NOs: 799 and 834, respectively;
    • ff) SEQ ID NOs: 800 and 835, respectively;
    • gg) SEQ ID NOs: 801 and 836, respectively;
    • hh) SEQ ID NOs: 802 and 837, respectively;
    • ii) SEQ ID NOs: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises a modified internucleotide linkage.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively;
    • j) SEQ ID NOs: 803 and 838, respectively; and
    • k) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises a modified internucleotide linkage.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 780 and 815, respectively;
    • c) SEQ ID NOs: 781 and 816, respectively;
    • d) SEQ ID NOs: 798 and 833, respectively;
    • e) SEQ ID NOs: 799 and 834, respectively;
    • f) SEQ ID NOs: 803 and 838, respectively; and
    • g) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises a modified internucleotide linkage.


Base Modifications


In some embodiments, an oligonucleotide herein (e.g., a RNAi oligonucleotide) has one or more modified nucleobases. In some embodiments, modified nucleobases (also referred to herein as base analogs) are linked at the 1′ position of a nucleotide sugar moiety. In certain embodiments, a modified nucleobase is a nitrogenous base. In certain embodiments, a modified nucleobase does not contain nitrogen atom. See, e.g., US Patent Application Publication No. 2008/0274462. In some embodiments, a modified nucleotide comprises a universal base. In some embodiments, a modified nucleotide does not contain a nucleobase (abasic).


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 769 and 804, respectively;
    • b) SEQ ID NOs: 770 and 805, respectively;
    • c) SEQ ID NOs: 771 and 806, respectively;
    • d) SEQ ID NOs: 772 and 807, respectively;
    • e) SEQ ID NOs: 773 and 808, respectively;
    • f) SEQ ID NOs: 774 and 809, respectively;
    • g) SEQ ID NOs: 775 and 810, respectively;
    • h) SEQ ID NOs: 776 and 811, respectively;
    • i) SEQ ID NOs: 777 and 812, respectively;
    • j) SEQ ID NOs: 778 and 813, respectively;
    • k) SEQ ID NOs: 779 and 814, respectively;
    • l) SEQ ID NOs: 780 and 815, respectively;
    • m) SEQ ID NOs: 781 and 816, respectively;
    • n) SEQ ID NOs: 782 and 817, respectively;
    • o) SEQ ID NOs: 783 and 818, respectively;
    • p) SEQ ID NOs: 784 and 819, respectively;
    • q) SEQ ID NOs: 785 and 820, respectively;
    • r) SEQ ID NOs: 786 and 821, respectively;
    • s) SEQ ID NOs: 787 and 822, respectively;
    • t) SEQ ID NOs: 788 and 823, respectively;
    • u) SEQ ID NOs: 789 and 824, respectively;
    • v) SEQ ID NOs: 790 and 825, respectively;
    • w) SEQ ID NOs: 791 and 826, respectively;
    • x) SEQ ID NOs: 792 and 827, respectively;
    • y) SEQ ID NOs: 793 and 828, respectively;
    • z) SEQ ID NOs: 794 and 829, respectively;
    • aa) SEQ ID NOs: 795 and 830, respectively;
    • bb) SEQ ID NOs: 796 and 831, respectively;
    • cc) SEQ ID NOs: 797 and 832, respectively;
    • dd) SEQ ID NOs: 798 and 833, respectively;
    • ee) SEQ ID NOs: 799 and 834, respectively;
    • ff) SEQ ID NOs: 800 and 835, respectively;
    • gg) SEQ ID NOs: 801 and 836, respectively;
    • hh) SEQ ID NOs: 802 and 837, respectively;
    • ii) SEQ ID NOs: 803 and 838, respectively; and
    • jj) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises one or more modified nucleobases.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively;
    • j) SEQ ID NOs: 803 and 838, respectively; and
    • k) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises one or more modified nucleobases.


In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 780 and 815, respectively;
    • c) SEQ ID NOs: 781 and 816, respectively;
    • d) SEQ ID NOs: 798 and 833, respectively;
    • e) SEQ ID NOs: 799 and 834, respectively;
    • f) SEQ ID NOs: 803 and 838, respectively;
    • g) SEQ ID NOs: 1681 and 815, respectively, wherein the oligonucleotide comprises one or more modified nucleobases.


In some embodiments, a universal base is a heterocyclic moiety located at the 1′ position of a nucleotide sugar moiety in a modified nucleotide, or the equivalent position in a nucleotide sugar moiety substitution, that, when present in a duplex, can be positioned opposite more than one type of base without substantially altering structure of the duplex. In some embodiments, compared to a reference ss nucleic acid (e.g., an oligonucleotide) that is fully complementary to a target nucleic acid, a ss nucleic acid containing a universal base forms a duplex with the target nucleic acid that has a lower Tm than a duplex formed with the complementary nucleic acid. In some embodiments, when compared to a reference ss nucleic acid in which the universal base has been replaced with a base to generate a single mismatch, the ss nucleic acid containing the universal base forms a duplex with the target nucleic acid that has a higher Tm than a duplex formed with the nucleic acid comprising the mismatched base.


Non-limiting examples of universal-binding nucleotides include, but are not limited to, inosine, 1-β-D-ribofuranosyl-5-nitroindole and/or 1-β-D-ribofuranosyl-3-nitropyrrole (see, US Patent Application Publication No. 2007/0254362; Van Aerschot et al. (1995) NUCLEIC ACIDS RES. 23:4363-4370; Loakes et al. (1995) NUCLEIC ACIDS RES. 23:2361-66; and Loakes & Brown (1994) NUCLEIC ACIDS RES. 22:4039-43).


Targeting Ligands


In some embodiments, it is desirable to target the oligonucleotide (e.g., a RNAi oligonucleotide) to one or more cells or one or more organs. Such a strategy can help to avoid undesirable effects in other organs or avoid undue loss of the oligonucleotide to cells, tissue, or organs that would not benefit from the oligonucleotide. Accordingly, in some embodiments, the oligonucleotide is modified to facilitate targeting and/or delivery to a particular tissue, cell, or organ (e.g., to facilitate delivery of the oligonucleotide to the CNS). In some embodiments, the oligonucleotide comprises at least one nucleotide (e.g., 1, 2, 3, 4, 5, 6, or more nucleotides) conjugated to one or more targeting ligand(s). In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 769 and 804, respectively;
    • b) SEQ ID NOs: 770 and 805, respectively;
    • c) SEQ ID NOs: 771 and 806, respectively;
    • d) SEQ ID NOs: 772 and 807, respectively;
    • e) SEQ ID NOs: 773 and 808, respectively;
    • f) SEQ ID NOs: 774 and 809, respectively;
    • g) SEQ ID NOs: 775 and 810, respectively;
    • h) SEQ ID NOs: 776 and 811, respectively;
    • i) SEQ ID NOs: 777 and 812, respectively;
    • j) SEQ ID NOs: 778 and 813, respectively;
    • k) SEQ ID NOs: 779 and 814, respectively;
    • l) SEQ ID NOs: 780 and 815, respectively;
    • m) SEQ ID NOs: 781 and 816, respectively;
    • n) SEQ ID NOs: 782 and 817, respectively;
    • o) SEQ ID NOs: 783 and 818, respectively;
    • p) SEQ ID NOs: 784 and 819, respectively;
    • q) SEQ ID NOs: 785 and 820, respectively;
    • r) SEQ ID NOs: 786 and 821, respectively;
    • s) SEQ ID NOs: 787 and 822, respectively;
    • t) SEQ ID NOs: 788 and 823, respectively;
    • u) SEQ ID NOs: 789 and 824, respectively;
    • v) SEQ ID NOs: 790 and 825, respectively;
    • w) SEQ ID NOs: 791 and 826, respectively;
    • x) SEQ ID NOs: 792 and 827, respectively;
    • y) SEQ ID NOs: 793 and 828, respectively;
    • z) SEQ ID NOs: 794 and 829, respectively;
    • aa) SEQ ID NOs: 795 and 830, respectively;
    • bb) SEQ ID NOs: 796 and 831, respectively;
    • cc) SEQ ID NOs: 797 and 832, respectively;
    • dd) SEQ ID NOs: 798 and 833, respectively;
    • ee) SEQ ID NOs: 799 and 834, respectively;
    • ff) SEQ ID NOs: 800 and 835, respectively;
    • gg) SEQ ID NOs: 801 and 836, respectively;
    • hh) SEQ ID NOs: 802 and 837, respectively; and
    • ii) SEQ ID NOs: 803 and 838, respectively, wherein the oligonucleotide comprises a targeting ligand conjugated to at least one nucleotide.


In some embodiments, the oligonucleotide comprises at least one nucleotide (e.g., 1, 2, 3, 4, 5, 6, or more nucleotides) conjugated to one or more targeting ligand(s). In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively; and
    • j) SEQ ID NOs: 803 and 838, respectively, wherein the oligonucleotide comprises a targeting ligand conjugated to at least one nucleotide.


In some embodiments, the oligonucleotide comprises at least one nucleotide (e.g., 1, 2, 3, 4, 5, 6, or more nucleotides) conjugated to one or more targeting ligand(s). In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 780 and 815, respectively;
    • c) SEQ ID NOs: 781 and 816, respectively;
    • d) SEQ ID NOs: 798 and 833, respectively;
    • e) SEQ ID NOs: 799 and 834, respectively; and
    • f) SEQ ID NOs: 803 and 838, respectively, wherein the oligonucleotide comprises a targeting ligand conjugated to at least one nucleotide.


In some embodiments, the targeting ligand comprises a carbohydrate, amino sugar, cholesterol, peptide, polypeptide, or protein or part of a protein (e.g., an antibody or antibody fragment). In some embodiments, the targeting ligand is an aptamer. For example, the targeting ligand may be an RGD peptide that is used to target tumor vasculature or glioma cells, CREKA peptide to target tumor vasculature or stoma, transferring, lactoferrin, or an aptamer to target transferrin receptors expressed on CNS vasculature, or an anti-EGFR antibody to target EGFR on glioma cells. In certain embodiments, the targeting ligand is one or more GalNAc moieties. In some embodiments, the targeting ligand is one or more lipid moieties.


In some embodiments, 1 or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides of the oligonucleotide are each conjugated to a separate targeting ligand. In some embodiments, 2 to 4 nucleotides of the oligonucleotide are each conjugated to a separate targeting ligand. In some embodiments, targeting ligands are conjugated to 2 to 4 nucleotides at either ends of the sense or antisense strand (e.g., targeting ligands are conjugated to a 2 to 4 nucleotide overhang or extension on the 5′ or 3′ end of the sense or antisense strand) such that the targeting ligands resemble bristles of a toothbrush and the oligonucleotide resembles a toothbrush. For example, the oligonucleotide may comprise a stem-loop at either the 5′ or 3′ end of the sense strand and 1, 2, 3, or 4 nucleotides of the loop of the stem may be individually conjugated to a targeting ligand. In some embodiments, the oligonucleotide comprises a stem-loop at the 3′ end of the sense strand, wherein the loop of the stem-loop comprises a triL or a tetraL, and wherein the 3 or 4 nucleotides comprising the triL or tetraL, respectfully, are individually conjugated to a targeting ligand. In some embodiments, the oligonucleotide comprises a blunt end at the 3′ end of the oligonucleotide and one or more targeting ligands conjugated to at least one nucleotide. In some embodiments, the oligonucleotide comprises a blunt end at the 3′ end of the oligonucleotide and one or more targeting ligands conjugated to the 5′ terminal nucleotide of the sense strand.


GalNAc Conjugation


GalNAc is a high affinity ligand for the asialoglycoprotein receptor (ASGPR), which is primarily expressed on the sinusoidal surface of hepatocyte cells and has a major role in binding, internalizing and subsequent clearing circulating glycoproteins that contain terminal galactose or GalNAc residues (asialoglycoproteins). Conjugation (either indirect or direct) of GalNAc moieties to the oligonucleotides herein can be used to target them to ASGPR expressed on cells. In some embodiments, the oligonucleotide is conjugated to at least one or more GalNAc moieties, wherein the GalNAc moieties target the oligonucleotide to ASGPR expressed on human liver cells (e.g., human hepatocytes). In some embodiments, the GalNAc moiety target the oligonucleotide to the liver.


In some embodiments, the oligonucleotide is conjugated directly or indirectly to a monovalent GalNAc. In some embodiments, the oligonucleotide is conjugated directly or indirectly to more than one monovalent GalNAc (i.e., is conjugated to 2, 3, or 4 monovalent GalNAc moieties, and is typically conjugated to 3 or 4 monovalent GalNAc moieties). In some embodiments, the oligonucleotide is conjugated to one or more bivalent GalNAc, trivalent GalNAc, or tetravalent GalNAc moieties. In some embodiments, the bivalent, trivalent, or tetravalent GalNAc moiety is conjugated to the oligonucleotide via a branched linker. In some embodiments, the monovalent GalNAc moiety is conjugated to a first nucleotide and the bivalent, trivalent, or tetravalent GalNAc moiety is conjugated to a second nucleotide via a branched linker.


In some embodiments, 1 or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides of the oligonucleotide are each conjugated to a GalNAc moiety. In some embodiments, 2 to 4 nucleotides of a tetraL are each conjugated to a separate GalNAc. In some embodiments, 1 to 3 nucleotides of a triL are each conjugated to a separate GalNAc. In some embodiments, targeting ligands are conjugated to 2 to 4 nucleotides at either ends of the sense or antisense strand (e.g., ligands are conjugated to a 2 to 4 nucleotide overhang or extension on the 5′ or 3′ end of the sense or antisense strand) such that the GalNAc moieties resemble bristles of a toothbrush and the oligonucleotide resembles a toothbrush. In some embodiments, GalNAc moieties are conjugated to a nucleotide of the sense strand. For example, 4 GalNAc moieties can be conjugated to nucleotides in the tetraL of the sense strand where each GalNAc moiety is conjugated to 1 nucleotide.


In some embodiments, the oligonucleotide comprises a tetraL, wherein the tetraL is any combination of adenine (A) and guanine (G) nucleotides. In some embodiments, the tetraL comprises a monovalent GalNAc moiety attached to any one or more guanine (G) nucleotides of the tetraloop via any linker described herein, as depicted below (X=heteroatom):




embedded image


In some embodiments, the tetraL has a monovalent GalNAc attached to any one or more adenine nucleotides of the tetraloop via any linker described herein, as depicted below (X=heteroatom):




embedded image


In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a monovalent GalNAc attached to a guanine nucleotide referred to as [ademG-GalNAc] or 2′-aminodiethoxymethanol-Guanine-GalNAc, as depicted below:




embedded image


In some embodiments, an oligonucleotide herein comprises a monovalent GalNAc attached to an adenine nucleotide, referred to as [ademA-GalNAc] or 2′-aminodiethoxymethanol-Adenine-GalNAc, as depicted below:




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An example of such conjugation is shown below for a loop comprising from 5′ to 3′ the nucleotide sequence GAAA (L=linker, X=heteroatom) stem attachment points are shown. Such a loop may be present, for example, at positions 27-30 of the sense strand of any one of the sense strands listed in Tables 4 and 5. In the chemical formula,




embedded image


is used to describe an attachment point to the oligonucleotide strand:




embedded image


Appropriate methods or chemistry (e.g., click chemistry) can be used to link a targeting ligand to a nucleotide. In some embodiments, a targeting ligand is conjugated to a nucleotide using a click linker. In some embodiments, an acetal-based linker is used to conjugate a targeting ligand to a nucleotide of any one of the oligonucleotides described herein. Acetal-based linkers are disclosed, for example, in Intl. Patent Application Publication No. WO 2016/100401. In some embodiments, the linker is a labile linker. However, in other embodiments, the linker is stable. Examples are shown below for a loop comprising from 5′ to 3′ the nucleotides GAAA, in which GalNAc moieties are attached to 3 or 4 nucleotides of the loop using an acetal linker. Such a loop may be present, for example, at positions 27-30 of the any one of the sense strands listed in Tables 4 and 5. In the chemical formula,




embedded image


is an attachment point to the oligonucleotide strand:




embedded image


embedded image


As mentioned, various appropriate methods or chemistry synthetic techniques (e.g., click chemistry) can be used to link a targeting ligand to a nucleotide. In some embodiments, a targeting ligand is conjugated to a nucleotide using a click linker. In some embodiments, an acetal-based linker is used to conjugate a targeting ligand to a nucleotide of any one of the oligonucleotides described herein. Acetal-based linkers are disclosed, for example, in Intl. Patent Application Publication No. WO 2016/100401. In some embodiments, the linker is a labile linker. However, in other embodiments, the linker is a stable linker.


In some embodiments, a duplex extension (e.g., of up to 3, 4, 5, or 6 bp in length) is provided between a targeting ligand (e.g., a GalNAc moiety) and a RNAi oligonucleotide. In some embodiments, the oligonucleotides herein do not have a GalNAc conjugated thereto.


In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 769 and 804, respectively;
    • b) SEQ ID NOs: 770 and 805, respectively;
    • c) SEQ ID NOs: 771 and 806, respectively;
    • d) SEQ ID NOs: 772 and 807, respectively;
    • e) SEQ ID NOs: 773 and 808, respectively;
    • f) SEQ ID NOs: 774 and 809, respectively;
    • g) SEQ ID NOs: 775 and 810, respectively;
    • h) SEQ ID NOs: 776 and 811, respectively;
    • i) SEQ ID NOs: 777 and 812, respectively;
    • j) SEQ ID NOs: 778 and 813, respectively;
    • k) SEQ ID NOs: 779 and 814, respectively;
    • l) SEQ ID NOs: 780 and 815, respectively;
    • m) SEQ ID NOs: 781 and 816, respectively;
    • n) SEQ ID NOs: 782 and 817, respectively;
    • o) SEQ ID NOs: 783 and 818, respectively;
    • p) SEQ ID NOs: 784 and 819, respectively;
    • q) SEQ ID NOs: 785 and 820, respectively;
    • r) SEQ ID NOs: 786 and 821, respectively;
    • s) SEQ ID NOs: 787 and 822, respectively;
    • t) SEQ ID NOs: 788 and 823, respectively;
    • u) SEQ ID NOs: 789 and 824, respectively;
    • v) SEQ ID NOs: 790 and 825, respectively;
    • w) SEQ ID NOs: 791 and 826, respectively;
    • x) SEQ ID NOs: 792 and 827, respectively;
    • y) SEQ ID NOs: 793 and 828, respectively;
    • z) SEQ ID NOs: 794 and 829, respectively;
    • aa) SEQ ID NOs: 795 and 830, respectively;
    • bb) SEQ ID NOs: 796 and 831, respectively;
    • cc) SEQ ID NOs: 797 and 832, respectively;
    • dd) SEQ ID NOs: 798 and 833, respectively;
    • ee) SEQ ID NOs: 799 and 834, respectively;
    • ff) SEQ ID NOs: 800 and 835, respectively;
    • gg) SEQ ID NOs: 801 and 836, respectively;
    • hh) SEQ ID NOs: 802 and 837, respectively; and
    • ii) SEQ ID NOs: 803 and 838, respectively, wherein the oligonucleotide comprises at least one GalNAc moiety conjugated to a nucleotide.


In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively; and
    • j) SEQ ID NOs: 803 and 838, respectively, wherein the oligonucleotide comprises at least one GalNAc moiety conjugated to a nucleotide.


In some embodiments, the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 780 and 815, respectively;
    • c) SEQ ID NOs: 781 and 816, respectively;
    • d) SEQ ID NOs: 798 and 833, respectively;
    • e) SEQ ID NOs: 799 and 834, respectively; and
    • f) SEQ ID NOs: 803 and 838, respectively, wherein the oligonucleotide comprises at least one GalNAc moiety conjugated to a nucleotide.


Lipid Conjugation

In some embodiments, one or more lipid moieties are conjugated to a 5′ terminal nucleotide of a sense strand. In some embodiments, one or more lipid moieties are conjugated to an adenine nucleotide. In some embodiments, one or more lipid moieties are conjugated to a guanine nucleotide. In some embodiments, one or more lipid moieties are conjugated to a cytosine nucleotide. In some embodiments, one or more lipid moieties are conjugated to a thymine nucleotide. In some embodiments, one or more lipid moieties are conjugated to a uracil nucleotide.


In some embodiments, the lipid moiety is a hydrocarbon chain. In some embodiments, the hydrocarbon chain is saturated. In some embodiments, the hydrocarbon chain is unsaturated. In some embodiments, the hydrocarbon chain is branched. In some embodiments, the hydrocarbon chain is straight. In some embodiments, the lipid moiety is a C8-C30 hydrocarbon chain. In some embodiments, the lipid moiety is a C8:0, C10:0, C11:0, C12:0, C14:0, C16:0, C17:0, C18:0, C18:1, C18:2, C22:5, C22:O, C24:0, C26:0, C22:6, C24:1, diacyl C16:0 or diacyl C18:1. In some embodiments, the lipid moiety is a C16 hydrocarbon chain. In some embodiments, the C16 hydrocarbon chain is represented as:




embedded image


In some embodiments, the sense strand is 20-22 nucleotides in length and the lipid moiety is a hydrocarbon chain that is conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the sense strand is 20-22 nucleotides in length and the hydrocarbon chain is conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the sense strand is 20-22 nucleotides in length and a C14-C22 hydrocarbon chain is conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the sense strand is 20-22 nucleotides in length and a C16 hydrocarbon chain is conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the sense strand is 20 nucleotides in length and the lipid moiety is conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the sense strand is 20 nucleotides in length and the lipid moiety is a hydrocarbon chain is conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the sense strand is 20 nucleotides in length and a C14-C22 hydrocarbon chain is conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the sense strand is 20 nucleotides in length and a C16 hydrocarbon chain is conjugated to the 5′ terminal nucleotide of the sense strand.


In some embodiments, the oligonucleotide comprises (i) a sense strand of 20-22 nucleotides in length; (ii) an antisense strand comprising a 3′ overhang sequence of one or more nucleotides in length; (iii) a blunt end comprising the 3′ end of the sense strand; and (iv) a lipid moiety conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) a sense strand of 20-22 nucleotides in length; (ii) an antisense strand comprising a 3′ overhang sequence of one or more nucleotides in length; (iii) a blunt end comprising the 3′ end of the sense strand; and (iv) a hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) a sense strand of 20-22 nucleotides in length; (ii) an antisense strand comprising a 3′ overhang sequence of one or more nucleotides in length; (iii) a blunt end comprising the 3′ end of the sense strand; and (iv) a C14-C22 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) a sense strand of 20-22 nucleotides in length; (ii) an antisense strand comprising a 3′ overhang sequence of one or more nucleotides in length; (iii) a blunt end comprising the 3′ end of the sense strand; and (iv) a C16 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand.


In some embodiments, the oligonucleotide comprises (i) a sense strand of 20 nucleotides in length; (ii) an antisense strand of 22 nucleotides in length comprising a 3′ overhang sequence of two nucleotides in length; (iii) a blunt end comprising the 3′ end of the sense strand; and (iv) a lipid moiety conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) a sense strand of 20 nucleotides in length; (ii) an antisense strand of 22 nucleotides in length comprising a 3′ overhang sequence of two nucleotides in length; (iii) a blunt end comprising the 3′ end of the sense strand; and (iv) a hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) a sense strand of 20 nucleotides in length; (ii) an antisense strand of 22 nucleotides in length comprising a 3′ overhang sequence of two nucleotides in length; (iii) a blunt end comprising the 3′ end of the sense strand; and (iv) a C14-C22 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) a sense strand of 20 nucleotides in length; (ii) an antisense strand of 22 nucleotides in length comprising a 3′ overhang sequence of two nucleotides in length; (iii) a blunt end comprising the 3′ end of the sense strand; and (iv) a C16 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand.


In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, and 1124; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a lipid moiety conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1061, 1108, 1119, 1120, 1124, 1130, 1065, 1095, 1096, and 1102; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a lipid moiety conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a lipid moiety conjugated to the 5′ terminal nucleotide of the sense strand.


In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, and 1124; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1061, 1108, 1119, 1120, 1124, 1130, 1065, 1095, 1096, and 1102; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand.


In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, and 1124; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a C14-C22 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1061, 1108, 1119, 1120, 1124, 1130, 1065, 1095, 1096, and 1102; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a C14-C22 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a C14-C22 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand.


In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1125, 1127, 1130, 1019, 1031, 1044, 1064, 1065, 1067, 1083, 915, 1095, 1096, 1102, 1110, 923, 925, 1025, 1039, 1049, 1061, 1070, 1072, 1075, 1081, 1108, 1111, 1114, 1119, 1120, 1121, 1122, 1123, and 1124; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a C16 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1061, 1108, 1119, 1120, 1124, 1130, 1065, 1095, 1096, and 1102; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a C16 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides comprising a region of complementarity to a MAPT mRNA target sequence selected from SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124; (ii) a sense strand of 19-25 nucleotides that forms a duplex region with the antisense strand; and (iii) a C16 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand.


In some embodiments, the oligonucleotide comprises a sense strand comprising the nucleotide sequence of SEQ ID NO: 1681 and an antisense strand comprising the nucleotide sequence of SEQ ID NO: 815, wherein the sense strand comprises a lipid moiety conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises a sense strand comprising the nucleotide sequence of SEQ ID NO: 1681 and an antisense strand comprising the nucleotide sequence of SEQ ID NO: 815, wherein the sense strand comprises a hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises a sense strand comprising the nucleotide sequence of SEQ ID NO: 1681 and an antisense strand comprising the nucleotide sequence of SEQ ID NO: 815, wherein the sense strand comprises a C14-C22 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand. In some embodiments, the oligonucleotide comprises a sense strand comprising the nucleotide sequence of SEQ ID NO: 1681 and an antisense strand comprising the nucleotide sequence of SEQ ID NO: 815, wherein the sense strand comprises a C16 hydrocarbon chain conjugated to the 5′ terminal nucleotide of the sense strand.


Exemplary MAPT-Targeting RNAi Oligonucleotides


In some embodiments, the MAPT-targeting RNAi oligonucleotide for reducing MAPT gene expression provided by the current disclosure comprises a sense strand and an antisense strand, wherein all nucleotides comprising the sense strand and the antisense strand are modified, wherein the antisense strand comprises a region of complementarity to a MAPT mRNA target sequence of any one of SEQ ID NOs: 912-1295, and wherein the region of complementarity is at least 15 contiguous nucleotides in length. In some embodiments, the 5′ terminal nucleotide of the antisense strand comprises 4′-O-monomethylphosphonate-2′-O-methyluridine [MePhosphonate-40-mU], as described herein. In some embodiments, the 5′ terminal nucleotide of the antisense strand comprises a phosphorothioate linkage. In some embodiments, the antisense strand and the sense strand comprise one or more 2′-F- and 2′-OMe-modified nucleotides and at least one phosphorothioate linkage. In some embodiments, the antisense strand comprises 4 phosphorothioate linkages and the sense strand comprises 1 phosphorothioate linkage. In some embodiments, the antisense strand comprises 5 phosphorothioate linkages and the sense strand comprises 1 phosphorothioate linkage.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 912-1295 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 1296-1679.


In some embodiments, the oligonucleotide comprises a sense strand having a sequence of any one of SEQ ID NOs: 1-384 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 385-768.


In some embodiments, the oligonucleotide comprises a sense strand having a sequence of any one of SEQ ID NOs: 769-803 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 804-838.


In some embodiments, the oligonucleotide comprises a sense strand having a sequence of any one of SEQ ID NOs: 769-803 and 1681, and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 804-838.


In some embodiments, the oligonucleotide comprises a sense strand having a sequence of any one of SEQ ID NOs: 839-873 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 874-908.


In some embodiments, the oligonucleotide comprises a sense strand having a sequence of any one of SEQ ID NOs: 839-873 and 1681, and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 874-908.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises:

    • a sense strand of 36 nucleotides comprising a 2′-F-modified nucleotide at positions 3, 5, 8, 10, 12, 13, 15, and 17; a 2′-OMe-modified nucleotide at positions 1, 2, 4, 6, 7, 9, 11, 14, 16, 18-27, and 31-36; a GalNAc-conjugated nucleotide at position 28, 29, and 30; and a phosphorothioate linkage between positions 1 and 2; and
    • an antisense strand of 22 nucleotides comprising a 2′-F-modified nucleotide at positions 2, 3, 4, 5, 7, 10, 14, 16, and 19; a 2′-OMe-modified nucleotide at positions 1, 6, 8, 9, 11, 12, 13, 15, 17, 18, and 20-22; a phosphorothioate linkage between positions 1 and 2, positions 2 and 3, positions 20 and 21, and positions 21 and 22; and a 5′ terminal nucleotide at position 1 comprising a 4′-phosphate analog, optionally wherein the 5′ terminal nucleotide comprises 4′-O-monomethylphosphonate-2′-O-methyluridine [MePhosphonate-4O-mU]; wherein positions 1-20 of the antisense strand form a duplex region with positions 1-20 of the sense strand, wherein positions 21-36 of the sense strand form a stem-loop, wherein positions 27-30 form the loop of the stem-loop, optionally wherein positions 27-30 comprise a tetraL, wherein positions 21 and 22 of the antisense strand comprise an overhang, and wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:
    • a) SEQ ID NOs: 769 and 804, respectively;
    • b) SEQ ID NOs: 770 and 805, respectively;
    • c) SEQ ID NOs: 771 and 806, respectively;
    • d) SEQ ID NOs: 772 and 807, respectively;
    • e) SEQ ID NOs: 773 and 808, respectively;
    • f) SEQ ID NOs: 774 and 809, respectively;
    • g) SEQ ID NOs: 775 and 810, respectively;
    • h) SEQ ID NOs: 776 and 811, respectively;
    • i) SEQ ID NOs: 777 and 812, respectively;
    • j) SEQ ID NOs: 778 and 813, respectively;
    • k) SEQ ID NOs: 779 and 814, respectively;
    • l) SEQ ID NOs: 780 and 815, respectively;
    • m) SEQ ID NOs: 781 and 816, respectively;
    • n) SEQ ID NOs: 782 and 817, respectively;
    • o) SEQ ID NOs: 783 and 818, respectively;
    • p) SEQ ID NOs: 784 and 819, respectively;
    • q) SEQ ID NOs: 785 and 820, respectively;
    • r) SEQ ID NOs: 786 and 821, respectively;
    • s) SEQ ID NOs: 787 and 822, respectively;
    • t) SEQ ID NOs: 788 and 823, respectively;
    • u) SEQ ID NOs: 789 and 824, respectively;
    • v) SEQ ID NOs: 790 and 825, respectively;
    • w) SEQ ID NOs: 791 and 826, respectively;
    • x) SEQ ID NOs: 792 and 827, respectively;
    • y) SEQ ID NOs: 793 and 828, respectively;
    • z) SEQ ID NOs: 794 and 829, respectively;
    • aa) SEQ ID NOs: 795 and 830, respectively;
    • bb) SEQ ID NOs: 796 and 831, respectively;
    • cc) SEQ ID NOs: 797 and 832, respectively;
    • dd) SEQ ID NOs: 798 and 833, respectively;
    • ee) SEQ ID NOs: 799 and 834, respectively;
    • ff) SEQ ID NOs: 800 and 835, respectively;
    • gg) SEQ ID NOs: 801 and 836, respectively;
    • hh) SEQ ID NOs: 802 and 837, respectively; and
    • ii) SEQ ID NOs: 803 and 838, respectively.


In some embodiments, an oligonucleotide (e.g., and RNAi oligonucleotide) for reducing MAPT gene expression comprises:

    • a sense strand of 36 nucleotides comprising a 2′-F-modified nucleotide at positions 3, 5, 8, 10, 12, 13, 15, and 17; a 2′-OMe-modified nucleotide at positions 1, 2, 4, 6, 7, 9, 11, 14, 16, 18-27, and 31-36; a GalNAc-conjugated nucleotide at position 28, 29, and 30; and a phosphorothioate linkage between positions 1 and 2; and
    • an antisense strand of 22 nucleotides comprising a 2′-F-modified nucleotide at positions 2, 3, 4, 5, 7, 10, 14, 16, and 19; a 2′-OMe-modified nucleotide at positions 1, 6, 8, 9, 11, 12, 13, 15, 17, 18, and 20-22; a phosphorothioate linkage between positions 1 and 2, positions 2 and 3, positions 20 and 21, and positions 21 and 22; and a 5′ terminal nucleotide at position 1 comprising a 4′-phosphate analog, optionally wherein the 5′ terminal nucleotide comprises 4′-O-monomethylphosphonate-2′-O-methyluridine [MePhosphonate-4O-mU]; wherein positions 1-20 of the antisense strand form a duplex region with positions 1-20 of the sense strand, wherein positions 21-36 of the sense strand form a stem-loop, wherein positions 27-30 form the loop of the stem-loop, optionally wherein positions 27-30 comprise a tetraloop, wherein positions 21 and 22 of the antisense strand comprise an overhang, and wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:
    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 776 and 811, respectively;
    • c) SEQ ID NOs: 780 and 815, respectively;
    • d) SEQ ID NOs: 781 and 816, respectively;
    • e) SEQ ID NOs: 782 and 817, respectively;
    • f) SEQ ID NOs: 790 and 825, respectively;
    • g) SEQ ID NOs: 795 and 830, respectively;
    • h) SEQ ID NOs: 798 and 833, respectively;
    • i) SEQ ID NOs: 799 and 834, respectively; and
    • j) SEQ ID NOs: 803 and 838, respectively.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises:

    • a sense strand of 36 nucleotides comprising a 2′-F-modified nucleotide at positions 3, 5, 8, 10, 12, 13, 15, and 17; a 2′-OMe-modified nucleotide at positions 1, 2, 4, 6, 7, 9, 11, 14, 16, 18-27, and 31-36; a GalNAc-conjugated nucleotide at position 28, 29, and 30; and a phosphorothioate linkage between positions 1 and 2; and
    • an antisense strand of 22 nucleotides comprising a 2′-F-modified nucleotide at positions 2, 3, 4, 5, 7, 10, 14, 16, and 19; a 2′-OMe-modified nucleotide at positions 1, 6, 8, 9, 11, 12, 13, 15, 17, 18, and 20-22; a phosphorothioate linkage between positions 1 and 2, positions 2 and 3, positions 20 and 21, and positions 21 and 22; and a 5′ terminal nucleotide at position 1 comprising a 4′-phosphate analog, optionally wherein the 5′ terminal nucleotide comprises 4′-O-monomethylphosphonate-2′-O-methyluridine [MePhosphonate-4O-mU]; wherein positions 1-20 of the antisense strand form a duplex region with positions 1-20 of the sense strand, wherein positions 21-36 of the sense strand form a stem-loop, wherein positions 27-30 form the loop of the stem-loop, optionally wherein positions 27-30 comprise a tetraloop, wherein positions 21 and 22 of the antisense strand comprise an overhang, and wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:
    • a) SEQ ID NOs: 771 and 806, respectively;
    • b) SEQ ID NOs: 780 and 815, respectively;
    • c) SEQ ID NOs: 781 and 816, respectively;
    • d) SEQ ID NOs: 798 and 833, respectively;
    • e) SEQ ID NOs: 799 and 834, respectively; and
    • f) SEQ ID NOs: 803 and 838, respectively.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises:

    • a sense strand of 20 nucleotides comprising a 2′-F-modified nucleotide at positions 3, 5, 8, 10, 12, 13, 15, and 17; a 2′-OMe-modified nucleotide at positions 2, 4, 6, 7, 9, 11, 14, 16, and 18-20; a C16 hydrocarbon chain conjugated to a nucleotide at position 1; and a phosphorothioate linkage between positions 1 and 2, between positions 18 and 19, and between positions 19 and 20; and
    • an antisense strand of 22 nucleotides comprising a 2′-F-modified nucleotide at positions 2, 3, 4, 5, 7, 10, 14, 16, and 19; a 2′-OMe modified-nucleotide at positions 1, 6, 8, 9, 11, 12, 13, 15, 17, 18, and 20-22; a phosphorothioate linkage between positions 1 and 2, positions 2 and 3, positions 20 and 21, and positions 21 and 22; and a 5′ terminal nucleotide at position 1 comprising a 4′-phosphate analog, optionally wherein the 5′ terminal nucleotide comprises 4′-O-monomethylphosphonate-2′-O-methyluridine [MePhosphonate-4O-mU]; wherein positions 1-20 of the antisense strand form a duplex region with positions 1-20 of the sense strand, wherein positions 21 and 22 of the antisense strand comprise an overhang, and wherein the sense strand and antisense strands comprise nucleotide sequences of SEQ ID NOs: 1681 and 815, respectively.


In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 771 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 806. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 780 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 815. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 781 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 816. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 798 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 833. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 799 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 834. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 803 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 838. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1681 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 815.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1479; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1480; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, a MAPT-targeting RNAi oligonucleotide for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1503; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1504; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1508; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1479; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the stem-loop is set forth as 51-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1480; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1503; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1504; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the stem-loop is set forth as 51-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1508; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1479; and (ii) a sense strand of 19-25 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the oligonucleotide comprises a blunt end comprising the 3′ end of the sense strand, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1130, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1479; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1095, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1480; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1096, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1503; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1119, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1504; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1120, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1508; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1124, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1130, wherein the stem-loop is set forth as 51-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1479; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1095, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1480; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1096, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1503; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1119, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1504; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1120, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1508; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′ terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1124, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a MAPT mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1479; and (ii) a sense strand of 19-25 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1095, wherein the oligonucleotide comprises a blunt end comprising the 3′ end of the sense strand, wherein the antisense and sense strands are separate strands that form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises a sense strand and an antisense strand according to:

    • Sense Strand: 5′-mX-S-mX-fX-mX-fX-mX-mX-fX-mX-fX-mX-fX-fX-mX-fX-mX-fX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-[ademX-GalNAc]-[ademX-GalNAc]-[ademX-GalNAc]-mX-mX-mX-mX-mX-mX-3′ hybridized to:
    • Antisense Strand: 5′-[MePhosphonate-4O-mX]-S-fX-S-fX-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-fX-mX-mX-fX-mX-S-mX-S-mX-3′, wherein mX=2′-OMe-modified nucleotide, fX=2′-F-modified nucleotide, -S-=phosphorothioate linkage, -=phosphodiester linkage, [MePhosphonate-4O-mX]=4′-O-monomethylphosphonate-2′-O-methyl-modified nucleotide, and ademX-GalNAc=GalNAc attached to a nucleotide.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises a sense strand and an antisense strand according to:

    • Sense Strand: 5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-[ademX-GalNAc]-[ademX-GalNAc]-[ademX-GalNAc]-mX-mX-mX-mX-mG-mX-3′ hybridized to:
    • Antisense Strand: 5′-[MePhosphonate-4O-mX]-S-fX-S-fX-S-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-3′, wherein mX=2′-OMe-modified nucleotide, fX=2′-F-modified nucleotide, -S-=phosphorothioate linkage, -=phosphodiester linkage, [MePhosphonate-4O-mX]=4′-O-monomethylphosphonate-2′-O-methyl modified nucleotide, and ademX-GalNAc=GalNAc attached to a nucleotide.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises a sense strand and an antisense strand according to:

    • Sense Strand: 5′-[AdemX-L]-S-mX-fX-mX-fX-mX-mX-fX-mX-fX-mX-fX-fX-mX-fX-mX-fX-mX-S-mX-S-mX-3′ hybridized to:
    • Antisense Strand: 5′-[MePhosphonate-4O-mX]-S-fX-S-fX-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-fX-mX-mX-fX-mX-S-mX-S-mX-3′, wherein mX=2′-OMe-modified nucleotide, fX=2′-F-modified nucleotide, -S-=phosphorothioate linkage, -=phosphodiester linkage, [MePhosphonate-4O-mX]=4′-O-monomethylphosphonate-2′-O-methyl modified nucleotide, and ademX-L=lipid moiety attached to a nucleotide.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises a sense strand and an antisense strand according to:

    • Sense Strand: 5′-[AdemX-C16]-S-mX-fX-mX-fX-mX-mX-fX-mX-fX-mX-fX-fX-mX-fX-mX-fX-mX-S-mX-S-mX-3′ hybridized to:
    • Antisense Strand: 5′-[MePhosphonate-4O-mX]-S-fX-S-fX-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-fX-mX-mX-fX-mX-S-mX-S-mX-3′, wherein mX=2′-OMe-modified nucleotide, fX=2′-F-modified nucleotide, -S-=phosphorothioate linkage, -=phosphodiester linkage, [MePhosphonate-4O-mX]=4′-O-monomethylphosphonate-2′-O-methyl modified nucleotide, and ademX-C16=C16 hydrocarbon chain attached to a nucleotide.


In some embodiments, the current disclosure provides an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression, wherein the oligonucleotide comprises a sense strand and an antisense strand comprising nucleotide sequences selected from the group consisting of:

    • a) SEQ ID NOs: 839 and 874, respectively;
    • b) SEQ ID NOs: 840 and 875, respectively;
    • c) SEQ ID NOs: 841 and 876, respectively;
    • d) SEQ ID NOs: 842 and 877, respectively;
    • e) SEQ ID NOs: 843 and 878, respectively;
    • f) SEQ ID NOs: 844 and 879, respectively;
    • g) SEQ ID NOs: 845 and 880, respectively;
    • h) SEQ ID NOs: 846 and 881, respectively;
    • i) SEQ ID NOs: 847 and 882, respectively;
    • j) SEQ ID NOs: 848 and 883, respectively;
    • k) SEQ ID NOs: 849 and 884, respectively;
    • l) SEQ ID NOs: 850 and 885, respectively;
    • m) SEQ ID NOs: 851 and 886, respectively;
    • n) SEQ ID NOs: 852 and 887, respectively;
    • o) SEQ ID NOs: 853 and 888, respectively;
    • p) SEQ ID NOs: 854 and 889, respectively;
    • q) SEQ ID NOs: 855 and 890, respectively;
    • r) SEQ ID NOs: 856 and 891, respectively;
    • s) SEQ ID NOs: 857 and 892, respectively;
    • t) SEQ ID NOs: 858 and 893, respectively;
    • u) SEQ ID NOs: 859 and 894, respectively;
    • v) SEQ ID NOs: 860 and 895, respectively;
    • w) SEQ ID NOs: 861 and 896, respectively;
    • x) SEQ ID NOs: 862 and 897, respectively;
    • y) SEQ ID NOs: 863 and 898, respectively;
    • z) SEQ ID NOs: 864 and 899, respectively;
    • aa) SEQ ID NOs: 865 and 900, respectively;
    • bb) SEQ ID NOs: 866 and 901, respectively;
    • cc) SEQ ID NOs: 867 and 902, respectively;
    • dd) SEQ ID NOs: 868 and 903, respectively;
    • ee) SEQ ID NOs: 869 and 904, respectively;
    • ff) SEQ ID NOs: 870 and 905, respectively;
    • gg) SEQ ID NOs: 871 and 906, respectively;
    • hh) SEQ ID NOs: 872 and 907, respectively;
    • ii) SEQ ID NOs: 873 and 908, respectively; and
    • jj) SEQ ID NOs: 1682 and 885, respectively.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises a sense strand and an antisense strand comprising nucleotide sequences selected from the group consisting of:

    • a) SEQ ID NOs: 860 and 895, respectively;
    • b) SEQ ID NOs: 865 and 900, respectively;
    • c) SEQ ID NOs: 868 and 903, respectively;
    • d) SEQ ID NOs: 869 and 904, respectively;
    • e) SEQ ID NOs: 873 and 908, respectively;
    • f) SEQ ID NOs: 841 and 876, respectively;
    • g) SEQ ID NOs: 846 and 881, respectively;
    • h) SEQ ID NOs: 850 and 885, respectively;
    • i) SEQ ID NOs: 851 and 886, respectively;
    • j) SEQ ID NOs: 852 and 887, respectively; and
    • k) SEQ ID NOs: 1682 and 885, respectively.


In some embodiments, an oligonucleotide (e.g., a RNAi oligonucleotide) for reducing MAPT gene expression comprises a sense strand and an antisense strand comprising nucleotide sequences selected from the group consisting of:

    • a) SEQ ID NOs: 841 and 876, respectively;
    • b) SEQ ID NOs: 850 and 885, respectively;
    • c) SEQ ID NOs: 851 and 886, respectively;
    • d) SEQ ID NOs: 868 and 903, respectively;
    • e) SEQ ID NOs: 869 and 904, respectively;
    • f) SEQ ID NOs: 873 and 908, respectively; and
    • g) SEQ ID NOs: 1682 and 885, respectively.


In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 841 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 876. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 850 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 885. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 851 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 886. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 868 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 903. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 869 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 904. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 873 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 908. In some embodiments, an oligonucleotide for reducing MAPT gene expression comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1682 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 885.


Formulations


Various formulations have been developed to facilitate oligonucleotide use. For example, oligonucleotides (e.g., RNAi oligonucleotides) can be delivered to a subject or a cellular environment using a formulation that minimizes degradation, facilitates delivery and/or uptake, or provides another beneficial property to the oligonucleotides in the formulation. In some embodiments, provided herein are compositions comprising oligonucleotides reduce MAPT gene expression. Such compositions can be suitably formulated such that when administered to a subject, either into the immediate environment of a target cell or systemically, a sufficient portion of the oligonucleotides enter the cell to reduce MAPT gene expression. Any variety of suitable oligonucleotide formulations can be used to deliver oligonucleotides for the reduction of MAPT gene expression as disclosed herein. In some embodiments, an oligonucleotide is formulated in buffer solutions such as phosphate buffered saline solutions, liposomes, micellar structures, and capsids. In some embodiments, an oligonucleotide is formulated in buffer solutions such as phosphate buffered saline solutions.


Formulations of oligonucleotides with cationic lipids can be used to facilitate transfection of the oligonucleotides into cells. For example, cationic lipids, such as lipofectin, cationic glycerol derivatives, and polycationic molecules (e.g., polylysine, can be used. Suitable lipids include Oligofectamine, Lipofectamine (Life Technologies), NC388 (Ribozyme Pharmaceuticals, Inc., Boulder, Colo.), or FuGene 6 (Roche) all of which can be used according to the manufacturer's instructions. In some embodiments, an oligonucleotide is not formulated with a component to facilitate transfection into cells.


Accordingly, in some embodiments, a formulation comprises a lipid nanoparticle. In some embodiments, an excipient comprises a liposome, a lipid, a lipid complex, a microsphere, a microparticle, a nanosphere or a nanoparticle, or may be otherwise formulated for administration to the cells, tissues, organs, or body of a subject in need thereof (see, e.g., Remington: THE SCIENCE AND PRACTICE OF PHARMACY, 22nd edition, Pharmaceutical Press, 2013).


In some embodiments, the formulations herein comprise an excipient. In some embodiments, an excipient confers to a composition improved stability, improved absorption, improved solubility and/or therapeutic enhancement of the active ingredient. In some embodiments, an excipient is a buffering agent (e.g., sodium citrate, sodium phosphate, a tris base, or sodium hydroxide) or a vehicle (e.g., a buffered solution, petrolatum, dimethyl sulfoxide, or mineral oil). In some embodiments, an oligonucleotide is lyophilized for extending its shelf-life and then made into a solution before use (e.g., administration to a subject). Accordingly, an excipient in a composition comprising any one of the oligonucleotides described herein may be a lyoprotectant (e.g., mannitol, lactose, polyethylene glycol, or polyvinylpyrrolidone) or a collapse temperature modifier (e.g., dextran, Ficoll™, or gelatin).


In some embodiments, a pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous, intramuscular, intraperitoneal, intradermal, subcutaneous), oral (e.g., inhalation), transdermal (e.g., topical), transmucosal, and rectal administration.


In some embodiments, a pharmaceutical composition is formulated for administration into the central nervous system. In some embodiments, a pharmaceutical composition is formulated for administration into the cerebral spinal fluid. In some embodiments, a pharmaceutical composition is formulated for administration to the spinal cord. In some embodiments, a pharmaceutical composition is formulated for intrathecal administration. In some embodiments, a pharmaceutical composition is formulated for administration to the brain. In some embodiments, a pharmaceutical composition is formulated for intracerebroventricular administration. In some embodiments, a pharmaceutical composition is formulated for the brain stem. In some embodiments, a pharmaceutical composition is formulated for intracisternal magna administration.


Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF), or phosphate buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and/or sodium chloride in the composition. Sterile injectable solutions can be prepared by incorporating the oligonucleotides in a required amount in a selected solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.


In some embodiments, a composition may contain at least about 0.1% of the therapeutic agent (e.g., a RNAi oligonucleotide for reducing MAPT gene expression) or more, although the percentage of the active ingredient(s) may be between about 1% to about 80% or more of the weight or volume of the total composition. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable.


Methods of Use


Reducing MAPT Gene Expression


In some embodiments, the disclosure provides methods for contacting or delivering to a cell or population of cells an effective amount of any of the oligonucleotides (e.g., RNAi oligonucleotides) herein to reduce MAPT gene expression. In some embodiments, a reduction of MAPT gene expression is determined by measuring a reduction in the amount or level of MAPT mRNA, Tau protein, or Tau activity in a cell. The methods include those described herein and known to one of ordinary skill in the art.


In some embodiments, the disclosure provides methods for reducing MAPT gene expression in the CNS. In some embodiments, the CNS comprises the brain and spinal cord. In some embodiments, MAPT gene expression is reduced in at least one region of the brain. In some embodiments, regions of the brain cervical spinal cord, thoracic spinal cord, lumbar spinal cord, frontal cortex, temporal cortex, cerebellum, midbrain, occipital cortex, parietal cortex, hippocampus, caudate nucleus, thalamus, and brainstem. In some embodiments, MAPT gene expression is reduced in at least one region of the spinal cord. In some embodiments, regions of the spinal cord include the cervical spinal cord, thoracic spinal cord, and lumbar spinal cord. In some embodiments, MAPT gene expression is reduced in at least one region of the brain and at least one region of the spinal cord. In some embodiments, MAPT gene expression is reduced in at least one of the cervical spinal cord, thoracic spinal cord, lumbar spinal cord, frontal cortex, temporal cortex, cerebellum, midbrain, occipital cortex, parietal cortex, hippocampus, caudate nucleus, thalamus, brainstem, motor cortex, globus pallidus, midbrain tegmentum, substantia nigra, pons, cerebellar white matter, and cerebellar dentate nucleus. In some embodiments, MAPT gene expression is reduced in at least one of the lumbar spinal cord, thoracic spinal cord, and cervical spinal cord. In some embodiments, MAPT gene expression is reduced in tissue of the brain and/or spinal cord associated with Alzheimer's disease. In some embodiments, tissue associated with AD includes, but is not limited to, prefrontal cortex, motor cortex, temporal cortex, parietal cortex, and hippocampus. In some embodiments, MAPT gene expression is reduced in tissue of the brain and/or spinal cord associated with progressive supranuclear palsy. In some embodiments, tissue associated with AD includes, but is not limited to caudate nucleus, globus pallidus, thalamus, midbrain tegmentum, substantia nigra, pons, cerebellar white matter, cerebellar dentate nucleus, medulla, cervical spinal cord, thoracic spinal cord, and lumbar spinal cord.


In some embodiments, MAPT gene expression is reduced for about 1 week to about 12 weeks after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks after administration of an oligonucleotide described herein. In some embodiments, MAPT expression is reduced for about 1 to about 4 months after administration of an oligonucleotide described herein. In some embodiments, MAPT expression is reduced for about 1 to about 6 months after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced for 1, 2, 3, or 4 months after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced for 1, 2, 3 4, 5, or 6 months after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced for about 7 to about 91 days after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced for 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, or 91 days after administration of an oligonucleotide described herein.


In some embodiments, MAPT gene expression is reduced in at least one region of the brain and/or at least one region of the spinal cord for about 1 to about 12 weeks after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced in at least one region of the brain and/or at least one region of the spinal cord for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced in at least one region of the brain and/or at least one region of the spinal cord for about 1 to about 4 months after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced in at least one region of the brain and/or at least one region of the spinal cord for about 1 to about 6 months after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced in at least one region of the brain and/or at least one region of the spinal cord for 1, 2, 3, or 4 months after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced in at least one region of the brain and/or at least one region of the spinal cord for 1, 2, 3 4, 5, or 6 months after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced in at least one region of the brain and/or at least one region of the spinal cord for about 7 to about 91 days after administration of an oligonucleotide described herein. In some embodiments, MAPT gene expression is reduced in at least one region of the brain and/or at least one region of the spinal cord for 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, or 91 days after administration of an oligonucleotide described herein.


Methods provided herein are useful in any appropriate cell type. In some embodiments, a cell is any cell that expresses MAPT mRNA (e.g., oligodendrocyte). In some embodiments, the cell is a primary cell obtained from a subject. In some embodiments, the primary cell has undergone a limited number of passages such that the cell substantially maintains is natural phenotypic properties. In some embodiments, a cell to which the oligonucleotide is delivered is ex vivo or in vitro (i.e., can be delivered to a cell in culture or to an organism in which the cell resides).


In some embodiments, the oligonucleotides disclosed herein are delivered to a cell or population of cells using a nucleic acid delivery method known in the art including, but not limited to, injection of a solution or pharmaceutical composition containing the oligonucleotide, bombardment by particles covered by the oligonucleotide, exposing the cell or population of cells to a solution containing the oligonucleotide, or electroporation of cell membranes in the presence of the oligonucleotide. Other methods known in the art for delivering oligonucleotides to cells may be used, such as lipid-mediated carrier transport, chemical-mediated transport, and cationic liposome transfection such as calcium phosphate, and others.


In some embodiments, reduction of MAPT gene expression is determined by an assay or technique that evaluates one or more molecules, properties or characteristics of a cell or population of cells associated with MAPT gene expression, or by an assay or technique that evaluates molecules that are directly indicative of MAPT gene expression in a cell or population of cells (e.g., MAPT mRNA or Tau protein). In some embodiments, the extent to which an oligonucleotide reduces MAPT gene expression is evaluated by comparing MAPT gene expression in a cell or population of cells contacted with the oligonucleotide to a control cell or population of cells (e.g., a cell or population of cells not contacted with the oligonucleotide or contacted with a control oligonucleotide). In some embodiments, a control amount or level of MAPT gene expression in a control cell or population of cells is predetermined, such that the control amount or level need not be measured in every instance the assay or technique is performed. The predetermined level or value can take a variety of forms. In some embodiments, a predetermined level or value can be single cut-off value, such as a median or mean.


In some embodiments, contacting or delivering an oligonucleotide to a cell or a population of cells results in a reduction in MAPT gene expression. In some embodiments, the reduction in MAPT gene expression is relative to a control amount or level of MAPT gene expression in cell or population of cells not contacted with the oligonucleotide or contacted with a control oligonucleotide. In some embodiments, the reduction in MAPT gene expression is about 1% or lower, about 5% or lower, about 10% or lower, about 15% or lower, about 20% or lower, about 25% or lower, about 30% or lower, about 35% or lower, about 40% or lower, about 45% or lower, about 50% or lower, about 55% or lower, about 60% or lower, about 70% or lower, about 80% or lower, or about 90% or lower relative to a control amount or level of MAPT gene expression. In some embodiments, the control amount or level of MAPT gene expression is an amount or level of MAPT mRNA and/or Tau protein in a cell or population of cells that has not been contacted with an oligonucleotide herein. In some embodiments, the effect of delivery of an oligonucleotide to a cell or population of cells according to a method herein is assessed after any finite period or amount of time (e.g., minutes, hours, days, weeks, months). For example, in some embodiments, MAPT gene expression is determined in a cell or population of cells at least about 4 hours, about 8 hours, about 12 hours, about 18 hours, about 24 hours; or at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, about 56 days, about 63 days, about 70 days, about 77 days, about 84 days, or more after contacting or delivering the oligonucleotide to the cell or population of cells. In some embodiments, MAPT gene expression is determined in a cell or population of cells at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or more after contacting or delivering the oligonucleotide to the cell or population of cells.


In some embodiments, the oligonucleotide is delivered in the form of a transgene that is engineered to express in a cell the oligonucleotide or strands comprising the oligonucleotide (e.g., its sense and antisense strands). In some embodiments, the oligonucleotide is delivered using a transgene engineered to express any oligonucleotide disclosed herein. Transgenes may be delivered using viral vectors (e.g., adenovirus, retrovirus, vaccinia virus, poxvirus, adeno-associated virus, or herpes simplex virus) or non-viral vectors (e.g., plasmids or synthetic mRNAs). In some embodiments, transgenes can be injected directly to a subject.


Treatment Methods


The disclosure also provides oligonucleotides (e.g., RNAi oligonucleotides) for use, or adaptable for use, to treat a subject (e.g., a human having a disease, disorder, or condition associated withMAPT gene expression) that would benefit from reducing MAPT gene expression. In some aspects, the disclosure provides oligonucleotides for use, or adapted for use, to treat a subject having a disease, disorder, or condition associated with MAPT gene expression. The disclosure also provides oligonucleotides for use, or adaptable for use, in the manufacture of a medicament or pharmaceutical composition for treating a disease, disorder, or condition associated with MAPT gene expression. In some embodiments, the oligonucleotides for use, or adaptable for use, target MAPT mRNA and reduce MAPT gene expression (e.g., via the RNAi pathway). In some embodiments, the oligonucleotides for use, or adaptable for use, target MAPT mRNA and reduce the amount or level of MAPT mRNA, Tau protein, and/or Tau activity.


In addition, in some embodiments of the methods herein, a subject having a disease, disorder or condition associated with MAPT gene expression or is predisposed to the same is selected for treatment with an oligonucleotide (e.g., a ds oligonucleotide) herein. In some embodiments, the method comprises selecting an individual having a marker (e.g., a biomarker) for a disease, disorder, or condition associated with MAPT gene expression, or predisposed to the same, such as, but not limited to, MAPT mRNA, Tau protein, or a combination thereof. Likewise, and as detailed below, some embodiments of the methods provided by the disclosure include steps such as measuring or obtaining a baseline value for a marker of MAPT gene expression (e.g., Tau protein or Tau activity), and then comparing such obtained value to one or more other baseline values or values obtained after the subject is administered the oligonucleotide to assess the effectiveness of treatment.


The disclosure also provides methods of treating a subject having, suspected of having, or at risk of developing a disease, disorder, or condition associated with MAPT gene expression with an oligonucleotide provided herein. In some aspects, the disclosure provides methods of treating or attenuating the onset or progression of a disease, disorder, or condition associated with MAPT gene expression using the oligonucleotides provided herein. In other aspects, the disclosure provides methods to achieve one or more therapeutic benefits in a subject having a disease, disorder, or condition associated with MAPT gene expression using the oligonucleotides provided herein. In some embodiments of the methods herein, the subject is treated by administering a therapeutically effective amount of any one or more of the oligonucleotides provided herein. In some embodiments, treatment comprises reducing MAPT gene expression. In some embodiments, the subject is treated therapeutically. In some embodiments, the subject is treated prophylactically.


In some embodiments of the methods herein, an oligonucleotide (e.g., a RNAi oligonucleotide), or a pharmaceutical composition comprising the oligonucleotide, is administered to a subject having a disease, disorder, or condition associated with MAPT gene expression such that MAPT gene expression is reduced in the subject, thereby treating the subject. In some embodiments, an amount or level of MAPT mRNA is reduced in the subject. In some embodiments, an amount or level of Tau protein is reduced in the subject.


In some embodiments of the methods herein, the oligonucleotide, or a pharmaceutical composition comprising the oligonucleotide, is administered to a subject having a disease, disorder, or condition associated with MAPT gene expression such that MAPT gene expression is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to MAPT gene expression prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments of the methods herein, the oligonucleotide, or the pharmaceutical composition comprising the oligonucleotide, is administered to a subject having a disease, disorder, or condition associated with MAPT gene expression such that MAPT gene expression is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% for about 1 week to about 12 weeks, about 1 month to about 6 months, or about 7 days to about 91 days when compared to MAPT gene expression prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, MAPT gene expression is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to MAPT gene expression in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or pharmaceutical composition or receiving a control oligonucleotide, pharmaceutical composition or treatment. In some embodiments, MAPT gene expression is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% for about 1 week to about 12 weeks, about 1 month to about 6 months, or about 7 days to about 91 days when compared to MAPT gene expression in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or pharmaceutical composition or receiving a control oligonucleotide, pharmaceutical composition or treatment.


In some embodiments of the methods herein, the oligonucleotide or the pharmaceutical composition is administered to a subject having a disease, disorder, or condition associated with MAPT gene expression such that an amount or level of MAPT mRNA is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to the amount or level of MAPT mRNA prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments of the methods, the oligonucleotide or the pharmaceutical composition is administered to a subject having a disease, disorder, or condition associated with MAPT gene expression such that an amount or level of MAPT mRNA is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% for about 1 week to about 12 weeks, about 1 month to about 6 months, or about 7 days to about 91 days when compared to the amount or level of MAPT mRNA prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, an amount or level of MAPT mRNA is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to an amount or level of MAPT mRNA in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or pharmaceutical composition or receiving a control oligonucleotide, pharmaceutical composition or treatment. In some embodiments, an amount or level of MAPT mRNA is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% for about 1 week to about 12 weeks, about 1 month to about 6 months, or about 7 days to about 91 days when compared to an amount or level of MAPT mRNA in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or pharmaceutical composition or receiving a control oligonucleotide, pharmaceutical composition or treatment.


In some embodiments of the methods, the oligonucleotide or the pharmaceutical composition is administered to a subject having a disease, disorder, or condition associated with MAPT gene expression such that an amount or level of Tau protein is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to the amount or level of Tau protein prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments of the methods herein, an oligonucleotide herein, or a pharmaceutical composition comprising the oligonucleotide, is administered to a subject having a disease, disorder, or condition associated with MAPT gene expression such that an amount or level of Tau protein is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% for about 1 week to about 12 weeks, about 1 month to about 6 months, or about 7 days to about 91 days when compared to the amount or level of Tau protein prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, an amount or level of Tau protein is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to an amount or level of Tau protein in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or pharmaceutical composition or receiving a control oligonucleotide, pharmaceutical composition or treatment. In some embodiments, an amount or level of Tau protein is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% for about 1 week to about 12 weeks, about 1 month to about 6 months, or about 7 days to about 91 days when compared to an amount or level of Tau protein in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or pharmaceutical composition or receiving a control oligonucleotide, pharmaceutical composition or treatment.


In some embodiments of the methods, the oligonucleotide or the pharmaceutical composition is administered to a subject having a disease, disorder, or condition associated with MAPT gene expression such that an amount or level of Tau activity is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to the amount or level of Tau activity prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, the oligonucleotide or the pharmaceutical composition is administered to a subject having a disease, disorder, or condition associated with MAPT gene expression such that an amount or level of Tau activity is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% for about 1 week to about 12 weeks, about 1 month to about 6 months, or about 7 days to about 91 days when compared to the amount or level of Tau activity prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, an amount or level of Tau activity is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to an amount or level of Tau activity in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or pharmaceutical composition or receiving a control oligonucleotide, pharmaceutical composition or treatment. In some embodiments, an amount or level of Tau activity is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% for about 1 week to about 12 weeks, about 1 month to about 6 months, or about 7 days to about 91 days when compared to an amount or level of Tau activity in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or pharmaceutical composition or receiving a control oligonucleotide, pharmaceutical composition or treatment.


Suitable methods for determining MAPT gene expression, an amount or level of MAPT mRNA, an amount or level of Tau protein, and/or an amount or level of Tau activity, in the subject, or in a sample from the subject, are known in the art. Further, the Examples set forth herein illustrate exemplary methods for determining MAPT gene expression.


In some embodiments, MAPT gene expression, an amount or level of MAPT mRNA, an amount or level of Tau protein, an amount or level of Tau activity, or any combination thereof, is reduced in a cell (e.g., an oligodendrocyte), a population or a group of cells (e.g., an organoid), an organ (e.g., frontal cortex), blood or a fraction thereof (e.g., plasma), a tissue (e.g., brain tissue), a sample (e.g., a brain biopsy sample), or any other biological material obtained or isolated from the subject. In some embodiments, MAPT gene expression, an amount or level of MAPT mRNA, an amount or level of Tau protein, an amount or level of Tau activity, or any combination thereof, is reduced in more than one type of cell (e.g., an oligodendrocyte and one or more other type(s) of cell), more than one groups of cells, more than one organ (e.g., brain and one or more other organ(s)), more than one fraction of blood (e.g., plasma and one or more other blood fraction(s)), more than one type of tissue (e.g., brain tissue and one or more other type(s) of tissue), more than one type of sample (e.g., a brain biopsy sample and one or more other type(s) of biopsy sample) obtained or isolated from the subject. In some embodiments, MAPT gene expression, an amount or level of MAPT mRNA, an amount or level of Tau protein, an amount or level of Tau activity, or any combination thereof is reduced in one or more of the cervical spinal cord, thoracic spinal cord, lumbar spinal cord, frontal cortex, temporal cortex, cerebellum, midbrain, occipital cortex, parietal cortex, hippocampus, caudate nucleus, thalamus, brainstem, motor cortex, globus pallidus, midbrain tegmentum, substantia nigra, pons, cerebellar white matter, and cerebellar dentate nucleus. In some embodiments, MAPT gene expression, an amount or level of MAPT mRNA, an amount or level of Tau protein, an amount or level of Tau activity, or any combination thereof is reduced in tissue of the brain and/or spinal cord associated with AD. In some embodiments, tissue associated with AD includes, but is not limited to, prefrontal cortex, motor cortex, temporal cortex, parietal cortex, and hippocampus. In some embodiments, MAPT gene expression, an amount or level of MAPT mRNA, an amount or level of Tau protein, an amount or level of Tau activity, or any combination thereof is reduced in tissue of the brain and/or spinal cord associated with PSP. In some embodiments, tissue associated with AD includes, but is not limited to caudate nucleus, globus pallidus, thalamus, midbrain tegmentum, substantia nigra, pons, cerebellar white matter, cerebellar dentate nucleus, medulla, cervical spinal cord, thoracic spinal cord, and lumbar spinal cord.


Examples of a disease, disorder, or condition associated with MAPT gene expression include, but are not limited to, AD, FTD, PD, PSP, and Tau protein associated diseases (e.g., primary age-related tauopathy, chronic traumatic encephalopathy, corticobasal degeneration, lytico-bodig disease, ganglioglioma, meningioangiomatosis, postencephalitic parkinsonism, and subacute sclerosing panencephalitis), which have aberrant MAPT gene expression that results in pathology of these diseases. Over 50 missense, silencing, and intronic mutations are known in MAPT (Ghetti et al. (2015) NEUROPATHOL. APPL. NEUROBIOL. 41:24-46) that lead to these diseases.


Because of their high specificity, the oligonucleotides herein (e.g., RNAi oligonucleotides) specifically target mRNAs of target genes of cells, tissue(s), or organ(s) (e.g., brain). In preventing disease, the target gene may be one that is required for initiation or maintenance of the disease or that has been identified as being associated with a higher risk of contracting the disease. In treating disease, the oligonucleotide can be brought into contact with the cells, tissue(s), or organ(s) (e.g., brain) exhibiting or responsible for mediating the disease. For example, an oligonucleotide substantially identical to all or part of a wild-type (i.e., native) or mutated gene associated with a disorder or condition associated withMAPT gene expression may be brought into contact with or introduced into a cell or tissue type of interest such as an oligodendrocyte or other brain cell.


In some embodiments, the target gene may be a target gene from any mammal, such as a human. Any gene may be silenced according to the method described herein.


Methods described herein are typically involve administering to a subject a therapeutically effective amount of an oligonucleotide (e.g., a RNAi oligonucleotide), that is, an amount capable of producing a desirable therapeutic result. A therapeutically acceptable amount may be an amount that can therapeutically treat a disease or disorder. The appropriate dosage for any one subject will depend on certain factors, including the subject's size, body surface area, age, the particular composition to be administered, the active ingredient(s) in the composition, time and route of administration, general health, and other drugs being administered concurrently.


In some embodiments, a subject is administered any one of the compositions herein either enterally (e.g., orally, by gastric feeding tube, by duodenal feeding tube, via gastrostomy or rectally), parenterally (e.g., subcutaneous injection, intravenous injection or infusion, intra-arterial injection or infusion, intraosseous infusion, intramuscular injection, intracerebral injection, intracerebroventricular injection, or intrathecal), topically (e.g., epicutaneous, inhalational, via eye drops, or through a mucous membrane), or by direct injection into a target organ (e.g., the brain of a subject). Typically, the oligonucleotides are administered intravenously or subcutaneously. In some embodiments, the oligonucleotides are administered to the cerebral spinal fluid. In some embodiments, the oligonucleotides described herein are administered intrathecally. In some embodiments, the oligonucleotides are administered intracerebroventricularly. In some embodiments, the oligonucleotides are administered by intracisternal magna injection.


As a non-limiting set of examples, the oligonucleotides would typically be administered quarterly (once every three months), bi-monthly (once every two months), monthly or weekly. For example, the oligonucleotides may be administered every week or at intervals of two, or three weeks. Alternatively, the oligonucleotides may be administered daily. In some embodiments, a subject is administered one or more loading doses of the oligonucleotide followed by one or more maintenance doses of the oligonucleotide.


In some embodiments, the subject to be treated is a human or NUP or other mammalian subject. Other exemplary subjects include domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and animals such as mice, rats, guinea pigs, and hamsters.


Kits


In some embodiments, the disclosure provides a kit comprising an oligonucleotide herein (e.g., a RNAi oligonucleotide), and instructions for use. In some embodiments, the kit comprises the oligonucleotide and a package insert containing instructions for use of the kit and/or any component thereof. In some embodiments, the kit comprises, in a suitable container, the oligonucleotide, one or more controls, and various buffers, reagents, enzymes and other standard ingredients well known in the art. In some embodiments, the container comprises at least one vial, well, test tube, flask, bottle, syringe, or other container means, into which the oligonucleotide is placed, and in some instances, suitably aliquoted. In some embodiments where an additional component is provided, the kit contains additional containers into which this component is placed. The kits can also include a means for containing the oligonucleotide and any other reagent in close confinement for commercial sale. Such containers may include injection or blow-molded plastic containers into which the desired vials are retained. Containers and/or kits can include labeling with instructions for use and/or warnings.


In some embodiments, the kit comprises the oligonucleotide and a pharmaceutically acceptable carrier, or a pharmaceutical composition comprising the oligonucleotide and instructions for treating or delaying progression of a disease, disorder or condition associated with MAPT gene expression in a subject in need thereof.


In some embodiments, the kit comprises the oligonucleotide and a pharmaceutically acceptable carrier or a pharmaceutical composition comprising the oligonucleotide, and instructions for administering the oligonucleotide or pharmaceutical composition to the cerebral spinal fluid to reduce MAPT gene expression in at least one region of the brain and/or at least one region of the spinal cord in a subject in need thereof.


Definitions

As used herein, “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).


As used herein, “administer,” “administering,” “administration” and the like refers to providing a substance (e.g., an oligonucleotide) to a subject in a manner that is pharmacologically useful (e.g., to treat a condition in the subject).


As used herein, “asialoglycoprotein receptor” or “ASGPR” refers to a bipartite C-type lectin formed by a major 48 kDa subunit (ASGPR-1) and minor 40 kDa subunit (ASGPR-2). ASGPR is primarily expressed on the sinusoidal surface of hepatocyte cells and has a major role in binding, internalizing and subsequent clearing of circulating glycoproteins that contain terminal galactose or GalNAc residues (asialoglycoproteins).


As used herein, “attenuate,” “attenuating,” “attenuation” and the like refers to reducing or effectively halting. As a non-limiting example, one or more of the treatments herein may reduce or effectively halt the onset or progression of a disease associated with MAPT gene expression (e.g., Tau-associated diseases) in a subject. This attenuation may be exemplified by, for example, a decrease in one or more aspects (e.g., symptoms, tissue characteristics, and cellular, inflammatory or immunological activity, etc.) of a disease associated with MAPT gene expression (e.g., Tau-associated diseases), no detectable progression (worsening) of one or more aspects of the disease, or no detectable aspects of the disease in a subject when they might otherwise be expected.


As used herein, “complementary” refers to a structural relationship between two nucleotides (e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid strand) that permits the two nucleotides to form base pairs with one another. For example, a purine nucleotide of one nucleic acid that is complementary to a pyrimidine nucleotide of an opposing nucleic acid may base pair together by forming hydrogen bonds with one another. In some embodiments, complementary nucleotides can base pair in the Watson-Crick manner or in any other manner that allows for the formation of stable duplexes. In some embodiments, two nucleic acids may have regions of multiple nucleotides that are complementary with each other to form regions of complementarity, as described herein.


As used herein, “deoxyribonucleotide” refers to a nucleotide having a hydrogen in place of a hydroxyl at the 2′ position of its pentose sugar when compared with a ribonucleotide. A modified deoxyribonucleotide is a deoxyribonucleotide having one or more modifications or substitutions of atoms other than at the 2′ position, including modifications or substitutions in or of the sugar, phosphate group or base.


As used herein, “double-stranded oligonucleotide” or “ds oligonucleotide” refers to an oligonucleotide that is substantially in a duplex form. In some embodiments, the complementary base-pairing of duplex region(s) of a ds oligonucleotide is formed between antiparallel sequences of nucleotides of covalently separate nucleic acid strands. In some embodiments, complementary base-pairing of duplex region(s) of a ds oligonucleotide is formed between antiparallel sequences of nucleotides of nucleic acid strands that are covalently linked. In some embodiments, complementary base-pairing of duplex region(s) of a ds oligonucleotide is formed from single nucleic acid strand that is folded (e.g., via a hairpin) to provide complementary antiparallel sequences of nucleotides that base pair together. In some embodiments, a ds oligonucleotide comprises two covalently separate nucleic acid strands that are fully duplexed with one another. However, in some embodiments, a ds oligonucleotide comprises two covalently separate nucleic acid strands that are partially duplexed (e.g., having overhangs at one or both ends). In some embodiments, a ds oligonucleotide comprises antiparallel sequence of nucleotides that are partially complementary, and thus, may have one or more mismatches, which may include internal mismatches or end mismatches.


As used herein, “duplex,” in reference to nucleic acids (e.g., oligonucleotides), refers to a structure formed through complementary base pairing of two antiparallel sequences of nucleotides.


As used herein, “excipient” refers to a non-therapeutic agent that may be included in a composition, for example, to provide or contribute to a desired consistency or stabilizing effect.


As used herein, “labile linker” refers to a linker that can be cleaved (e.g., by acidic pH). A “fairly stable linker” refers to a linker that cannot be cleaved.


As used herein, “loop” refers to an unpaired region of a nucleic acid (e.g., oligonucleotide) that is flanked by two antiparallel regions of the nucleic acid that are sufficiently complementary to one another, such that under appropriate hybridization conditions (e.g., in a phosphate buffer, in a cells), the two antiparallel regions, which flank the unpaired region, hybridize to form a duplex (referred to as a “stem”).


As used herein, “modified internucleotide linkage” refers to an internucleotide linkage having one or more chemical modifications when compared with a reference internucleotide linkage comprising a phosphodiester bond. In some embodiments, a modified nucleotide is a non-naturally occurring linkage. Typically, a modified internucleotide linkage confers one or more desirable properties to a nucleic acid in which the modified internucleotide linkage is present. For example, a modified nucleotide may improve thermal stability, resistance to degradation, nuclease resistance, solubility, bioavailability, bioactivity, reduced immunogenicity, etc.


As used herein, “modified nucleotide” refers to a nucleotide having one or more chemical modifications when compared with a corresponding reference nucleotide selected from: adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribonucleotide, adenine deoxyribonucleotide, guanine deoxyribonucleotide, cytosine deoxyribonucleotide and thymidine deoxyribonucleotide. In some embodiments, a modified nucleotide is a non-naturally occurring nucleotide. In some embodiments, a modified nucleotide has one or more chemical modification in its sugar, nucleobase and/or phosphate group. In some embodiments, a modified nucleotide has one or more chemical moieties conjugated to a corresponding reference nucleotide. Typically, a modified nucleotide confers one or more desirable properties to a nucleic acid in which the modified nucleotide is present. For example, a modified nucleotide may improve thermal stability, resistance to degradation, nuclease resistance, solubility, bioavailability, bioactivity, reduced immunogenicity, etc.


As used herein, “nicked tetraloop structure” refers to a structure of an RNAi oligonucleotide that is characterized by separate sense (passenger) and antisense (guide) strands, in which the sense strand has a region of complementarity with the antisense strand, and in which at least one of the strands, generally the sense strand, has a tetraL configured to stabilize an adjacent stem region formed within the at least one strand.


As used herein, “oligonucleotide” refers to a short nucleic acid (e.g., less than about 100 nucleotides in length). An oligonucleotide may be ss or ds. An oligonucleotide may or may not have duplex regions. As a set of non-limiting examples, an oligonucleotide may be, but is not limited to, a small interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), dicer substrate interfering RNA (dsiRNA), antisense oligonucleotide, short siRNA, or ss siRNA. In some embodiments, a ds oligonucleotide is an RNAi oligonucleotide.


As used herein, “overhang” refers to terminal non-base pairing nucleotide(s) resulting from one strand or region extending beyond the terminus of a complementary strand with which the one strand or region forms a duplex. In some embodiments, an overhang comprises one or more unpaired nucleotides extending from a duplex region at the 5′ terminus or 3′ terminus of a ds oligonucleotide. In certain embodiments, the overhang is a 3′ or 5′ overhang on the antisense strand or sense strand of a ds oligonucleotides.


As used herein, “phosphate analog” refers to a chemical moiety that mimics the electrostatic and/or steric properties of a phosphate group. In some embodiments, a phosphate analog is positioned at the 5′ terminal nucleotide of an oligonucleotide in place of a 5′-phosphate, which is often susceptible to enzymatic removal. In some embodiments, a 5′-phosphate analog contains a phosphatase-resistant linkage. Examples of phosphate analogs include, but are not limited to, 5′ phosphonates, such as 5′ methylenephosphonate (5′-MP) and 5′-(E)-vinylphosphonate (5′-VP). In some embodiments, an oligonucleotide has a phosphate analog at a 4′-carbon position of the sugar (referred to as a “4′-phosphate analog”) at a 5′ terminal nucleotide. An example of a 4′-phosphate analog is oxymethylphosphonate, in which the oxygen atom of the oxymethyl group is bound to the sugar moiety (e.g., at its 4′-carbon) or analog thereof. See, e.g., US Provisional Patent Application Nos. 62/383,207 (filed on 2 Sep. 2016) and 62/393,401 (filed on 12 Sep. 2016). Other modifications have been developed for the 5′ end of oligonucleotides (see, e.g., Intl. Patent Application Publication No. WO 2011/133871; U.S. Pat. No. 8,927,513; and Prakash et al. (2015) NUCLEIC ACIDS RES. 43:2993-3011).


As used herein, “MAPT” refers to Microtubule-Associated Protein Tau. The MAPT transcript undergoes several types of alternative splicing to produce different mRNA species and Tau proteins. There are six known Tau isoforms produced by the splicing of MAPT mRNA. MAPT gene expression is found primarily in the axons of neurons in the CNS. Tau protein interacts with tubulin to generate microtubules which are involved in several cellular processes. The MAPT mRNA encoding wild-type human Tau protein is set forth in SEQ ID NO: 909. The MAPT mRNA encoding mouse Tau protein is set forth in SEQ ID NO: 910. The MAPT mRNA encoding monkey Tau protein is set forth in SEQ ID NO: 911. One of skill in the art, however, understands that additional examples of MAPT mRNA sequences are readily available using publicly available databases such as, for example, GenBank and UniProt.


As used herein, “reduced expression” of a gene (e.g., MAPT) refers to a decrease in the amount or level of RNA transcript (e.g., MAPT mRNA) or protein encoded by the gene and/or a decrease in the amount or level of activity of the gene in a cell, a population of cells, a sample or a subject, when compared to an appropriate reference (e.g., a reference cell, population of cells, sample, or subject). For example, the act of contacting a cell with an oligonucleotide herein (e.g., an oligonucleotide comprising an antisense strand having a nucleotide sequence that is complementary to a nucleotide sequence comprising MAPT mRNA) may result in a decrease in the amount or level of MAPT mRNA, Tau protein, and/or Tau activity (e.g., via inactivation and/or degradation of MAPT mRNA by the RNAi pathway) when compared to a cell that is not treated with the ds oligonucleotide. Similarly, and as used herein, “reducing expression” refers to an act that results in reduced expression of a gene (e.g., MAPT).


As used herein, “reduction of MAPT gene expression” refers to a decrease in the amount or level of MAPT mRNA, Tau protein, and/or Tau activity in a cell, a population of cells, a sample, or a subject when compared to an appropriate reference (e.g., a reference cell, population of cells, sample, or subject).


As used herein, “region of complementarity” refers to a sequence of nucleotides of a nucleic acid (e.g., a ds oligonucleotide) that is sufficiently complementary to an antiparallel sequence of nucleotides to permit hybridization between the two sequences of nucleotides under appropriate hybridization conditions (e.g., in a phosphate buffer, in a cell, etc.). In some embodiments, an oligonucleotide herein comprises a targeting sequence having a region of complementary to a mRNA target sequence.


As used herein, “ribonucleotide” refers to a nucleotide having a ribose as its pentose sugar, which contains a hydroxyl group at its 2′ position. A modified ribonucleotide is a ribonucleotide having one or more modifications or substitutions of atoms other than at the 2′ position, including modifications or substitutions in or of the ribose, phosphate group or base.


As used herein, “RNAi oligonucleotide” refers to either (a) a ds oligonucleotide having a sense strand (passenger) and antisense strand (guide), in which the antisense strand or part of the antisense strand is used by the Argonaute 2 (Ago2) endonuclease in the cleavage of a target mRNA (e.g., MAPT mRNA) or (b) a ss oligonucleotide having a single antisense strand, where that antisense strand (or part of that antisense strand) is used by the Ago2 endonuclease in the cleavage of a target mRNA (e.g., MAPT mRNA).


As used herein, “strand” refers to a single, contiguous sequence of nucleotides linked together through internucleotide linkages (e.g., phosphodiester linkages or phosphorothioate linkages). In some embodiments, a strand has two free ends (e.g., a 5′ end and a 3′ end).


As used herein, “subject” means any mammal, including mice, rabbits, and humans. In one embodiment, the subject is a human or NUP. Moreover, “individual” or “patient” may be used interchangeably with “subject.”


As used herein, “synthetic” refers to a nucleic acid or other molecule that is artificially synthesized (e.g., using a machine (e.g., a solid-state nucleic acid synthesizer)) or that is otherwise not derived from a natural source (e.g., a cell or organism) that normally produces the molecule.


As used herein, “targeting ligand” refers to a molecule (e.g., a carbohydrate, amino sugar, cholesterol, or polypeptide) that selectively binds to a cognate molecule (e.g., a receptor) of a tissue or cell of interest and that is conjugatable to another substance for purposes of targeting the other substance to the tissue or cell of interest. For example, in some embodiments, a targeting ligand may be conjugated to an oligonucleotide for purposes of targeting the oligonucleotide to a specific tissue or cell of interest. In some embodiments, a targeting ligand selectively binds to a cell surface receptor. Accordingly, in some embodiments, a targeting ligand when conjugated to an oligonucleotide facilitates delivery of the oligonucleotide into a particular cell through selective binding to a receptor expressed on the surface of the cell and endosomal internalization by the cell of the complex comprising the oligonucleotide, targeting ligand and receptor. In some embodiments, a targeting ligand is conjugated to an oligonucleotide via a linker that is cleaved following or during cellular internalization such that the oligonucleotide is released from the targeting ligand in the cell.


As used herein, “tetraloop” or “tetraL” refers to a loop that increases stability of an adjacent duplex formed by hybridization of flanking sequences of nucleotides. The increase in stability is detectable as an increase in melting temperature (Tm) of an adjacent stem duplex that is higher than the Tm of the adjacent stem duplex expected, on average, from a set of loops of comparable length consisting of randomly selected sequences of nucleotides. For example, a tetraL can confer a Tm of at least about 50° C., at least about 55° C., at least about 56° C., at least about 58° C., at least about 60° C., at least about 65° C. or at least about 75° C. in 10 mM NaIPO4 to a hairpin comprising a duplex of at least 2 base pairs (bp) in length. In some embodiments, a tetraL may stabilize a bp in an adjacent stem duplex by stacking interactions. In addition, interactions among the nucleotides in a tetraL include, but are not limited to, non-Watson-Crick base pairing, stacking interactions, hydrogen bonding and contact interactions (Cheong et al. (1990) NATURE 346:680-682; Heus & Pardi (1991) SCIENCE 253:191-94). In some embodiments, a tetraL comprises or consists of 3 to 6 nucleotides and is typically 4 to 5 nucleotides. In certain embodiments, a tetraL comprises or consists of 3, 4, 5, or 6 nucleotides, which may or may not be modified (e.g., which may or may not be conjugated to a targeting moiety). In certain embodiments, a tetraL comprises or consists of 3, 4, 5, or 6 nucleotides, which may or may not be modified (e.g., which may or may not be conjugated to a targeting ligand). In one embodiment, a tetraL consists of 4 nucleotides. Any nucleotide may be used in the tetraloop and standard IUPAC-IUB symbols for such nucleotides may be used as described in Cornish-Bowden (1985) NUCLEIC ACIDS RES. 13:3021-30. For example, the letter “N” may be used to mean that any base may be in that position, the letter “R” may be used to show that A (adenine) or G (guanine) may be in that position, and “B” may be used to show that C (cytosine), G (guanine), T (thymine) or U (uracil) may be in that position. Examples of tetraLs include the UNCG family of tetraLs (e.g., UUCG), the GNRA family of tetraLs (e.g., GAAA), and the CUUG tetraloop (Woese et al. (1990) PROC. NATL. ACAD. SCI. USA 87:8467-71; Antao et al. (1991) NUCLEIC ACIDS RES. 19:5901-05). Examples of DNA tetraLs include the d(GNNA) family of tetraLs (e.g., d(GTTA), the d(GNRA)) family of tetraLs, the d(GNAB) family of tetraLs, the d(CNNG) family of tetraLs, and the d(TNCG) family of tetraLs (e.g., d(TTCG)). See, e.g., Nakano et al. (2002) BIOCHEM. 41:4281-92; Shinji et al. (2000) NIPPON KAGAKKAI KOEN YOKOSHU 78:731. In some embodiments, the tetraloop is contained within a nicked tetraL structure.


As used herein, “treat” or “treating” refers to the act of providing care to a subject in need thereof, for example, by administering a therapeutic agent (e.g., an oligonucleotide herein) to the subject, for purposes of improving the health and/or well-being of the subject with respect to an existing condition (e.g., a disease, disorder) or to prevent or decrease the likelihood of the occurrence of a condition. In some embodiments, treatment involves reducing the frequency or severity of at least one sign, symptom, or contributing factor of a condition (e.g., disease or disorder) experienced by a subject.


EXAMPLES

The following non-limiting examples are offered for purposes of illustration, not limitation.


Example 1: Preparation of RNAi Oligonucleotides

Oligonucleotide Synthesis and Purification


The oligonucleotides (RNAi oligonucleotides) described in the foregoing Examples are chemically synthesized using methods described herein. Generally, RNAi oligonucleotides are synthesized using solid phase oligonucleotide synthesis methods as described for 19-23mer siRNAs (see, e.g., Scaringe et al. (1990) NUCLEIC ACIDS RES. 18:5433-5441 and Usman et al. (1987) J. AM. CHEM. SOC. 109:7845-45; see also, U.S. Pat. Nos. 5,804,683; 5,831,071; 5,998,203; 6,008,400; 6,111,086; 6,117,657; 6,353,098; 6,362,323; 6,437,117 and 6,469,158) in addition to using known phosphoramidite synthesis (see, e.g. Hughes & Ellington (2017) COLD SPRING HARB. PERSPECT. BIOL. 9(1):a023812; Beaucage & Caruthers (1981) TETRAHEDRON LETT. 22:1859-62). dsRNAi oligonucleotides have a 19mer core sequence were formatted into constructs having a 25mer sense strand and a 27mer antisense strand to allow for processing by the RNAi machinery. The 19mer core sequence is complementary to a region in the MAPT mRNA.


Individual RNA strands were synthesized and HPLC purified according to standard methods (Integrated DNA Technologies). For example, RNA oligonucleotides were synthesized using solid phase phosphoramidite chemistry, deprotected, and desalted on NAP-5 columns (Amersham Pharmacia Biotech) using standard techniques (Damha & Olgivie (1993) METHODS MOL. BIOL. 20:81-114; Wincott et al. (1995) NUCLEIC ACIDS RES. 23:2677-84). The oligomers were purified using ion-exchange high performance liquid chromatography (IE-HPLC) on an Amersham Source 15Q column (1.0 cm×25 cm; Amersham Pharmacia Biotech) using a 15 min step-linear gradient. The gradient varied from 90:10 Buffers A:B to 52:48 Buffers A:B, where Buffer A is 100 mM Tris pH 8.5 and Buffer B is 100 mM Tris pH 8.5, 1 M NaCl. Samples were monitored at 260 nm and peaks corresponding to the full-length oligonucleotide species were collected, pooled, desalted on NAP-5 columns, and lyophilized.


The purity of each oligomer was determined by capillary electrophoresis (CE) on a Beckman PACE 5000 (Beckman Coulter, Inc.). The CE capillaries have a 100 m inner diameter and contain ssDNA 100R Gel (Beckman-Coulter). Typically, about 0.6 nmole of oligonucleotide was injected into a capillary, run in an electric field of 444 V/cm, and was detected by UV absorbance at 260 nm. Denaturing Tris-Borate-7 M-urea running buffer was purchased from Beckman-Coulter. Oligoribonucleotides were obtained that were at least 90% pure as assessed by CE for use in experiments described below. Compound identity was verified by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectroscopy on a Voyager DE™ Biospectometry Work Station (Applied Biosystems) following the manufacturer's recommended protocol. Relative molecular masses of all oligomers were obtained, often within 0.2% of expected molecular mass.


Preparation of Duplexes


ss RNA oligomers were resuspended (e.g., at 100 μM concentration) in duplex buffer consisting of 100 mM potassium acetate, 30 mM HEPES, pH 7.5. Complementary sense and antisense strands were mixed in equal molar amounts to yield a final solution of, for example, 50 M duplex. Samples were heated to 100° C. for 5 min in RNA buffer (IDT) and were allowed to cool to room temperature before use. The RNAi oligonucleotides were stored at −20° C. ss RNA oligomers were stored lyophilized or in nuclease-free water at −80° C.


Example 2: Generation of MAPT-Targeting ds RNAi Oligonucleotides

Identification of MAPT mRNA Target Sequences


To generate MAPT-targeting RNAi oligonucleotides, a computer-based algorithm was used to computationally identify MAPT mRNA target sequences suitable for assaying inhibition of MAPT gene expression by the RNAi pathway. The algorithm provided RNAi oligonucleotide antisense (guide) strand sequences each having a region of complementarity to a suitable MAPT mRNA target sequence of human (Hs) or murine (Mm) mRNA (e.g., SEQ ID NOs: 909 and 910, respectively; Table 1). Due to sequence conservation across species, some of the MAPT mRNA target sequences identified for human MAPT mRNA are homologous to the corresponding MAPT mRNA target sequence of murine (mM) MAPT mRNA (SEQ ID NO: 910; Table 1) and/or monkey (Mf) MAPT mRNA (SEQ ID NO: 911; Table 1). MAPT-targeting RNAi oligonucleotides comprising a region of complementarity to homologous MAPT mRNA target sequences with nucleotide sequence similarity are predicted to have the ability to target homologous MAPT mRNAs (e.g., human and monkey MAPT mRNAs).









TABLE 1







Exemplary Human, Monkey, and


Mouse MAPT mRNA Sequences.









Species
GenBank Ref Seq #
SEQ ID NO





Human (Hs)
NM_001123066.3
909


Mouse (Mm)
NM_001038609.02
910


Cynomolgus monkey (Mf)
XM_005584531.2
911









RNAi oligonucleotides (formatted as DsiRNA oligonucleotides) were generated as described in Example 1 for evaluation in vitro. Each DsiRNA was generated with the same modification pattern, and each with a unique guide strand having a region of complementarity to a MAPT target sequence identified by the algorithm. Modifications for the sense and antisense DsiRNA included the following (X—any nucleotide; m—2′-OMe-modified nucleotide; r—ribosyl-modified nucleotide):









Sense Strand:



rXmXrXmXrXrXrXrXrXrXrXrXrXmXrXmXrXrXrXrXrXrXrXXX






Anti-sense Strand:



mXmXmXmXrXrXrXrXrXrXmXrXmXrXrXrXrXrXrXrXrXrXmXrXmX




mXmX







In Vitro Cell-Based Assays


The ability of each of the modified DsiRNA in Table 2 to reduce MAPT mRNA was measured using in vitro cell-based assays. Briefly, human T98G cells (glioblastoma cell line) expressing endogenous human MAPT gene were transfected with each of the DsiRNAs listed in Table 2 at 1 nM in separate wells of a multi-well cell-culture plate. Cells were maintained for 24 hours following transfection with the modified DsiRNA, and then the amount of remaining MAPT mRNA from the transfected cells was determined using TAQMAN®-based qPCR assays. Two qPCR assays, a 3′ assay (Forward; GAA GAT TGG GTC CCT GGA (SEQ ID NO: 1683), Reverse; TGT CTT GGC TTT GGC GTT (SEQ ID NO: 1684), Probe; 5′-6FAM-CGG AAG GTC/ZEN/AGC TTG TGG GTT TCA (SEQ ID NO: 1685); and a 5′ assay (Forward; CAC CAC AGC CAC CTT CTC (SEQ ID NO: 1686), Reverse; CTT CCA TCA CTT CGA ACT CCT (SEQ ID NO: 1687), Probe; 5′-6FAM-CGT CCT CGC/ZEN/CTC TGT CGA CTA (SEQ ID NO: 1688) were used to determine MAPT mRNA levels as measured using PCR probes conjugated to 6-carboxy-fluorescein (FAM). Primer pairs were assayed for % remaining mRNA as shown in Table 2. DsiRNAs resulting in less than or equal to 10% MAPT mRNA remaining in DsiRNA-transfected cells when compared to mock-transfected cells were considered DsiRNA “hits.” The T98G cell-based assay evaluating the ability of the DsiRNAs listed in Table 2 to inhibit MAPT gene expression identified several candidate DsiRNAs.


Taken together, these results show that DsiRNAs designed to target human MAPT mRNA inhibit MAPT gene expression in cells, as determined by a reduced amount of MAPT mRNA in DsiRNA-transfected cells relative to control cells. These results demonstrate that the nucleotide sequences comprising the DsiRNA are useful for generating RNAi oligonucleotides to inhibit MAPT gene expression. Further, these results demonstrate that multiple MAPT mRNA target sequences are suitable for the RNAi-mediated inhibition of MAPT gene expression.









TABLE 2







In Vitro Screening Results.

















Anti-









Sense
sense




















strand
strand


HsMAPT-
HsMAPT-













SEQ
SEQ
1 nM; T98G Cells
5′/SFRS9-F569
3′/HPRT1-F517
















ID
ID
average %

%

%



Construct
NO
NO
remaining
average SD
remaining
SEM
remaining
SEM


















MAPT-
1
385
95.01
25.6510056
76.872
12.015
113.148
14.537


2141










MAPT-
2
386
45.0915
14.8556064
34.587
3.412
55.596
5.956


2142










MAPT-
3
387
49.649
1.54149278
48.559
4.694
50.739
7.759


2303










MAPT-
4
388
14.9465
2.79802153
16.925
2.294
12.968
2.03


2347










MAPT-
5
389
36.102
6.40497322
40.631
12.81
31.573
8.578


2349










MAPT-
6
390
40.698
0.85701342
40.092
7.14
41.304
6.668


2350










MAPT-
7
391
34.233
1.88514668
35.566
7.156
32.9
12.834


2351










MAPT-
8
392
18.5755
5.96161727
22.791
7.452
14.36
4.732


2352










MAPT-
9
393
48.36
11.8822224
39.958
4.633
56.762
6.089


2353










MAPT-
10
394
24.094
3.67271262
26.691
5.688
21.497
6.358


2354










MAPT-
11
395
18.7485
3.90252233
21.508
3.374
15.989
2.482


2355










MAPT-
12
396
14.572
3.86645988
17.306
5.142
11.838
2.977


2459










MAPT-
13
397
13.041
4.14647416
15.973
2.64
10.109
1.577


2460










MAPT-
14
398
16.537
3.28097546
14.217
6.702
18.857
2.975


2461










MAPT-
15
399
21.8695
2.158797
23.396
6.242
20.343
6.622


2462










MAPT-
16
400
36.615
1.28127749
35.709
11
37.521
8.285


2463










MAPT-
17
401
24.302
4.31335137
21.252
4.336
27.352
3.33


2464










MAPT-
18
402
57.3185
24.0494087
40.313
6.657
74.324
8.436


2465










MAPT-
19
403
43.9035
1.65109433
42.736
8.925
45.071
6.344


2466










MAPT-
20
404
42.107
27.9957717
22.311
4.822
61.903
9.046


2467










MAPT-
21
405
38.319
5.58472936
34.37
10.991
42.268
9.76


2495










MAPT-
22
406
24.6465
2.92105811
26.712
4.387
22.581
6.794


2496










MAPT-
23
407
82.684
13.0956176
73.424
15.054
91.944
13.074


3686










MAPT-
24
408
55.0335
15.0691526
65.689
6.468
44.378
10.238


3687










MAPT-
25
409
87.266
1.77200959
88.519
15.089
86.013
15.763


3688










MAPT-
26
410
44.8115
4.63932759
48.092
12.584
41.531
10.617


3691










MAPT-
27
411
42.868
1.70412734
41.663
6.449
44.073
5.791


3692










MAPT-
28
412
49.581
11.071878
41.752
5.802
57.41
8.211


3693










MAPT-
29
413
47.3565
11.3016877
39.365
3.71
55.348
6.574


4534










MAPT-
30
414
56.0275
17.8608102
43.398
5.409
68.657
9.992


4535










MAPT-
31
415
62.025
10.3096169
54.735
7.123
69.315
12.404


4536










MAPT-
32
416
38.464
6.65811745
43.172
7.528
33.756
11.817


4537










MAPT-
33
417
44.9465
13.5743289
35.348
11.081
54.545
9.032


4538










MAPT-
34
418
38.0325
1.6058395
36.897
10.035
39.168
10.49


4566










MAPT-
35
419
40.872
8.78650886
34.659
6.539
47.085
6.222


4567










MAPT-
36
420
39.4745
0.77428193
40.022
6.35
38.927
3.497


4568










MAPT-
37
421
44.188
6.29183614
39.739
5.336
48.637
6.198


4569










MAPT-
38
422
52.8135
22.3947789
36.978
7.769
68.649
12.743


4570










MAPT-
39
423
50.4355
6.61639815
45.757
6.03
55.114
10.233


4571










MAPT-
40
424
51.2905
5.50765472
47.396
8.8
55.185
7.514


4572










MAPT-
41
425
41.6435
3.91100761
44.409
11.822
38.878
5.955


4573










MAPT-
42
426
44.6415
3.87140963
47.379
14.765
41.904
17.629


4574










MAPT-
43
427
43.044
4.46184379
39.889
4.461
46.199
6.498


4575










MAPT-
44
428
35.613
5.81100353
31.504
2.99
39.722
6.824


4576










MAPT-
45
429
32.979
3.62462936
35.542
4.01
30.416
7.004


4577










MAPT-
46
430
59.0835
11.5053344
50.948
8.8
67.219
11.491


4578










MAPT-
47
431
44.268
11.4565441
36.167
4.845
52.369
5.65


4579










MAPT-
48
432
57.2225
22.8713688
41.05
10.952
73.395
8.852


4580










MAPT-
49
433
96.059
3.22440692
93.779
15.189
98.339
15.945


4605










MAPT-
50
434
57.348
2.49467272
59.112
13.383
55.584
9.058


4606










MAPT-
51
435
67.9825
13.5799857
58.38
10.161
77.585
9.466


4607










MAPT-
52
436
35.004
14.4589195
45.228
5.369
24.78
7.968


4608










MAPT-
53
437
52.854
7.33552575
58.041
9.122
47.667
6.181


4609










MAPT-
54
438
56.244
5.2764308
52.513
8.718
59.975
11.85


4610










MAPT-
55
439
60.552
13.7489843
70.274
19.308
50.83
9.512


4611










MAPT-
56
440
44.801
10.820148
37.15
9.793
52.452
16.948


4612










MAPT-
57
441
55.2605
12.1374879
46.678
13.942
63.843
4.47


4613










MAPT-
58
442
51.7385
24.0451661
68.741
10.458
34.736
6.591


4614










MAPT-
59
443
47.4125
3.24915566
45.115
14.811
49.71
8.998


5969










MAPT-
60
444
44.3725
3.58998113
41.834
5.855
46.911
3.033


5970










MAPT-
61
445
63.7505
23.6336299
47.039
6.803
80.462
9.959


5971










MAPT-
62
446
49.5005
23.8089924
32.665
4.895
66.336
6.085


5972










MAPT-
63
447
52.079
7.14884956
57.134
10.719
47.024
8.743


5973










MAPT-
64
448
44.9585
12.1686006
36.354
12.432
53.563
8.866


5974










MAPT-
65
449
45.1555
0.32456201
45.385
9.699
44.926
10.859


5975










MAPT-
66
450
43.056
1.32511811
43.993
18.502
42.119
5.098


5976










MAPT-
67
451
47.3185
1.16319066
48.141
6.434
46.496
7.198


5977










MAPT-
68
452
58.9385
3.69887557
56.323
8.866
61.554
8.153


5978










MAPT-
69
453
90.251
49.5568717
55.209
23.067
125.293
41.072


5979










MAPT-
70
454
93.5025
1.75433192
92.262
15.249
94.743
12.851


5980










MAPT-
71
455
73.614
15.0401612
62.979
9.331
84.249
10.224


5981










MAPT-
72
456
52.7605
4.23627673
55.756
7.219
49.765
6.897


5982










MAPT-
73
457
52.0305
13.3805816
61.492
16.873
42.569
15.962


5983










MAPT-
74
458
39.226
13.1267303
29.944
8.671
48.508
18.496


5984










MAPT-
75
459
47.514
0.09475231
47.581
10.955
47.447
15.502


5985










MAPT-
76
460
56.8945
5.52321107
52.989
23.098
60.8
21.716


6662










MAPT-
77
461
50.6
16.8984379
38.651
7.897
62.549
14.03


6663










MAPT-
78
462
59.894
1.37461558
60.866
17.793
58.922
20.062


6664










MAPT-
79
463
45.514
6.31022092
49.976
19.816
41.052
16.434


6665










MAPT-
80
464
49.963
1.58391919
51.083
13.407
48.843
10.693


6800










MAPT-
81
465
78.6545
21.2761359
63.61
10.347
93.699
12.651


6801










MAPT-
82
466
36.959
2.8468119
34.946
11.719
38.972
6.592


6802










MAPT-
83
467
60.1565
7.48896792
54.861
6.209
65.452
7.341


6803










MAPT-
84
468
58.1295
25.573931
40.046
7.718
76.213
14.881


6804










MAPT-
85
469
40.6695
7.0180348
35.707
8.81
45.632
6.173


6805










MAPT-
86
470
49.47
9.29421153
42.898
13.633
56.042
8.573


6806










MAPT-
87
471
44.6315
14.4172002
34.437
12.547
54.826
14.094


6807










MAPT-
88
472
47.8265
1.73311872
46.601
15.127
49.052
9.845


6808










MAPT-
89
473
100.4455
12.3199214
91.734
32.653
109.157
62.617


6809










MAPT-
90
474
38.2355
5.25168206
34.522
8.787
41.949
19.197


6810










MAPT-
91
475
64.862
2.72801796
66.791
6.959
62.933
10.212


6811










MAPT-
92
476
78.776
32.6782328
55.669
16.433
101.883
16.548


6812










MAPT-
93
477
67.15
7.39068008
61.924
11.954
72.376
13.616


6813










MAPT-
94
478
44.55
0.562857
44.152
9.142
44.948
5.743


6814










MAPT-
95
479
72.563
12.5695301
63.675
13.171
81.451
15.732


6815










MAPT-
96
480
42.662
7.06258253
37.668
7.799
47.656
9.971


6816










MAPT-
97
481
10.801
0.99843478
11.507
5.145
10.095
2.3


363










MAPT-
98
482
17.493
1.23319423
18.365
8.672
16.621
3.855


364










MAPT-
99
483
49.6115
18.8917719
36.253
12.86
62.97
12.877


365










MAPT-
100
484
60.2915
5.79898271
64.392
9.598
56.191
8.387


367










MAPT-
101
485
18.496
5.14349473
14.859
2.908
22.133
5.121


369










MAPT-
102
486
54.2605
7.24855161
49.135
6.979
59.386
8.929


374










MAPT-
103
487
29.862
11.7125167
38.144
8.293
21.58
5.252


395










MAPT-
104
488
34.402
16.4246763
22.788
7.436
46.016
11.445


400










MAPT-
105
489
17.7005
6.73802052
12.936
4.852
22.465
4.318


443










MAPT-
106
490
62.8045
3.40047651
65.209
13.424
60.4
5.794


688










MAPT-
107
491
26.4395
3.02853834
28.581
4.295
24.298
6.236


689










MAPT-
108
492
14.6445
4.81327586
11.241
2.659
18.048
2.561


690










MAPT-
109
493
63.3205
15.4368481
52.405
6.513
74.236
8.881


693










MAPT-
110
494
116.4165
9.93838581
123.444
17.981
109.389
37.256


695










MAPT-
111
495
31.593
2.7322606
33.525
9.92
29.661
8.245


696










MAPT-
112
496
26.2465
9.29491864
19.674
5.59
32.819
7.787


1475










MAPT-
113
497
30.5425
1.07975205
29.779
5.507
31.306
6.256


1476










MAPT-
114
498
13.127
0.9588368
13.805
1.935
12.449
2.983


1479










MAPT-
115
499
47.5765
5.71554411
43.535
9.405
51.618
7.164


1480










MAPT-
116
500
37.489
3.0349023
39.635
3.962
35.343
5.214


1481










MAPT-
117
501
24.0215
8.67690731
17.886
3.238
30.157
3.712


1484










MAPT-
118
502
55.319
27.0807755
36.17
8.411
74.468
21.392


1485










MAPT-
119
503
77.784
20.2685088
63.452
9.291
92.116
8.346


1492










MAPT-
120
504
15.4475
3.58432427
12.913
5.176
17.982
3.997


1494










MAPT-
121
505
18.204
1.04793225
18.945
3.15
17.463
3.766


1495










MAPT-
122
506
20.014
2.4607316
18.274
6.805
21.754
5.32


1498










MAPT-
123
507
65.7465
24.832883
48.187
11.539
83.306
19.091


1499










MAPT-
124
508
18.62
5.80393246
14.516
4.376
22.724
5.504


1500










MAPT-
125
509
34.775
5.02187236
38.326
10.536
31.224
4.366


1502










MAPT-
126
510
31.277
11.1058191
39.13
11.069
23.424
3.92


1503










MAPT-
127
511
24.627
3.87211673
27.365
4.52
21.889
2.089


1504










MAPT-
128
512
10.3425
2.81074946
12.33
1.998
8.355
2.686


1505










MAPT-
129
513
57.631
0.21354625
57.48
23.99
57.782
17.417


1506










MAPT-
130
514
32.112
3.45068109
34.552
9.62
29.672
4.255


1507










MAPT-
131
515
27.841
5.67099639
31.851
8.28
23.831
6.196


1508










MAPT-
132
516
38.7
4.51699812
41.894
7.785
35.506
5.674


1509










MAPT-
133
517
15.758
4.39961839
18.869
4.717
12.647
3.372


1733










MAPT-
134
518
78.742
9.03116781
85.128
12.726
72.356
9.03


1796










MAPT-
135
519
77.3505
24.4199327
94.618
20.422
60.083
13.368


1835










MAPT-
136
520
24.699
5.16329372
28.35
13.873
21.048
4.701


1912










MAPT-
137
521
18.8405
9.74463855
25.731
6.678
11.95
1.689


2094










MAPT-
138
522
13.6925
1.29471252
14.608
3.403
12.777
2.067


2096










MAPT-
139
523
21.9025
4.07081374
19.024
4.924
24.781
3.696


2097










MAPT-
140
524
17.656
9.87828173
10.671
3.205
24.641
2.915


2098










MAPT-
141
525
22.912
10.0098036
29.99
6.919
15.834
5.794


2105










MAPT-
142
526
16.6545
1.53937146
17.743
3.658
15.566
3.854


2106










MAPT-
143
527
33.657
2.05343809
35.109
4.469
32.205
5.491


2107










MAPT-
144
528
27.0645
15.2940126
37.879
8.018
16.25
2.844


2108










MAPT-
145
529
18.066
0.36769553
18.326
6.375
17.806
4.395


2109










MAPT-
146
530
70.417
5.66958217
66.408
16.607
74.426
11.191


2117










MAPT-
147
531
30.333
0.4794184
30.672
6.394
29.994
3.926


2136










MAPT-
148
532
30.2155
0.61023315
29.784
5.066
30.647
4.74


2137










MAPT-
149
533
22.638
2.83974083
20.63
4.29
24.646
6.881


2269










MAPT-
150
534
12.216
1.87241876
10.892
3.111
13.54
3.021


2270










MAPT-
151
535
31.5845
14.4270997
21.383
9.46
41.786
5.402


2271










MAPT-
152
536
27.5985
12.4514433
36.403
7.932
18.794
4.51


2272










MAPT-
153
537
14.2115
3.25764094
11.908
3.525
16.515
2.483


2273










MAPT-
154
538
13.829
4.75317178
10.468
4.009
17.19
2.488


2274










MAPT-
155
539
19.6215
0.85772053
19.015
6.27
20.228
3.6


2275










MAPT-
156
540
13.741
6.74155605
8.974
4.323
18.508
4.472


2276










MAPT-
157
541
35.06
2.40133463
33.362
8.636
36.758
4.222


2277










MAPT-
158
542
62.9755
7.38007348
57.757
15.426
68.194
14.479


2278










MAPT-
159
543
12.3635
0.0629325
12.408
6.106
12.319
4.131


2279










MAPT-
160
544
22.4485
4.5672027
19.219
6.284
25.678
6.587


2280










MAPT-
161
545
11.262
3.82544769
13.967
4.235
8.557
4.509


2281










MAPT-
162
546
22.766
10.3704281
30.099
11.793
15.433
2.563


2282










MAPT-
163
547
22.093
2.21748687
23.661
9.459
20.525
5.485


2283










MAPT-
164
548
9.3375
0.48578236
9.681
3.741
8.994
2.065


2284










MAPT-
165
549
43.909
5.46452121
40.045
5.708
47.773
11.236


2286










MAPT-
166
550
44.999
0.15839192
45.111
3.984
44.887
11.572


2288










MAPT-
167
551
16.7085
2.74710984
18.651
6.81
14.766
5.374


2289










MAPT-
168
552
20.7095
1.76423142
19.462
4.227
21.957
4.191


2291










MAPT-
169
553
36.6055
15.5033162
47.568
9.742
25.643
7.144


2294










MAPT-
170
554
12.62
3.60624458
15.17
3.604
10.07
3.636


2299










MAPT-
171
555
17.296
0.32385491
17.525
5.091
17.067
4.382


2300










MAPT-
172
556
14.4115
2.7838794
12.443
3.439
16.38
5.47


2301










MAPT-
173
557
39.5035
12.6225632
48.429
8.232
30.578
4.345


2308










MAPT-
174
558
36.121
1.50755166
35.055
9.878
37.187
6.948


2316










MAPT-
175
559
23.2925
4.71145248
19.961
7.977
26.624
5.453


2317










MAPT-
176
560
46.479
18.4795286
33.412
7.15
59.546
16.236


2319










MAPT-
177
561
34.5325
16.1340554
45.941
18.317
23.124
5.385


2320










MAPT-
178
562
49.3475
9.8747462
56.33
10.684
42.365
6.267


2322










MAPT-
179
563
37.4055
9.99071171
44.47
7.337
30.341
7.651


2323










MAPT-
180
564
29.453
6.20981175
25.062
3.998
33.844
9.822


2324










MAPT-
181
565
40.7595
0.49709607
41.111
8.995
40.408
14.253


2326










MAPT-
182
566
53.6645
1.63129534
54.818
11.735
52.511
11.097


2330










MAPT-
183
567
41.555
10.4071976
34.196
6.582
48.914
10.912


2356










MAPT-
184
568
16.16
7.5702852
21.513
1.827
10.807
3.58


2357










MAPT-
185
569
15.9115
0.34718943
16.157
5.317
15.666
2.953


2358










MAPT-
186
570
38.779
13.5198817
48.339
12.534
29.219
3.728


2359










MAPT-
187
571
56.6595
2.41759808
58.369
9.583
54.95
7.626


2360










MAPT-
188
572
19.9675
15.8893965
31.203
7.037
8.732
1.814


2361










MAPT-
189
573
25.7945
4.27021785
28.814
11.436
22.775
6.312


2362










MAPT-
190
574
29.327
6.8094383
34.142
13.111
24.512
10.071


2363










MAPT-
191
575
13.174
2.66154992
11.292
3.193
15.056
3.026


2364










MAPT-
192
576
22.5375
0.18314066
22.408
4.494
22.667
3.198


2365










MAPT-
193
577
10.775
5.70918015
14.812
6.29
6.738
2.466


2372










MAPT-
194
578
14.297
0.80468752
13.728
3.586
14.866
3.452


2373










MAPT-
195
579
11.664
0.88529769
11.038
4.433
12.29
2.181


2374










MAPT-
196
580
19.954
1.3449171
20.905
3.625
19.003
5.119


2375










MAPT-
197
581
11.6305
7.16228459
6.566
2.913
16.695
5.49


2376










MAPT-
198
582
17.774
4.86630887
14.333
4.695
21.215
5.419


2377










MAPT-
199
583
15.912
6.94096016
11.004
7.297
20.82
6.571


2378










MAPT-
200
584
10.8575
3.47825826
8.398
3.267
13.317
2.091


2379










MAPT-
201
585
54.1995
16.1213275
42.8
16.849
65.599
12.511


2380










MAPT-
202
586
23.8745
5.39027499
20.063
5.735
27.686
4.702


2381










MAPT-
203
587
6.365
0.30547013
6.581
2.357
6.149
2.123


2382










MAPT-
204
588
6.377
0.34931075
6.13
2.062
6.624
1.482


2390










MAPT-
205
589
12.498
2.13121984
10.991
5.358
14.005
4.476


2391










MAPT-
206
590
66.506
38.9842111
38.94
9.142
94.072
16.71


2414










MAPT-
207
591
101.6285
16.4791235
89.976
32.779
113.281
40.057


2448










MAPT-
208
592
6.118
1.94171522
7.491
2.885
4.745
2.142


2449










MAPT-
209
593
5.428
0.44264885
5.741
1.379
5.115
0.708


2450










MAPT-
210
594
9.3195
2.04141728
7.876
3.092
10.763
3.026


2451










MAPT-
211
595
12.4495
0.23688077
12.282
3.89
12.617
3.728


2452










MAPT-
212
596
6.363
2.26981277
4.758
1.495
7.968
1.487


2453










MAPT-
213
597
7.1635
0.37264527
7.427
3.314
6.9
1.49


2454










MAPT-
214
598
5.641
0.69437886
6.132
1.582
5.15
2.739


2456










MAPT-
215
599
16.472
7.58584155
11.108
2.63
21.836
5.922


2457










MAPT-
216
600
12.6805
3.12329065
14.889
6.56
10.472
3.719


2567










MAPT-
217
601
64.8695
33.2927086
41.328
16.719
88.411
33.918


2598










MAPT-
218
602
68.409
37.9249651
41.592
8.109
95.226
13.823


2657










MAPT-
219
603
11.61
0.04384062
11.579
8.192
11.641
11.451


2723










MAPT-
220
604
233.808

233.808
161.639




2724










MAPT-
221
605
1302.476

1302.476
848.106




2726










MAPT-
222
606
10.97
5.81100353
6.861
1.876
15.079
4.091


2784










MAPT-
223
607
40.636
1.52876486
39.555
13.364
41.717
9.834


2963










MAPT-
224
608
67.4985
25.5979726
49.398
18.559
85.599
30.988


3110










MAPT-
225
609
34.0185
10.2622407
26.762
7.333
41.275
9.007


3114










MAPT-
226
610
23.677
5.0883404
20.079
5.942
27.275
7.786


3116










MAPT-
227
611
17.6195
5.74948524
21.685
7.03
13.554
4.395


3118










MAPT-
228
612
33.388
17.8502036
20.766
7.711
46.01
13.684


3158










MAPT-
229
613
108.324
38.5344911
135.572
60.571
81.076
13.918


3503










MAPT-
230
614
39.759
3.12258355
41.967
10.832
37.551
6.071


3589










MAPT-
231
615
204.4415
111.869243
125.338
69.843
283.545
162.626


3591










MAPT-
232
616
136.1045
32.3423571
113.235
30.524
158.974
46.677


3592










MAPT-
233
617
63.914
14.1619346
53.9
10.02
73.928
12.246


3593










MAPT-
234
618
80.7265
46.8465314
47.601
28.291
113.852
56.081


3594










MAPT-
235
619
33.518
3.51997756
31.029
3.774
36.007
4.987


3595










MAPT-
236
620
50.5415
9.44623949
57.221
22.189
43.862
7.353


3596










MAPT-
237
621
207.694
70.014885
158.186
64.728
257.202
178.898


3597










MAPT-
238
622
52.1005
3.0865211
49.918
5.249
54.283
7.413


3598










MAPT-
239
623
364.1355
362.407075
620.396
189.266
107.875
48.489


3599










MAPT-
240
624
100.4525
30.5364063
122.045
56.065
78.86
42.186


3600










MAPT-
241
625
47.233
12.1297097
38.656
5.821
55.81
7.764


3601










MAPT-
242
626
43.078
9.10894956
36.637
5.569
49.519
8.21


3602










MAPT-
243
627
46.1485
9.83797665
39.192
6.61
53.105
14.334


3603










MAPT-
244
628
38.537
6.97490129
43.469
6.803
33.605
12.721


3605










MAPT-
245
629
52.929
12.1099107
44.366
6.167
61.492
10.195


3607










MAPT-
246
630
61.4085
31.4839294
39.146
5.412
83.671
11.371


3609










MAPT-
247
631
53.294
26.6211561
34.47
5.122
72.118
6.918


3610










MAPT-
248
632
72.7675
16.9755125
60.764
8.013
84.771
12.398


3677










MAPT-
249
633
44.9005
19.9778879
30.774
5.138
59.027
10.698


3678










MAPT-
250
634
72.05
31.5638325
49.731
5.218
94.369
10.439


3679










MAPT-
251
635
58.9445
1.90565278
60.292
9.168
57.597
15.808


3680










MAPT-
252
636
60.937
9.03682466
54.547
8.505
67.327
20.084


3958










MAPT-
253
637
76.6655
34.4580206
52.3
5.769
101.031
26.056


3959










MAPT-
254
638
75.305
39.354735
47.477
5.803
103.133
19.335


3960










MAPT-
255
639
45.3385
7.61483293
39.954
10.197
50.723
5.643


3961










MAPT-
256
640
72.0995
2.20688026
70.539
7.456
73.66
8.937


3965










MAPT-
257
641
74.1615
12.9549033
65.001
14.647
83.322
16.913


3970










MAPT-
258
642
77.359
47.5543452
43.733
6.924
110.985
17.09


4146










MAPT-
259
643
42.89
0.51194531
43.252
6.788
42.528
13.112


4474










MAPT-
260
644
66.3895
44.1764962
35.152
5.684
97.627
19.713


4475










MAPT-
261
645
68.927
35.8870834
43.551
6.949
94.303
12.932


4477










MAPT-
262
646
50.6895
22.0624387
35.089
7.887
66.29
21.359


4478










MAPT-
263
647
40.2915
16.0223326
51.621
8.132
28.962
6.75


4479










MAPT-
264
648
62.963
18.7227734
76.202
15.622
49.724
17.779


4480










MAPT-
265
649
62.488
35.7329341
37.221
8.557
87.755
19.687


4481










MAPT-
266
650
96.4665
98.6859437
26.685
10.537
166.248
71.368


4482










MAPT-
267
651
67.466
56.8216867
27.287
9.898
107.645
19.981


4485










MAPT-
268
652
64.4675
54.6770319
25.805
8.223
103.13
13.135


4486










MAPT-
269
653
50.712
44.6028815
19.173
5.038
82.251
13.252


4532










MAPT-
270
654
56.2795
28.997742
35.775
6.797
76.784
17.19


4533










MAPT-
271
655
84.0985
66.4744014
37.094
8.676
131.103
23.594


4539










MAPT-
272
656
56.93
25.0980481
39.183
14.927
74.677
14.251


4540










MAPT-
273
657
42.061
23.7969716
25.234
4.689
58.888
6.414


4541










MAPT-
274
658
37.3465
16.4183124
25.737
2.55
48.956
6.301


4543










MAPT-
275
659
49.8975
30.8022785
28.117
6.319
71.678
14.003


4544










MAPT-
276
660
52.179
17.3524004
39.909
9.44
64.449
17.044


4545










MAPT-
277
661
34.6085
5.14420183
30.971
6.568
38.246
10.405


4546










MAPT-
278
662
38.51
12.7293363
29.509
9.311
47.511
5.308


4547










MAPT-
279
663
46.233
8.19678181
52.029
9.095
40.437
10.11


4548










MAPT-
280
664
46.195
5.19440641
49.868
9.773
42.522
9.731


4549










MAPT-
281
665
64.53
30.5625693
42.919
7.626
86.141
16.456


4550










MAPT-
282
666
48.566
4.18890057
45.604
10.327
51.528
13.065


4551










MAPT-
283
667
38.5625
36.1041651
13.033
5.295
64.092
10.666


4552










MAPT-
284
668
58.8795
40.1375022
30.498
5.099
87.261
14.948


4554










MAPT-
285
669
60.179
22.017891
44.61
13.332
75.748
6.493


4556










MAPT-
286
670
44.634
7.32704047
39.453
7.608
49.815
7.645


4557










MAPT-
287
671
44.4695
15.0436968
55.107
13.83
33.832
4.355


4558










MAPT-
288
672
62.3795
19.7912117
76.374
17.486
48.385
7.434


4559










MAPT-
289
673
48.0585
20.8518719
33.314
11.514
62.803
7.869


4560










MAPT-
290
674
45.0945
0.04030509
45.123
15.353
45.066
13.72


4561










MAPT-
291
675
31.412
1.63341666
32.567
5.823
30.257
5.108


4562










MAPT-
292
676
40.812
16.5957962
29.077
4.004
52.547
13.653


4563










MAPT-
293
677
51.221
23.9878904
34.259
9.457
68.183
17.349


4564










MAPT-
294
678
50.634
4.53396868
47.428
11.37
53.84
9.461


4615










MAPT-
295
679
50.985
5.68372431
55.004
11.45
46.966
8.038


4616










MAPT-
296
680
55.1025
21.5702924
70.355
20.557
39.85
5.507


4617










MAPT-
297
681
48.908
3.70665375
46.287
11.781
51.529
19.126


4618










MAPT-
298
682
38.3115
20.5859997
23.755
5.348
52.868
12.438


4619










MAPT-
299
683
34.8815
12.0597062
26.354
7.457
43.409
13.598


4620










MAPT-
300
684
50.155
18.3437641
37.184
8.204
63.126
8.376


4621










MAPT-
301
685
32.6225
1.30178358
33.543
5.593
31.702
6.676


4622










MAPT-
302
686
45.0005
13.5983705
35.385
8.943
54.616
7.648


4623










MAPT-
303
687
48.5845
6.76347636
43.802
5.103
53.367
7.374


4625










MAPT-
304
688
54.916
15.3710872
65.785
13.194
44.047
13.218


4627










MAPT-
305
689
35.7
2.4508321
33.967
6.77
37.433
7.946


4628










MAPT-
306
690
31.7615
4.28718841
28.73
7.064
34.793
10.844


4629










MAPT-
307
691
26.347
10.6235723
18.835
4.239
33.859
12.366


4630










MAPT-
308
692
39.4495
7.60917607
34.069
5.742
44.83
10.263


4632










MAPT-
309
693
61.3835
14.1074874
51.408
15.912
71.359
22.804


4633










MAPT-
310
694
52.238
12.4252804
43.452
10.809
61.024
10.061


4825










MAPT-
311
695
48.2045
2.66508546
46.32
8.016
50.089
16.64


4828










MAPT-
312
696
89.127
35.3779665
114.143
29.128
64.111
16.557


5682










MAPT-
313
697
46.249
12.6359982
37.314
6.879
55.184
14.344


5958










MAPT-
314
698
43.587
19.7523208
29.62
8.048
57.554
13.293


5959










MAPT-
315
699
40.428
6.24658131
36.011
10.381
44.845
4.108


5961










MAPT-
316
700
38.295
2.01808275
36.868
5.593
39.722
10.772


5963










MAPT-
317
701
52.7395
16.4678098
41.095
8.774
64.384
7.757


5964










MAPT-
318
702
45.2395
21.7541401
29.857
7.021
60.622
8.921


5965










MAPT-
319
703
51.0255
9.61877354
44.224
6.395
57.827
9.074


5966










MAPT-
320
704
56.756
19.2488608
43.145
10.168
70.367
13.456


5967










MAPT-
321
705
49.755
14.8365145
60.246
12.788
39.264
9.459


5968










MAPT-
322
706
30.953
2.88358145
32.992
7.492
28.914
6.891


6006










MAPT-
323
707
46.1245
14.5968053
35.803
7.552
56.446
6.025


6007










MAPT-
324
708
52.218
3.03065966
54.361
9.738
50.075
7.532


6008










MAPT-
325
709
76.4995
42.195183
106.336
19.189
46.663
11.419


6009










MAPT-
326
710
58.729
23.2892689
42.261
7.547
75.197
5.272


6010










MAPT-
327
711
52.692
4.01212388
49.855
12.113
55.529
14.5


6011










MAPT-
328
712
63.9645
0.68377226
64.448
15.339
63.481
10.773


6012










MAPT-
329
713
53.8995
17.2314852
66.084
23.254
41.715
10.372


6013










MAPT-
330
714
33.9865
1.58886894
32.863
4.884
35.11
8.916


6014










MAPT-
331
715
47.801
25.4077609
29.835
8.764
65.767
6.147


6015










MAPT-
332
716
46.9375
0.02192031
46.953
10.206
46.922
11.089


6017










MAPT-
333
717
54.6625
9.43492578
61.334
13.818
47.991
12.587


6119










MAPT-
334
718
64.7155
0.73468395
65.235
6.382
64.196
10.199


6628










MAPT-
335
719
50.0975
11.687768
58.362
10.929
41.833
14.095


6629










MAPT-
336
720
81.9435
12.0568777
73.418
19.87
90.469
17.638


6631










MAPT-
337
721
33.822
12.4677068
25.006
8.472
42.638
12.985


6672










MAPT-
338
722
24.959
10.8512607
17.286
2.982
32.632
9.031


6731










MAPT-
339
723
38.0145
13.7228213
28.311
11.443
47.718
15.906


6732










MAPT-
340
724
34.031
28.3691241
13.971
3.303
54.091
13.69


6738










MAPT-
341
725
38.316
29.593833
17.39
2.841
59.242
14.056


6739










MAPT-
342
726
34.866
13.8847488
25.048
11.345
44.684
6.187


6740










MAPT-
343
727
34.507
11.2825958
26.529
7.507
42.485
10.487


6741










MAPT-
344
728
62.1435
29.7882874
41.08
12.738
83.207
17.359


6742










MAPT-
345
729
29.6205
23.3790715
13.089
2.767
46.152
5.76


6743










MAPT-
346
730
26.926
10.1229407
19.768
4.146
34.084
5.015


6745










MAPT-
347
731
60.0265
3.40471915
57.619
11.694
62.434
11.211


6748










MAPT-
348
732
50.6395
36.3502383
24.936
4.104
76.343
16.107


6749










MAPT-
349
733
44.856
3.86080303
47.586
12.024
42.126
13.817


6750










MAPT-
350
734
78.4055
17.0730932
66.333
7.978
90.478
12.547


6751










MAPT-
351
735
50.173
15.0231907
60.796
7.566
39.55
9.59


6752










MAPT-
352
736
71.371
11.5413969
63.21
16.035
79.532
21.212


6753










MAPT-
353
737
36.8455
3.50654253
34.366
6.737
39.325
9.505


6754










MAPT-
354
738
49.7045
24.223357
66.833
10.306
32.576
5.734


6755










MAPT-
355
739
44.4755
32.1599235
21.735
7.721
67.216
9.314


6756










MAPT-
356
740
33.5075
4.63225652
30.232
9.588
36.783
6.407


6757










MAPT-
357
741
31.353
12.2753737
22.673
6.04
40.033
9.561


6758










MAPT-
358
742
41.85
0.46669048
41.52
10.866
42.18
7.164


6759










MAPT-
359
743
32.4735
18.9158135
45.849
11.71
19.098
3.864


6760










MAPT-
360
744
45.049
19.3718974
31.351
10.31
58.747
11.659


6761










MAPT-
361
745
38.174
8.13031377
43.923
15.429
32.425
4.765


6762










MAPT-
362
746
53.7735
2.06828733
52.311
15.07
55.236
8.063


6763










MAPT-
363
747
53.1035
33.2686669
29.579
9.81
76.628
17.226


6764










MAPT-
364
748
52.8995
16.5795327
41.176
10.853
64.623
15.24


6765










MAPT-
365
749
49.2605
4.00293149
52.091
10.614
46.43
16.518


6766










MAPT-
366
750
71.423
0.85701342
72.029
26.702
70.817
16.417


6767










MAPT-
367
751
55.4255
9.05308812
61.827
22.465
49.024
12.369


6768










MAPT-
368
752
72.08
0.29839906
71.869
16.441
72.291
37.177


6769










MAPT-
369
753
49.619
14.4377063
59.828
20.675
39.41
13.235


6772










MAPT-
370
754
48.624
11.5583674
56.797
12.783
40.451
6.391


6773










MAPT-
371
755
52.4405
31.8855661
29.894
6.706
74.987
5.573


6774










MAPT-
372
756
28.415
6.30456406
32.873
8.748
23.957
5.955


6775










MAPT-
373
757
39.772
4.84509566
43.198
3.707
36.346
9.384


6777










MAPT-
374
758
50.719
5.85342993
54.858
14.257
46.58
14.17


6778










MAPT-
375
759
35.5865
10.7459018
43.185
6.174
27.988
3.65


6779










MAPT-
376
760
71.501
11.9614183
79.959
23.953
63.043
14.252


6780










MAPT-
377
761
43.875
9.50210093
37.156
6.446
50.594
8.933


6781










MAPT-
378
762
43.4265
3.49381461
40.956
13.993
45.897
6.518


6789










MAPT-
379
763
46.25
28.0028427
26.449
10.778
66.051
11.602


6792










MAPT-
380
764
33.324
13.8762635
43.136
13.663
23.512
6.983


6793










MAPT-
381
765
33.747
11.8765655
42.145
13.155
25.349
9.4


6795










MAPT-
382
766
65.7615
8.10556503
71.493
9.454
60.03
12.964


6796










MAPT-
383
767
55.439
15.7302975
66.562
17.934
44.316
16.313


6797










MAPT-
384
768
50.3055
4.55023214
47.088
13.033
53.523
13.441


6798

















Example 3: GalNAc-Conjugated MAPT RNAi Oligonucleotides Inhibit Human MAPT mRNA Expression In Vivo

The in vitro screening assays in Example 2 validated the ability of MAPT-targeting oligonucleotides to knockdown target mRNA. To further evaluate the ability of MAPT RNAi oligonucleotides to inhibit MAPT mRNA expression, GalNAc-conjugated MAPT-targeting oligonucleotides were generated to confirm knockdown in vivo.


Specifically, a subset of the DsiRNAs identified in Example 2 were used to generate corresponding ds RNAi oligonucleotides comprising a nicked tetraloop GalNAc-conjugated structure (referred to herein as “GalNAc-conjugated MAPT oligonucleotides” or “GalNAc-MAPT oligonucleotides”) having a 36-mer sense strand and a 22-mer antisense strand (Tables 4 and 5). Further, the nucleotide sequences comprising the sense strand and antisense strand have a distinct pattern of modified nucleotides and phosphorothioate linkages. Three of the nucleotides comprising the tetraL were each conjugated to a GalNAc moiety (CAS #14131-60-3). The benchmark control (MA-PT-2460) has a different modification pattern than the remaining oligonucleotides. The modification patterns are illustrated below:









Sense Strand:


5′-X-S-mX-fX-mX-fX-mX-mX-fX-mX-fX-mX-fX-fX-mX-fX-


mX-fX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-[ademX-


GalNAc]-[ademX-GalNAc]-[ademX-GalNAc]-mX-mX-mX-mX-


mX-mX-3′ hybridized to:





Antisense Strand:


5′-[MePhosphonate-4O-mX]-S-fX-S-fX-fX-fX-mX-fX-mX-


mX-fX-mX-mX-mX-fX-mX-fX-mX-mX-fX-mX-S-mX-S-mX-3′.


(Modification key: Table 3).






Or, represented as:









Sense Strand:


[mXs][mX][fX][mX][fX][mX][mX][fX][mX][fX][mX][fX]


[fX][mX][fX][mX][fX][mX][mX][X][mX][mX][X][mX][mX]


[mX][mX][ademX-GalNAc][ademX-GalNAc][ademX-GalNAc]


[mX][mX][X][mX][mX][mX] hybridized to:





Antisense Strand:


[MePhosphonate-4O-mXs][fXs][fX][fX][fX][mX][fX]


[mX][mX][fX][mX][mX][mX][fX][mX][fX][mX][mX][fX]


[mXs][mXs][mX].


(Modification key: Table 3).






Benchmark Modification Pattern









Sense Strand:


5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX-mX-mX-mX-mX-


mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-[ademX-


GalNAc]-[ademX-GalNAc]-[ademX-GalNAc]-mX-mX-mX-mX-


mX-mX-3′ hybridized to:





Antisense Strand:


5′-[MePhosphonate-4O-mX]-S-fX-S-fX-S-fX-fX-mX-fX-


mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-


3′. (Modification key: Table 3).






Or, represented as:









Sense Strand:


[mXs][mX][mX][mX][mX][mX][mX][fX][fX][fX][fX][mX]


[mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX]


[mX][mX][mX][ademX-GalNAc][ademX-GalNAc][ademX-


GalNAc][mX][mX][mX][mX][mX][X] hybridized to:





Antisense Strand:


[MePhosphonate-4O-mXs][fXs][fX][fX][fX][X][fX][mX]


[mX][fX][mX][mX][mX][fX][mX][mX][mX][mX][mX][mXs]


[mXs][mX]. (Modification key: Table 3).













TABLE 3







Key for Modification Patterns.








Symbol
Modification/linkage










Key 1








mX
2′-OMe-modified nucleotide


fX
2′-F-modified nucleotide


-S-
phosphorothioate linkage


-
phosphodiester linkage


[MePhosphonate-
4′-O-monomethylphosphonate-2′-O-methyl modified


4O-mX]
nucleotide


ademX-GalNAc
GalNAc attached to a nucleotide


ademX-C16
C16 hydrocarbon chain attached to a nucleotide







Key 2








[mXs]
2′-OMe-modified nucleotide with a phosphorothioate



linkage to the neighboring nucleotide


[fXs]
2′-F-modified nucleotide with a phosphorothioate



linkage to the neighboring nucleotide


[mX]
2′-OMe-modified nucleotide with phosphodiester



linkages to neighboring nucleotides


[fX]
2′-F-modified nucleotide with phosphodiester linkages



to neighboring nucleotides


[ademXs-C16]
C16 hydrocarbon chain attached to a nucleotide with



phosphodiester linkages to neighboring nucleotides









The GalNAc-conjugated MAPT-targeting oligonucleotides were used in an HDI model to confirm the ability of the RNAi oligonucleotides to knockdown MAPT gene expression in vivo. The GalNAc-conjugated MAPT-targeting oligonucleotides listed in Tables 4 and 5 were evaluated in mice engineered to transiently express human MAPT mRNA in hepatocytes of the mouse liver. Briefly, 6-8-week-old female CD-i mice (n=4-5) were subcutaneously administered the indicated GalNAc-conjugated MAPT-targeting oligonucleotides at a dose of 3 mg/kg formulated in PBS. A control group of mice (n=5) were administered only PBS. Four days later (96 hours), the mice were HDI with a DNA plasmid encoding the full human MAPT gene (SEQ TD NO: 909) (10 μg) under control of a ubiquitous cytomegalovirus (CMV) promoter sequence. One day after introduction of the DNA plasmid, liver samples from HDI mice were collected. Total RNA derived from these HDI mice were subjected to qRT-PCR analysis to determine human MAPT mRNA levels as described in Example 2. The values were normalized for transfection efficiency using the NeoR gene included on the DNA plasmid. Benchmark controls (MA-PT-2460) were used to confirm successful knock-down.









TABLE 4







GalNAc-Conjugated Human MAPT-Targeting RNAi


Oligonucleotides for HDI Screen (Set I).











RNAi
SEQ ID NO
SEQ ID NO
SEQ ID NO
SEQ ID NO


Oligonucleo-
(Sense)
(Antisense)
(Sense)
(Antisense)









tide
Unmodified
Modified














MAPT-1479
787
822
857
892


MAPT-1505
788
823
858
893


MAPT-2096
789
824
859
894


MAPT-2270
790
825
860
895


MAPT-2279
791
826
861
896


MAPT-2281
792
827
862
897


MAPT-2284
793
828
863
898


MAPT-2299
794
829
864
899


MAPT-2376
795
830
865
900


MAPT-2379
796
831
866
901


MAPT-2382
797
832
867
902


MAPT-2449
798
833
868
903


MAPT-2450
799
834
869
904


MAPT-2451
800
835
870
905


MAPT-2452
801
836
871
906


MAPT-2453
802
837
872
907


MAPT-2454
803
838
873
908


MAPT-2460
786
821
856
891
















TABLE 5







GalNAc-Conjugated Human MAPT-Targeting RNAi


Oligonucleotides for HDI Screen (Set II).











RNAi
SEQ ID NO
SEQ ID NO
SEQ ID NO
SEQ ID NO


Oligonucleo-
(Sense)
(Antisense)
(Sense)
(Antisense)









tide
Unmodified
Modified














MAPT-2456
769
804
839
874


MAPT-2567
770
805
840
875


MAPT-2723
771
806
841
876


MAPT-0690
772
807
842
877


MAPT-1494
773
808
843
878


MAPT-1733
774
809
844
879


MAPT-2273
775
810
845
880


MAPT-2274
776
811
846
881


MAPT-2276
777
812
847
882


MAPT-2301
778
813
848
883


MAPT-2347
779
814
849
884


MAPT-2357
780
815
850
885


MAPT-2358
781
816
851
886


MAPT-2364
782
817
852
887


MAPT-2378
783
818
853
888


MAPT-2459
784
819
854
889


MAPT-2461
785
820
855
890


MAPT-2460
786
821
856
891









The results in FIGS. 1A and 1B demonstrate that GalNAc-conjugated MAPT-targeting oligonucleotides (as shown in Tables 4 and 5, respectively) designed to target human MAPT mRNA successfully inhibited human MAPT mRNA expression in HDI mice, as determined by a reduction in the amount of human MAPT mRNA expression in liver samples from HDI mice treated with GalNAc-conjugated MAPT-targeting oligonucleotides relative to control HDI mice treated with only PBS.


Example 4: GalNAc-Conjugated MAPT-Targeting RNAi Oligonucleotides Inhibit Human MAPT Gene Expression in A Dose-Dependent Manner

To further evaluate the ability of GalNAc-conjugated MAPT-targeting RNAi oligonucleotides to inhibit MAPT gene expression, a dose response study was carried out. Specifically, in separate treatment groups, selected GalNAc-conjugated MAPT-targeting RNAi oligonucleotides (Tables 6 and 7) were formulated in PBS and were administered to CD-1 mice at doses of 0.3 mg/kg, 1 mg/kg, or 3 mg/kg subcutaneously. As described in Example 3, a human MAPT DNA expression plasmid was administered to the mice 4 days post-oligonucleotide dosing, and livers were collected 20 hours later for qRT-PCR analysis. As shown in FIGS. 2A and 2B, all of the GalNAc-conjugated MAPT-targeting RNAi oligonucleotides tested inhibited human MAPT gene expression in a dose-dependent manner. Potent GalNAc-conjugated MAPT-targeting oligonucleotides (i.e., MAPT-2449, MAPT-2357, MAPT-2450, MAPT-2358, MAPT-2454, and MAPT-2723) reduced MAPT mRNA by around 50% or more at 1 mg/kg and even further at 3 mg/kg. These constructs were selected for further studies in NHPs.









TABLE 6







GalNAc-Conjugated Human MAPT-Targeting RNAi


Oligonucleotides for Dose Screen (Set I).











RNAi
SEQ ID NO
SEQ ID NO
SEQ ID NO
SEQ ID NO


Oligonucleo-
(Sense)
(Antisense)
(Sense)
(Antisense)









tide
Unmodified
Modified














MAPT-2270
790
825
860
895


MAPT-2376
795
830
865
900


MAPT-2449
798
833
868
903


MAPT-2450
799
834
869
904


MAPT-2454
803
838
873
908
















TABLE 7







GalNAc-Conjugated Human MAPT-Targeting RNAi


Oligonucleotides for Dose Screen (Set II).











RNAi
SEQ ID NO
SEQ ID NO
SEQ ID NO
SEQ ID NO


Oligonucleo-
(Sense)
(Antisense)
(Sense)
(Antisense)









tide
Unmodified
Modified














MAPT-2723
771
806
841
876


MAPT-2274
776
811
846
881


MAPT-2357
780
815
850
885


MAPT-2358
781
816
851
886


MAPT-2364
782
817
852
887









Example 5: RNAi Oligonucleotide Inhibition of MAPT Gene Expression in NHP CNS

Effective GalNAc-conjugated MAPT-targeting oligonucleotides identified in the HDI mouse studies were assayed for inhibition in NHP. Specifically, GalNAc-conjugated MAPT-targeting oligonucleotides listed in Table 8 were evaluated in non-naïve cynomolgus monkeys (Macaca fascicularis; Mf). Each cohort contained 4 female subjects weighing 2.6-4.3 kg. The GalNAc-conjugated MAPT-targeting oligonucleotides were administered at a dose of 50 mg in 1.6 mL of artificial cerebrospinal fluid (aCSF) on study days 0 and 7 via intra cisterna magna (i.c.m.) injection.









TABLE 8







GalNAc-Conjugated MAPT-Targeting RNAi


Oligonucleotides for NHP Study.














SEQ
SEQ
SEQ
SEQ


RNAi

ID NO
ID NO
ID NO
ID NO


Oligonucleo-
Alternate
(Sense)
(Antisense)
(Sense)
(Antisense)










tide
name
Unmodified
Modified















MAPT-2723
DCR 214
771
806
841
876


MAPT-2357
DCR 211
780
815
850
885


MAPT-2358
DCR 212
781
816
851
886


MAPT-2449
DCR 207
798
833
868
903


MAPT-2450
DCR 208
799
834
869
904


MAPT-2454
DCR 209
803
838
873
908









On study day 14, CNS tissue was collected and subjected to qRT-PCR analysis to measure MAPT mRNA in oligonucleotide-treated monkeys relative to those treated with a comparable volume of aCSF. To normalize the data, the measurements were made relative to the reference gene, RPL23. The following SYBR assays purchased from Integrated DNA Technologies were used to evaluate gene expressions:











Forward: AGGACAGAGTGCAGTCGAAGATC;







Reverse: AGGTCAGCTTGTGGGTTTCAA;



and







Probe: CACCCATGTCCCTGGCGGAGG.






As shown in FIGS. 3A-3M (Day 14), treating NHPs with the GalNAc-conjugated MAPT-targeting oligonucleotides inhibited MAPT gene expression in several regions of the CNS, as determined by a reduced amount of MAPT mRNA in brain samples from oligonucleotide-treated NHPs relative to NHPs treated with aCSF. Several GalNAc-conjugated MAPT-targeting oligonucleotides reduced MAPT gene expression throughout the CNS. MAPT-2357 (DCR 211) was particularly potent in the cervical spinal cord, thoracic spinal cord, lumbar spinal cord, frontal cortex, temporal cortex, occipital cortex, and brain stem. These results demonstrate that treating NHPs with the GalNAc-conjugated MAPT-targeting oligonucleotides reduces the amount of MAPT mRNA in the CNS.


Example 6: Lipid Conjugation of MAPT-Targeting Oligonucleotides Reduces

Expression in NHP CNS


To further investigate the efficacy of oligonucleotides targeting MAPT, a lipid-conjugated oligonucleotide was assessed in NHP compared to a GalNAc-conjugated oligonucleotide. Specifically, the GalNAc-conjugated MAPT-2357 (DCR 211) described in Example 3, having a 36-mer sense strand and 22-mer antisense strand (SEQ ID NOs: 850 and 885, respectively) was compared to a lipid-conjugated MAPT-2357 (DCR 211), having a 20-mer sense strand and 22-mer antisense strand (SEQ ID NOs: 1682 and 885, respectively). FIGS. 4A-4B show the chemical modification patterns of each oligonucleotide, and the chemical modification pattern of the lipid-conjugated oligonucleotide is provided below:









Sense Strand:


5′-[ademX-C16]-S-mX-fX-mX-fX-mX-mX-fX-mX-fX-mX-fX-


fX-mX-fX-mX-fX-mX- S-mX-S-mX-3′ hybridized to:





Antisense Strand:


5′-[MePhosphonate-4O-mX]-S-fX-S-fX-fX-fX-mX-fX-mX-


mX-fX-mX-mX-mX-fX-mX-fX-mX-mX-fX-mX-S-mX-S-mX-3′.


(Modification key: Table 3).






Or, represented as:









Sense Strand:


[ademXs-C16][mX][fX][mX][fX][mX][mX][fX][mX][fX]


[mX][fX][fX][mX][fX][mX][fX][mXs][mXs][mX]


hybridized to:





Antisense Strand:


[MePhosphonate-4O-mXs][fXs][fX][fX][fX][mX][fX]


[mX][mX][fX][mX][mX][mX][fX][mX][fX][mX][mX][fX]


[mXs][mXs][mX] (Modification key: Table 3).






Lipid Conjugation


Conjugation of a lipid moiety to the MAPT-targeting oligonucleotide was carried out using phosphoramidite synthesis as shown below.


Synthesis of 2-(2-((((6aR,8R,9R,9aR)-8-(6-benzamido-9H-purin-9-vl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl)oxy)methoxy)ethoxy) ethan-1-ammonium formate (1-6)



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A solution of compound 1-1 (25.00 g, 67.38 mmol) in 20 mL of dimethylformamide (DMF) was treated with pyridine (11 mL, 134.67 mmol) and tetraisopropyldisiloxane dichloride (22.63 mL, 70.75 mmol) at 10° C. The resulting mixture was stirred at 25° C. for 3 hours and quenched with 20% citric acid (50 mL). The aqueous layer was extracted with ethyl acetate (EtOAc; 3×50 mL) and the combined organic layers were concentrated in vacuo. The crude residue was recrystallized from a mixture of methyl tert-butyl ether (MTBE) and n-heptane (1:15, 320 mL) to afford compound 1-2 (37.20 g, 90%) as a white oily solid.


A solution of compound 1-2 (37.00 g, 60.33 mmol) in 20 mL of DMSO was treated with acetic acid (AcOH; 20 mL, 317.20 mmol) and Ac2O (15 mL, 156.68 mmol). The mixture was stirred at 25° C. for 15 h. The reaction was diluted with EtOAc (100 mL) and quenched with sat. potassium carbonate (K2CO3; 50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were concentrated and recrystallized with acetonitrile (can; 30 mL) to afford compound 1-3 (15.65 g, 38.4%) as a white solid.


A solution of compound 1-3 (20.00 g, 29.72 mmol) in 120 mL of dichloromethane (DCM) was treated with Fmoc-amino-ethoxy ethanol (11.67 g, 35.66 mmol) at 25° C. The mixture was stirred to afford a clear solution and then treated with 4 Å molecular sieves (20.0 g), N-iodosuccinimide (8.02 g, 35.66 mmol), and trifluoromethanesulfonic acid (TfOH; 5.25 mL, 59.44 mmol). The mixture was stirred at 30° C. until the HPLC analysis indicated>95% consumption of compound 1-3. The reaction was quenched with TEA (6 mL) and filtered. The filtrate was diluted with EtOAc, washed with sat. Sodium bicarbonate (NaHCO3; 2×100 mL), sat. sodium sulfite (Na2SO3; 2×100 mL), and water (2×100 mL) and concentrated in vacuo to afford crude compound 1-4 (26.34 g, 93.9%) as a yellow solid, which was used directly for the next step without further purification.


A solution of compound 1-4 (26.34 g, 27.62 mmol) in a mixture of DCM/water (10:7, 170 mL) was treated with 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU; 7.00 mL, 45.08 mmol) at 5° C. The mixture was stirred at 5-25° C. for 1 hour. The organic layer was then separated, washed with water (100 mL), and diluted with DCM (130 mL). The solution was treated with fumaric acid (7.05 g, 60.76 mmol) and 4 Å molecular sieves (26.34 g) in four portions. The mixture was stirred for 1 hour, concentrated, and recrystallized from a mixture of MTBE and DCM (5:1) to afford compound 1-6 (14.74 g, 62.9%) as a white solid: 1H NMR (400 MHz, d6-DMSO) 8.73 (s, 1H), 8.58 (s, 1H), 8.15-8.02 (m, 2H), 7.65-7.60 (m, 1H), 7.59-7.51 (m, 2H), 6.52 (s, 2H), 6.15 (s, 1H), 5.08-4.90 (m, 3H), 4.83-4.78 (m, 1H), 4.15-3.90 (m, 3H), 3.79-3.65 (m, 2H), 2.98-2.85 (m, 6H), 1.20-0.95 (m, 28H).


Synthesis of (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((2-(2-[lipid]-amidoethoxy)ethoxy)methoxy) tetrahydrofuran-3-vl (2-cyanoethyl) diisopropylphosphoramidite (2-4a to 2-4e)



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A solution of compound 1-6 (50.00 g, 59.01 mmol) in 150 mL of 2-methyltetrahydrofuran was washed with ice cold aqueous dipotassium hydrogen phosphate (K2HPO4; 6%, 100 mL) and brine (20%, 2×100 mL). The organic layer was separated and treated with hexanoic acid (10.33 mL, 82.61 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 33.66 g, 88.52 mmol), and 4-dimethylaminopyridine (DMAP; 10.81 g, 147.52 mmol) at 0° C. The resulting mixture was warmed to 25° C. and stirred for 1 hour. The solution was washed with water (2×100 mL), brine (100 mL), and concentrated in vacuo to afford a crude residue. Flash chromatography on silica gel (1:1 hexanes/acetone) gave compound 2-1a (34.95 g, 71.5%) as a white solid.


A mixture of compound 2-1a (34.95 g, 42.19 mmol) and TEA (9.28 mL, 126.58 mmol) in 80 mL of tetrahydrofuran (THF) was treated with triethylamine trihydrofluoride (20.61 mL, 126.58 mmol) dropwise at 10° C. The mixture was warmed to 25° C. and stirred for 2 hours. The reaction was concentrated, dissolved in DCM (100 mL), and washed with sat. NaHCO3 (5×20 mL) and brine (50 mL). The organic layer was concentrated in vacuo to afford crude compound 2-2a (24.72 g, 99%), which was used directly for the next step without further purification.


A solution of compound 2-2a (24.72 g, 42.18 mmol) in 50 mL of DCM was treated with N-methylmorpholine (18.54 mL, 168.67 mmol) and DMTr-Cl (15.69 g, 46.38 mmol). The mixture was stirred at 25° C. for 2 hours and quenched with sat. NaHCO3 (50 mL). The organic layer was separated, washed with water, and concentrated to afford a slurry crude. Flash chromatography on silica gel (1:1 hexanes/acetone) gave compound 2-3a (30.05 g, 33.8 mmol, 79.9%) as a white solid.


A solution of compound 2-3a (25.00 g, 28.17 mmol) in 50 mL of DCM was treated with N-methylmorpholine (3.10 mL, 28.17 mmol) and tetrazole (0.67 mL, 14.09 mmol) under nitrogen atmosphere. Bis(diisopropylamino) chlorophosphine (9.02 g, 33.80 mmol) was added to the solution dropwise, and the resulting mixture was stirred at 25° C. for 4 hours. The reaction was quenched with water (15 mL), and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were washed with sat. NaHCO3 (50 mL), concentrated to afford a crude solid that was recrystallized from a mixture of DCM/MTBE/n-hexane (1:4:40) to afford compound 2-4a (25.52 g, 83.4%) as a white solid: 1H NMR (400 MHz, d6-DMSO) 11.25 (s, 1H), 8.65-8.60 (m, 2H), 8.09-8.02 (m, 2H), 7.71 (s, 1H), 7.67-7.60 (m, 1H), 7.59-7.51 (m, 2H), 7.38-7.34 (m, 2H), 7.30-7.25 (m, 7H), 6.85-6.79 (m, 4H), 6.23-6.20 (m, 1H), 5.23-5.14 (m, 1H), 4.80-4.69 (m, 3H), 4.33-4.23 (m, 2H), 3.90-3.78 (m, 1H), 3.75 (s, 6H), 3.74-3.52 (m, 3H), 3.50-3.20 (m, 6H), 3.14-3.09 (m, 2H), 3.09 (s, 1H), 2.82-2.80 (m, 1H), 2.65-2.60 (m, 1H), 2.05-1.96 (m, 2H), 1.50-1.39 (m, 2H), 1.31-1.10 (m, 14H), 1.08-1.05 (m, 2H), 0.85-0.79 (m, 3H); 31P NMR (162 MHz, d6-DMSO) 149.43, 149.18.


Compound 2-4b, 2-4c, 2-4d, and 2-4e were prepared using similar procedures described above for compound 2-4a. Compound 2-4b was obtained (25.50 g, 85.4%) as a white solid: 1H NMR (400 MHz, d6-DMSO) 11.23 (s, 1H), 8.65-8.60 (m, 2H), 8.05-8.02 (m, 2H), 7.73-7.70 (m, 1H), 7.67-7.60 (m, 1H), 7.59-7.51 (m, 2H), 7.38-7.34 (m, 2H), 7.30-7.25 (m, 7H), 6.89-6.80 (m, 4H), 6.21-6.15 (m, 1H), 5.23-5.17 (m, 1H), 4.80-4.69 (m, 3H), 4.40-4.21 (m, 2H), 3.91-3.80 (m, 1H), 3.74 (s, 6H), 3.74-3.52 (m, 3H), 3.50-3.20 (m, 6H), 3.14-3.09 (m, 2H), 3.09 (s, 1H), 2.83-2.79 (m, 1H), 2.68-2.62 (m, 1H), 2.05-1.97 (m, 2H), 1.50-1.38 (m, 2H), 1.31-1.10 (m, 18H), 1.08-1.05 (m, 2H), 0.85-0.78 (m, 3H); 31P NMR (162 MHz, d6-DMSO) 149.43, 149.19.


Compound 2-4c was obtained (36.60 g, 66.3%) as an off-white solid: 1H NMR (400 MHz, d6-DMSO) 11.22 (s, 1H), 8.64-8.59 (m, 2H), 8.05-8.00 (m, 2H), 7.73-7.70 (m, 1H), 7.67-7.60 (m, 1H), 7.59-7.51 (m, 2H), 7.38-7.34 (m, 2H), 7.30-7.25 (m, 7H), 6.89-6.80 (m, 4H), 6.21-6.15 (m, 1H), 5.25-5.17 (m, 1H), 4.80-4.69 (m, 3H), 4.40-4.21 (m, 2H), 3.91-3.80 (m, 1H), 3.74 (s, 6H), 3.74-3.50 (m, 3H), 3.50-3.20 (m, 6H), 3.14-3.09 (m, 2H), 3.09 (s, 1H), 2.83-2.79 (m, 1H), 2.68-2.62 (m, 1H), 2.05-1.99 (m, 2H), 1.50-1.38 (m, 2H), 1.33-1.12 (m, 38H), 1.08-1.05 (m, 2H), 0.86-0.80 (m, 3H); 31P NMR (162 MHz, d6-DMSO) 149.42, 149.17.


Compound 2-4d was obtained (26.60 g, 72.9%) as an off-white solid: 1H NMR (400 MHz, d6-DMSO) 11.22 (s, 1H), 8.64-8.59 (m, 2H), 8.05-8.00 (m, 2H), 7.73-7.70 (m, 1H), 7.67-7.60 (m, 1H), 7.59-7.51 (m, 2H), 7.38-7.33 (m, 2H), 7.30-7.25 (m, 7H), 6.89-6.80 (m, 4H), 6.21-6.15 (m, 1H), 5.22-5.17 (m, 1H), 4.80-4.69 (m, 3H), 4.40-4.21 (m, 2H), 3.91-3.80 (m, 1H), 3.74 (s, 6H), 3.74-3.52 (m, 3H), 3.50-3.20 (m, 6H), 3.14-3.09 (m, 2H), 3.09 (s, 1H), 2.83-2.79 (m, 1H), 2.68-2.62 (m, 1H), 2.05-1.99 (m, 2H), 1.50-1.38 (m, 2H), 1.35-1.08 (m, 38H), 1.08-1.05 (m, 2H), 0.85-0.79 (m, 3H); 31P NMR (162 MHz, d6-DMSO) 149.47, 149.22.


Compound 2-4e was obtained (38.10 g, 54.0%) as a white solid: 1H NMR (400 MHz, d6-DMSO) 11.21 (s, 1H), 8.64-8.59 (m, 2H), 8.05-8.00 (m, 2H), 7.73-7.70 (m, 1H), 7.67-7.60 (m, 1H), 7.59-7.51 (m, 2H), 7.38-7.34 (m, 2H), 7.30-7.25 (m, 7H), 6.89-6.80 (m, 4H), 6.21-6.15 (m, 1H), 5.23-5.17 (m, 1H), 4.80-4.69 (m, 3H), 4.40-4.21 (m, 2H), 3.91-3.80 (m, 1H), 3.73 (s, 6H), 3.74-3.52 (m, 3H), 3.47-3.22 (m, 6H), 3.14-3.09 (m, 2H), 3.09 (s, 1H), 2.83-2.79 (m, 1H), 2.68-2.62 (m, 1H), 2.05-1.99 (m, 2H), 1.50-1.38 (m, 2H), 1.35-1.06 (m, 46H), 1.08-1.06 (m, 2H), 0.85-0.77 (m, 3H); 31P NMR (162 MHz, d6-DMSO) 149.41, 149.15.


Lipid-conjugated blunt-ended oligonucleotides described herein were synthesized using a standard procedure known in the literature for oligo synthesis on a synthesizer using amidite chemistry.


NHP Study


NHPs (n=4) were intrathecally administered 37.5 mg lipid-conjugated or 45 mg GalNAc-conjugated MAPT-2357 (DCR 211) via lumbar infusion at L1 (see Table 9). Artificial cerebral spinal fluid (aCSF) was used as a control.









TABLE 9







Conjugated MAPTRNAi Oligonucleotides for NHP Study.
















SEQ ID NO
SEQ ID NO
SEQ ID NO
SEQ ID NO



Alternate

(Sense)
(Antisense)
(Sense)
(Antisense)











RNAi Oligo
Name
Conjugate
Unmodified
Modified
















MAPT-2357
DCR 211
C16
1681
815
1682
885


MAPT-2357
DCR 211
GalNAc
 780
815
 850
885









28 days after administration, CNS tissue was collected to determine the concentration of the oligonucleotide and the level of MAPT gene expression. AD is a chronic neurodegenerative disease characterized by a progressive decline in cognitive abilities such as memory, thinking, language, and learning; whereas, PSP is a less common brain disorder characterized by deterioration in brain regions responsible for movement, coordination, and eventually cognition. Accordingly, CNS tissues associated with AD or PSP were analyzed separately.


As shown in FIG. 5A, MAPT gene expression was reduced in tissues associated with AD, including the prefrontal cortex, motor cortex, temporal cortex, parietal cortex, and hippocampus, with both lipid-conjugated and GalNAc-conjugated MAPT-2357. Lipid conjugation resulted in a higher reduction of MAPT gene expression compared to GalNAc conjugation. MAPT gene expression was determined as described in the above Examples. FIG. 5B shows a higher concentration of lipid-conjugated MAPT-2357 in the same tissues compared to GalNAc-conjugated MAPT-2357. These results indicate lipid-conjugated MAPT-targeting oligonucleotides have enhanced potency even at a reduced dose compared to GalNAc-conjugated MAPT-targeting oligonucleotides across tissues associated with AD.


As shown in FIG. 6A, MAPT gene expression was reduced in tissues associated with PSP, including the caudate nucleus, thalamus, midbrain tegmentum, substantia nigra, pons, cerebellar white matter, cerebellar dentate nucleus, medulla, cervical spinal cord, thoracic spinal cord, and lumbar spinal cord with both lipid-conjugated and GalNAc-conjugated MAPT-2357. Lipid-conjugation resulted in a higher reduction of MAPT gene expression compared to GalNAc-conjugation. MAPT gene expression was determined as described in the above Examples. FIG. 6B shows a higher concentration of lipid-conjugated MAPT-2357 in the same tissues compared to GalNAc-conjugated MAPT-2357. These results indicate lipid-conjugated MAPT-targeting oligonucleotides have enhanced potency even at a reduced dose compared to GalNAc-conjugated MAPT-targeting oligonucleotides across tissues associated with PSP.


SEQUENCE LISTING

The following nucleic and/or amino acid sequences are referred to in the disclosure and are provided below for reference.


















Species

SEQ




and

ID


Construct

location
Sequence
NO



















MAPT-
25 mer
2141-2218-
GAGAACCUGAAGCACCAGCAGGGAG
1


2141
sense
966 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2142-2219-
AGAACCUGAAGCACCAGCCAGGAGG
2


2142
sense
967 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2303-2380-
GUGACCUCCAAGUGUGGCUAAUUAG
3


2303
sense
1128 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2347-2424-
AGGAGGUGGCCAGGUGGAAAUAAAA
4


2347
sense
1172 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2349-2426-
GAGGUGGCCAGGUGGAAGUAAAATC
5


2349
sense
1174 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2350-2427-
AGGUGGCCAGGUGGAAGUAAAAUCT
6


2350
sense
1175 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2351-2428-
GGUGGCCAGGUGGAAGUAAAAUCTG
7


2351
sense
1176 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2352-2429-
GUGGCCAGGUGGAAGUAAAAUCUGA
8


2352
sense
1177 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2353-2430-
UGGCCAGGUGGAAGUAAAAACUGAG
9


2353
sense
1178 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2354-2431-
GGCCAGGUGGAAGUAAAAUAUGAGA
10


2354
sense
1179 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2355-2432-
GCCAGGUGGAAGUAAAAUCAGAGAA
11


2355
sense
1180 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2459-2536-
AAGAUUGAAACCCACAAGCAGACCT
12


2459
sense
1284 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2460-2537-
AGAUUGAAACCCACAAGCUAACCTT
13


2460
sense
1285 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2461-2538-
GAUUGAAACCCACAAGCUGACCUTC
14


2461
sense
1286 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2462-2539-
AUUGAAACCCACAAGCUGAACUUCC
15


2462
sense
1287 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2463-2540-
UUGAAACCCACAAGCUGACAUUCCG
16


2463
sense
1288 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2464-2541-
UGAAACCCACAAGCUGACCAUCCGC
17


2464
sense
1289 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2465-2542-
GAAACCCACAAGCUGACCUACCGCG
18


2465
sense
1290 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2466-2543-
AAACCCACAAGCUGACCUUACGCGA
19


2466
sense
1291 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2467-2544-
AACCCACAAGCUGACCUUCAGCGAG
20


2467
sense
1292 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2495-2572-
GCCAAAGCCAAGACAGACCACGGGG
21


2495
sense
1320 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
2496-2573-
CCAAAGCCAAGACAGACCAAGGGGC
22


2496
sense
1321 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
3686-3758-
UCUUUGUAAGGACUUGUGCAUCUTG
23


3686
sense
2505 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
3687-3759-
CUUUGUAAGGACUUGUGCCACUUGG
24


3687
sense
2506 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
3688-3760-
UUUGUAAGGACUUGUGCCUAUUGGG
25


3688
sense
2507 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
3691-3763-
GUAAGGACUUGUGCCUCUUAGGAGA
26


3691
sense
2510 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
3692-3764-
UAAGGACUUGUGCCUCUUGAGAGAC
27


3692
sense
2511 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
3693-3765-
AAGGACUUGUGCCUCUUGGAAGACG
28


3693
sense
2512 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4534-4605-
GUUGUAGUUGGAUUUGUCUAUUUAT
29


4534
sense
3332 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4535-4606-
UUGUAGUUGGAUUUGUCUGAUUATG
30


4535
sense
3333 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4536-4607-
UGUAGUUGGAUUUGUCUGUAUAUGC
31


4536
sense
3334 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4537-4608-
GUAGUUGGAUUUGUCUGUUAAUGCT
32


4537
sense
3335 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4538-4609-
UAGUUGGAUUUGUCUGUUUAUGCTT
33


4538
sense
3336 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4566-4637-
UUCACCAGAGUGACUAUGAAAGUGA
34


4566
sense
3362 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4567-4638-
UCACCAGAGUGACUAUGAUAGUGAA
35


4567
sense
3363 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4568-4639-
CACCAGAGUGACUAUGAUAAUGAAA
36


4568
sense
3364 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4569-4640-
ACCAGAGUGACUAUGAUAGAGAAAA
37


4569
sense
3365 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4570-4641-
CCAGAGUGACUAUGAUAGUAAAAAG
38


4570
sense
3366 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4571-4642-
CAGAGUGACUAUGAUAGUGAAAAGA
39


4571
sense
3367 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4572-4643-
AGAGUGACUAUGAUAGUGAAAAGAA
40


4572
sense
3368 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4573-4644-
GAGUGACUAUGAUAGUGAAAAGAAA
41


4573
sense
3369 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4574-4645-
AGUGACUAUGAUAGUGAAAAGAAAA
42


4574
sense
3370 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4575-4646-
GUGACUAUGAUAGUGAAAAAAAAAA
43


4575
sense
3371 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4576-4647-
UGACUAUGAUAGUGAAAAGAAAAAA
44


4576
sense
3372 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4577-4648-
GACUAUGAUAGUGAAAAGAAAAAAA
45


4577
sense
3373 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4578-4649-
ACUAUGAUAGUGAAAAGAAAAAAAA
46


4578
sense
3374 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4579-4650-
CUAUGAUAGUGAAAAGAAAAAAAAA
47


4579
sense
3375 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4580-4651-
UAUGAUAGUGAAAAGAAAAAAAAAA
48


4580
sense
3376 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4605-4677-
AAAAAAAAGGACGCAUGUAACUUGA
49


4605
sense
3439 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4606-4678-
AAAAAAAGGACGCAUGUAUAUUGAA
50


4606
sense
3440 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4607-4679-
AAAAAAGGACGCAUGUAUCAUGAAA
51


4607
sense
3441 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4608-4680-
AAAAAGGACGCAUGUAUCUAGAAAT
52


4608
sense
3442 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4609-4681-
AAAAGGACGCAUGUAUCUUAAAATG
53


4609
sense
3443 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4610-4682-
AAAGGACGCAUGUAUCUUGAAAUGC
54


4610
sense
3444 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4611-4683-
AAGGACGCAUGUAUCUUGAAAUGCT
55


4611
sense
3445 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4612-4684-
AGGACGCAUGUAUCUUGAAAUGCTT
56


4612
sense
3446 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4613-4685-
GGACGCAUGUAUCUUGAAAAGCUTG
57


4613
sense
3447 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
4614-4686-
GACGCAUGUAUCUUGAAAUACUUGT
58


4614
sense
3448 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5969-6024-
UCACUUUAUCAAUAGUUCCAUUUAA
59


5969
sense
4540 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5970-6025-
CACUUUAUCAAUAGUUCCAAUUAAA
60


5970
sense
4541 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5971-6026-
ACUUUAUCAAUAGUUCCAUAUAAAT
61


5971
sense
4542 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5972-6027-
CUUUAUCAAUAGUUCCAUUAAAATT
62


5972
sense
4543 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5973-6028-
UUUAUCAAUAGUUCCAUUUAAAUTG
63


5973
sense
4544 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5974-6029-
UUAUCAAUAGUUCCAUUUAAAUUGA
64


5974
sense
4545 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5975-6030-
UAUCAAUAGUUCCAUUUAAAUUGAC
65


5975
sense
4546 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5976-6031-
AUCAAUAGUUCCAUUUAAAAUGACT
66


5976
sense
4547 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5977-6032-
UCAAUAGUUCCAUUUAAAUAGACTT
67


5977
sense
4548 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5978-6033-
CAAUAGUUCCAUUUAAAUUAACUTC
68


5978
sense
4549 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5979-6034-
AAUAGUUCCAUUUAAAUUGACUUCA
69


5979
sense
4550 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5980-6035-
AUAGUUCCAUUUAAAUUGAAUUCAG
70


5980
sense
4551 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5981-6036-
UAGUUCCAUUUAAAUUGACAUCAGT
71


5981
sense
4552 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5982-6037-
AGUUCCAUUUAAAUUGACUACAGTG
72


5982
sense
4553 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5983-6038-
GUUCCAUUUAAAUUGACUUAAGUGG
73


5983
sense
4554 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5984-6039-
UUCCAUUUAAAUUGACUUCAGUGGT
74


5984
sense
4555 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
5985-6040-
UCCAUUUAAAUUGACUUCAAUGGTG
75


5985
sense
4556 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6662-6723-
CUUGCAAGUCCCAUGAUUUAUUCGG
76


6662
sense
5230 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6663-6724-
UUGCAAGUCCCAUGAUUUCAUCGGT
77


6663
sense
5231 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6664-6725-
UGCAAGUCCCAUGAUUUCUACGGTA
78


6664
sense
5232 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6665-6726-
GCAAGUCCCAUGAUUUCUUAGGUAA
79


6665
sense
5233 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6800-6861-
GUAAAAGUGAAUUUGGAAAAAAAGT
80


6800
sense
5365 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6801-6862-
UAAAAGUGAAUUUGGAAAUAAAGTT
81


6801
sense
5366 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6802-6863-
AAAAGUGAAUUUGGAAAUAAAGUTA
82


6802
sense
5367 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6803-6864-
AAAGUGAAUUUGGAAAUAAAGUUAT
83


6803
sense
5368 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6804-6865-
AAGUGAAUUUGGAAAUAAAAUUATT
84


6804
sense
5369 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6805-6866-
AGUGAAUUUGGAAAUAAAGAUAUTA
85


6805
sense
5370 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6806-6867-
GUGAAUUUGGAAAUAAAGUAAUUAC
86


6806
sense
5371 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6807-6868-
UGAAUUUGGAAAUAAAGUUAUUACT
87


6807
sense
5372 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6808-6869-
GAAUUUGGAAAUAAAGUUAAUACTC
88


6808
sense
5373 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6809-6870-
AAUUUGGAAAUAAAGUUAUAACUCT
89


6809
sense
5374 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6810-6871-
AUUUGGAAAUAAAGUUAUUACUCTG
90


6810
sense
5375 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6811-6872-
UUUGGAAAUAAAGUUAUUAAUCUGA
91


6811
sense
5376 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6812-6873-
UUGGAAAUAAAGUUAUUACACUGAT
92


6812
sense
5377 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6813-6874-
UGGAAAUAAAGUUAUUACUAUGATT
93


6813
sense
5378 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6814-6875-
GGAAAUAAAGUUAUUACUCAGAUTA
94


6814
sense
5379 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6815-6876-
GAAAUAAAGUUAUUACUCUAAUUAA
95


6815
sense
5380 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
6816-6877-
AAAUAAAGUUAUUACUCUGAUUAAA
96


6816
sense
5381 (Hs-





strand
Mf-Mm)







MAPT-
25 mer
 363 (Hs)
AGGAGUUCGAAGUGAUGGAAGAUCA
97


363
sense






strand








MAPT-
25 mer
 364 (Hs)
GGAGUUCGAAGUGAUGGAAAAUCAC
98


364
sense






strand








MAPT-
25 mer
 365 (Hs)
GAGUUCGAAGUGAUGGAAGAUCACG
99


365
sense






strand








MAPT-
25 mer
 367 (Hs)
GUUCGAAGUGAUGGAAGAUAACGCT
100


367
sense






strand








MAPT-
25 mer
 369 (Hs)
UCGAAGUGAUGGAAGAUCAAGCUGG
101


369
sense






strand








MAPT-
25 mer
 374-226
GUGAUGGAAGAUCACGCUGAGACGT
102


374
sense
(Hs-Mf)





strand








MAPT-
25 mer
 395-247
ACGUACGGGUUGGGGGACAAGAAAG
103


395
sense
(Hs-Mf)





strand








MAPT-
25 mer
 400-252
CGGGUUGGGGGACAGGAAAAAUCAG
104


400
sense
(Hs-Mf)





strand








MAPT-
25 mer
 443-295
CAAGACCAAGAGGGUGACAAGGACG
105


443
sense
(Hs-Mf)





strand








MAPT-
25 mer
 688-453
GGAAGACGAAGCUGCUGGUAACGTG
106


688
sense
(Hs-Mf)





strand








MAPT-
25 mer
 689-454
GAAGACGAAGCUGCUGGUCACGUGA
107


689
sense
(Hs-Mf)





strand








MAPT-
25 mer
 690-455
AAGACGAAGCUGCUGGUCAAGUGAC
108


690
sense
(Hs-Mf)





strand








MAPT-
25 mer
 693-458
ACGAAGCUGCUGGUCACGUAACCCA
109


693
sense
(Hs-Mf)





strand








MAPT-
25 mer
 695-460
GAAGCUGCUGGUCACGUGAACCAAG
110


695
sense
(Hs-Mf)





strand








MAPT-
25 mer
 696-461
AAGCUGCUGGUCACGUGACACAAGA
111


696
sense
(Hs-Mf)





strand








MAPT-
25 mer
1475-1552
CGCAUGGUCAGUAAAAGCAAAGACG
112


1475
sense
(Hs-Mf)





strand








MAPT-
25 mer
1476-1553
GCAUGGUCAGUAAAAGCAAAGACGG
113


1476
sense
(Hs-Mf)





strand








MAPT-
25 mer
1479-1556
UGGUCAGUAAAAGCAAAGAAGGGAC
114


1479
sense
(Hs-Mf)





strand








MAPT-
25 mer
1480-1557
GGUCAGUAAAAGCAAAGACAGGACT
115


1480
sense
(Hs-Mf)





strand








MAPT-
25 mer
1481-1558
GUCAGUAAAAGCAAAGACGAGACTG
116


1481
sense
(Hs-Mf)





strand








MAPT-
25 mer
1484-1561
AGUAAAAGCAAAGACGGGAAUGGAA
117


1484
sense
(Hs-Mf)





strand








MAPT-
25 mer
1485-1562
GUAAAAGCAAAGACGGGACAGGAAG
118


1485
sense
(Hs-Mf)





strand








MAPT-
25 mer
1492-1569
CAAAGACGGGACUGGAAGCAAUGAC
119


1492
sense
(Hs-Mf)





strand








MAPT-
25 mer
1494-1571
AAGACGGGACUGGAAGCGAAGACAA
120


1494
sense
(Hs-Mf)





strand








MAPT-
25 mer
1495-1572
AGACGGGACUGGAAGCGAUAACAAA
121


1495
sense
(Hs-Mf)





strand








MAPT-
25 mer
1498-1575
CGGGACUGGAAGCGAUGACAAAAAA
122


1498
sense
(Hs-Mf)





strand








MAPT-
25 mer
1499-1576
GGGACUGGAAGCGAUGACAAAAAAG
123


1499
sense
(Hs-Mf)





strand








MAPT-
25 mer
1500-1577
GGACUGGAAGCGAUGACAAAAAAGC
124


1500
sense
(Hs-Mf)





strand








MAPT-
25 mer
1502-1579
ACUGGAAGCGAUGACAAAAAAGCCA
125


1502
sense
(Hs-Mf)





strand








MAPT-
25 mer
1503-1580
CUGGAAGCGAUGACAAAAAAGCCAA
126


1503
sense
(Hs-Mf)





strand








MAPT-
25 mer
1504-1581
UGGAAGCGAUGACAAAAAAACCAAG
127


1504
sense
(Hs-Mf)





strand








MAPT-
25 mer
1505-1582
GGAAGCGAUGACAAAAAAGACAAGA
128


1505
sense
(Hs-Mf)





strand








MAPT-
25 mer
1506-1583
GAAGCGAUGACAAAAAAGCAAAGAC
129


1506
sense
(Hs-Mf)





strand








MAPT-
25 mer
1507-1584
AAGCGAUGACAAAAAAGCCAAGACA
130


1507
sense
(Hs-Mf)





strand








MAPT-
25 mer
1508-1585
AGCGAUGACAAAAAAGCCAAGACAT
131


1508
sense
(Hs-Mf)





strand








MAPT-
25 mer
1509-1586
GCGAUGACAAAAAAGCCAAAACATC
132


1509
sense
(Hs-Mf)





strand








MAPT-
25 mer
1733 (Hs)
GAUGGUAAAACGAAGAUCGACACAC
133


1733
sense






strand








MAPT-
25 mer
1796-1873
AACGCCACCAGGAUUCCAGAAAAAA
134


1796
sense
(Hs-Mf)





strand








MAPT-
25 mer
1835-1912
AAGACACCACCCAGCUCUGAGACTA
135


1835
sense
(Hs-Mf)





strand








MAPT-
25 mer
1912-1989
ACCUCCAAAAUCAGGGGAUAGCAGC
136


1912
sense
(Hs-Mf)





strand








MAPT-
25 mer
2094-2171
UGCCCAUGCCAGACCUGAAAAAUGT
137


2094
sense
(Hs-Mf)





strand








MAPT-
25 mer
2096-2173
CCCAUGCCAGACCUGAAGAAUGUCA
138


2096
sense
(Hs-Mf)





strand








MAPT-
25 mer
2097-2174
CCAUGCCAGACCUGAAGAAAGUCAA
139


2097
sense
(Hs-Mf)





strand








MAPT-
25 mer
2098 (Hs)
CAUGCCAGACCUGAAGAAUAUCAAG
140


2098
sense






strand








MAPT-
25 mer
2105 (Hs)
GACCUGAAGAAUGUCAAGUACAAGA
141


2105
sense






strand








MAPT-
25 mer
2106 (Hs)
ACCUGAAGAAUGUCAAGUCAAAGAT
142


2106
sense






strand








MAPT-
25 mer
2107 (Hs)
CCUGAAGAAUGUCAAGUCCAAGATC
143


2107
sense






strand








MAPT-
25 mer
2108 (Hs)
CUGAAGAAUGUCAAGUCCAAGAUCG
144


2108
sense






strand








MAPT-
25 mer
2109 (Hs)
UGAAGAAUGUCAAGUCCAAAAUCGG
145


2109
sense






strand








MAPT-
25 mer
2117-2194
GUCAAGUCCAAGAUCGGCUACACTG
146


2117
sense
(Hs-Mf)





strand








MAPT-
25 mer
2136 (Hs)
CCACUGAGAACCUGAAGCAACAGCC
147


2136
sense






strand








MAPT-
25 mer
2137 (Hs)
CACUGAGAACCUGAAGCACAAGCCG
148


2137
sense






strand








MAPT-
25 mer
2269-2346
GCAAAUAGUCUACAAACCAAUUGAC
149


2269
sense
(Hs-Mf)





strand








MAPT-
25 mer
2270-2347
CAAAUAGUCUACAAACCAGAUGACC
150


2270
sense
(Hs-Mf)





strand








MAPT-
25 mer
2271-2348
AAAUAGUCUACAAACCAGUAGACCT
151


2271
sense
(Hs-Mf)





strand








MAPT-
25 mer
2272-2349
AAUAGUCUACAAACCAGUUAACCTG
152


2272
sense
(Hs-Mf)





strand








MAPT-
25 mer
2273-2350
AUAGUCUACAAACCAGUUGACCUGA
153


2273
sense
(Hs-Mf)





strand








MAPT-
25 mer
2274-2351
UAGUCUACAAACCAGUUGAACUGAG
154


2274
sense
(Hs-Mf)





strand








MAPT-
25 mer
2275-2352
AGUCUACAAACCAGUUGACAUGAGC
155


2275
sense
(Hs-Mf)





strand








MAPT-
25 mer
2276-2353
GUCUACAAACCAGUUGACCAGAGCA
156


2276
sense
(Hs-Mf)





strand








MAPT-
25 mer
2277-2354
UCUACAAACCAGUUGACCUAAGCAA
157


2277
sense
(Hs-Mf)





strand








MAPT-
25 mer
2278-2355
CUACAAACCAGUUGACCUGAGCAAG
158


2278
sense
(Hs-Mf)





strand








MAPT-
25 mer
2279-2356
UACAAACCAGUUGACCUGAACAAGG
159


2279
sense
(Hs-Mf)





strand








MAPT-
25 mer
2280-2357
ACAAACCAGUUGACCUGAGAAAGGT
160


2280
sense
(Hs-Mf)





strand








MAPT-
25 mer
2281-2358
CAAACCAGUUGACCUGAGCAAGGTG
16


2281
sense
(Hs-Mf)





strand








MAPT-
25 mer
2282-2359
AAACCAGUUGACCUGAGCAAGGUGA
162


2282
sense
(Hs-Mf)





strand








MAPT-
25 mer
2283-2360
AACCAGUUGACCUGAGCAAAGUGAC
163


2283
sense
(Hs-Mf)





strand








MAPT-
25 mer
2284-2361
ACCAGUUGACCUGAGCAAGAUGACC
164


2284
sense
(Hs-Mf)





strand








MAPT-
25 mer
2286-2363
CAGUUGACCUGAGCAAGGUAACCTC
165


2286
sense
(Hs-Mf)





strand








MAPT-
25 mer
2288-2365
GUUGACCUGAGCAAGGUGAACUCCA
166


2288
sense
(Hs-Mf)





strand








MAPT-
25 mer
2289-2366
UUGACCUGAGCAAGGUGACAUCCAA
167


2289
sense
(Hs-Mf)





strand








MAPT-
25 mer
2291-2368
GACCUGAGCAAGGUGACCUACAAGT
168


2291
sense
(Hs-Mf)





strand








MAPT-
25 mer
2294-2371
CUGAGCAAGGUGACCUCCAAGUGTG
169


2294
sense
(Hs-Mf)





strand








MAPT-
25 mer
2299-2376
CAAGGUGACCUCCAAGUGUAGCUCA
170


2299
sense
(Hs-Mf)





strand








MAPT-
25 mer
2300-2377
AAGGUGACCUCCAAGUGUGACUCAT
171


2300
sense
(Hs-Mf)





strand








MAPT-
25 mer
2301-2378
AGGUGACCUCCAAGUGUGGAUCATT
172


2301
sense
(Hs-Mf)





strand








MAPT-
25 mer
2308-2385
CUCCAAGUGUGGCUCAUUAAGCAAC
173


2308
sense
(Hs-Mf)





strand








MAPT-
25 mer
2316-2393
GUGGCUCAUUAGGCAACAUACAUCA
174


2316
sense
(Hs-Mf)





strand








MAPT-
25 mer
2317-2394
UGGCUCAUUAGGCAACAUCAAUCAT
175


2317
sense
(Hs-Mf)





strand








MAPT-
25 mer
2319-2396
GCUCAUUAGGCAACAUCCAACAUAA
176


2319
sense
(Hs-Mf)





strand








MAPT-
25 mer
2320-2397
CUCAUUAGGCAACAUCCAUAAUAAA
177


2320
sense
(Hs-Mf)





strand








MAPT-
25 mer
2322-2399
CAUUAGGCAACAUCCAUCAAAAACC
178


2322
sense
(Hs-Mf)





strand








MAPT-
25 mer
2323-2400
AUUAGGCAACAUCCAUCAUAAACCA
179


2323
sense
(Hs-Mf)





strand








MAPT-
25 mer
2324-2401
UUAGGCAACAUCCAUCAUAAACCAG
180


2324
sense
(Hs-Mf)





strand








MAPT-
25 mer
2326-2403
AGGCAACAUCCAUCAUAAAACAGGA
181


2326
sense
(Hs-Mf)





strand








MAPT-
25 mer
2330-2407
AACAUCCAUCAUAAACCAGAAGGTG
182


2330
sense
(Hs-Mf)





strand








MAPT-
25 mer
2356-2433
CCAGGUGGAAGUAAAAUCUAAGAAG
183


2356
sense
(Hs-Mf)





strand








MAPT-
25 mer
2357-2434
CAGGUGGAAGUAAAAUCUGAGAAGC
184


2357
sense
(Hs-Mf)





strand








MAPT-
25 mer
2358-2435
AGGUGGAAGUAAAAUCUGAAAAGCT
185


2358
sense
(Hs-Mf)





strand








MAPT-
25 mer
2359-2436
GGUGGAAGUAAAAUCUGAGAAGCTT
186


2359
sense
(Hs-Mf)





strand








MAPT-
25 mer
2360-2437
GUGGAAGUAAAAUCUGAGAAGCUTG
187


2360
sense
(Hs-Mf)





strand








MAPT-
25 mer
2361-2438
UGGAAGUAAAAUCUGAGAAACUUGA
188


2361
sense
(Hs-Mf)





strand








MAPT-
25 mer
2362-2439
GGAAGUAAAAUCUGAGAAGAUUGAC
189


2362
sense
(Hs-Mf)





strand








MAPT-
25 mer
2363-2440
GAAGUAAAAUCUGAGAAGCAUGACT
190


2363
sense
(Hs-Mf)





strand








MAPT-
25 mer
2364-2441
AAGUAAAAUCUGAGAAGCUAGACTT
191


2364
sense
(Hs-Mf)





strand








MAPT-
25 mer
2365 (Hs)
AGUAAAAUCUGAGAAGCUUAACUTC
192


2365
sense






strand








MAPT-
25 mer
2372 (Hs)
UCUGAGAAGCUUGACUUCAAGGACA
193


2372
sense






strand








MAPT-
25 mer
2373 (Hs)
CUGAGAAGCUUGACUUCAAAGACAG
194


2373
sense






strand








MAPT-
25 mer
2374 (Hs)
UGAGAAGCUUGACUUCAAGAACAGA
195


2374
sense






strand








MAPT-
25 mer
2375 (Hs)
GAGAAGCUUGACUUCAAGGACAGAG
196


2375
sense






strand








MAPT-
25 mer
2376 (Hs)
AGAAGCUUGACUUCAAGGAAAGAGT
197


2376
sense






strand








MAPT-
25 mer
2377 (Hs)
GAAGCUUGACUUCAAGGACAGAGTC
198


2377
sense






strand








MAPT-
25 mer
2378 (Hs)
AAGCUUGACUUCAAGGACAAAGUCC
199


2378
sense






strand








MAPT-
25 mer
2379 (Hs)
AGCUUGACUUCAAGGACAGAGUCCA
200


2379
sense






strand








MAPT-
25 mer
2380 (Hs)
GCUUGACUUCAAGGACAGAAUCCAG
201


2380
sense






strand








MAPT-
25 mer
2381 (Hs)
CUUGACUUCAAGGACAGAGACCAGT
202


2381
sense






strand








MAPT-
25 mer
2382 (Hs)
UUGACUUCAAGGACAGAGUACAGTC
203


2382
sense






strand








MAPT-
25 mer
2390 (Hs)
AAGGACAGAGUCCAGUCGAAGAUTG
204


2390
sense






strand








MAPT-
25 mer
2391 (Hs)
AGGACAGAGUCCAGUCGAAAAUUGG
205


2391
sense






strand








MAPT-
25 mer
2414-2491
GGGUCCCUGGACAAUAUCAACCACG
206


2414
sense
(Hs-Mf)





strand








MAPT-
25 mer
2448-2525
GAGGAAAUAAAAAGAUUGAAACCCA
207


2448
sense
(Hs-Mf)





strand








MAPT-
25 mer
2449-2526
AGGAAAUAAAAAGAUUGAAACCCAC
208


2449
sense
(Hs-Mf)





strand








MAPT-
25 mer
2450-2527
GGAAAUAAAAAGAUUGAAAACCACA
209


2450
sense
(Hs-Mf)





strand








MAPT-
25 mer
2451-2528
GAAAUAAAAAGAUUGAAACACACAA
210


2451
sense
(Hs-Mf)





strand








MAPT-
25 mer
2452-2529
AAAUAAAAAGAUUGAAACCAACAAG
211


2452
sense
(Hs-Mf)





strand








MAPT-
25 mer
2453-2530
AAUAAAAAGAUUGAAACCCACAAGC
212


2453
sense
(Hs-Mf)





strand








MAPT-
25 mer
2454-2531
AUAAAAAGAUUGAAACCCAAAAGCT
213


2454
sense
(Hs-Mf)





strand








MAPT-
25 mer
2456-2533
AAAAAGAUUGAAACCCACAAGCUGA
214


2456
sense
(Hs-Mf)





strand








MAPT-
25 mer
2457-2534
AAAAGAUUGAAACCCACAAACUGAC
215


2457
sense
(Hs-Mf)





strand








MAPT-
25 mer
2567 (Hs)
CGGCAUCUCAGCAAUGUCUACUCCA
216


2567
sense






strand








MAPT-
25 mer
2598-2675
GCAUCGACAUGGUAGACUCACCCCA
217


2598
sense
(Hs-Mf)





strand








MAPT-
25 mer
2657-2734
CUGGCCAAGCAGGGUUUGUAAUCAG
218


2657
sense
(Hs-Mf)





strand








MAPT-
25 mer
2723-2800
AGAGUGUGGAAAAAAAAAGAAUAAT
219


2723
sense
(Hs-Mf)





strand








MAPT-
25 mer
2724-2801
GAGUGUGGAAAAAAAAAGAAUAATG
220


2724
sense
(Hs-Mf)





strand








MAPT-
25 mer
2726-2803
GUGUGGAAAAAAAAAGAAUAAUGAC
221


2726
sense
(Hs-Mf)





strand








MAPT-
25 mer
2784-2860-
GCAGUUCGGUUAAUUGGUUAAUCAC
222


2784
sense
1 mismatch





strand
(Hs-Mf)







MAPT-
25 mer
2963-3039
GGCAAUUCCUUUUGAUUCUAUUUTC
223


2963
sense
(Hs-Mf)





strand








MAPT-
25 mer
3110-3186
AGCAACAAAGGAUUUGAAAAUUGGT
224


3110
sense
(Hs-Mf)





strand








MAPT-
25 mer
3114-3190
ACAAAGGAUUUGAAACUUGAUGUGT
225


3114
sense
(Hs-Mf)





strand








MAPT-
25 mer
3116-3192
AAAGGAUUUGAAACUUGGUAUGUTC
226


3116
sense
(Hs-Mf)





strand








MAPT-
25 mer
3118-3194
AGGAUUUGAAACUUGGUGUAUUCGT
227


3118
sense
(Hs-Mf)





strand








MAPT-
25 mer
3158-3234
CGAUGUCAACCUUGUGUGAAUGUGA
228


3158
sense
(Hs-Mf)





strand








MAPT-
25 mer
3503-3576
AAAGACUGACCUUGAUGUCAUGAGA
229


3503
sense
(Hs-Mf)





strand








MAPT-
25 mer
3589-3661
CUCCACAGAAACCCUGUUUAAUUGA
230


3589
sense
(Hs-Mf)





strand








MAPT-
25 mer
3591-3663
CCACAGAAACCCUGUUUUAAUGAGT
231


3591
sense
(Hs-Mf)





strand








MAPT-
25 mer
3592-3664
CACAGAAACCCUGUUUUAUAGAGTT
232


3592
sense
(Hs-Mf)





strand








MAPT-
25 mer
3593-3665
ACAGAAACCCUGUUUUAUUAAGUTC
233


3593
sense
(Hs-Mf)





strand








MAPT-
25 mer
3594-3666
CAGAAACCCUGUUUUAUUGAGUUCT
234


3594
sense
(Hs-Mf)





strand








MAPT-
25 mer
3595-3667
AGAAACCCUGUUUUAUUGAAUUCTG
235


3595
sense
(Hs-Mf)





strand








MAPT-
25 mer
3596-3668
GAAACCCUGUUUUAUUGAGAUCUGA
236


3596
sense
(Hs-Mf)





strand








MAPT-
25 mer
3597-3669
AAACCCUGUUUUAUUGAGUACUGAA
237


3597
sense
(Hs-Mf)





strand








MAPT-
25 mer
3598-3670
AACCCUGUUUUAUUGAGUUAUGAAG
238


3598
sense
(Hs-Mf)





strand








MAPT-
25 mer
3599-3671
ACCCUGUUUUAUUGAGUUCAGAAGG
239


3599
sense
(Hs-Mf)





strand








MAPT-
25 mer
3600-3672
CCCUGUUUUAUUGAGUUCUAAAGGT
240


3600
sense
(Hs-Mf)





strand








MAPT-
25 mer
3601-3673
CCUGUUUUAUUGAGUUCUGAAGGTT
241


3601
sense
(Hs-Mf)





strand








MAPT-
25 mer
3602-3674
CUGUUUUAUUGAGUUCUGAAGGUTG
242


3602
sense
(Hs-Mf)





strand








MAPT-
25 mer
3603-3675
UGUUUUAUUGAGUUCUGAAAGUUGG
243


3603
sense
(Hs-Mf)





strand








MAPT-
25 mer
3605-3677
UUUUAUUGAGUUCUGAAGGAUGGAA
244


3605
sense
(Hs-Mf)





strand








MAPT-
25 mer
3607-3679
UUAUUGAGUUCUGAAGGUUAGAACT
245


3607
sense
(Hs-Mf)





strand








MAPT-
25 mer
3609-3681
AUUGAGUUCUGAAGGUUGGAACUGC
246


3609
sense
(Hs-Mf)





strand








MAPT-
25 mer
3610-3682
UUGAGUUCUGAAGGUUGGAACUGCT
247


3610
sense
(Hs-Mf)





strand








MAPT-
25 mer
3677-3749
AACCAGUUCUCUUUGUAAGAACUTG
248


3677
sense
(Hs-Mf)





strand








MAPT-
25 mer
3678-3750
ACCAGUUCUCUUUGUAAGGACUUGT
249


3678
sense
(Hs-Mf)





strand








MAPT-
25 mer
3679-3751
CCAGUUCUCUUUGUAAGGAAUUGTG
250


3679
sense
(Hs-Mf)





strand








MAPT-
25 mer
3680-3752
CAGUUCUCUUUGUAAGGACAUGUGC
251


3680
sense
(Hs-Mf)





strand








MAPT-
25 mer
3958-4030
CUACUCCAUACUGAGGGUGAAAUTA
252


3958
sense
(Hs-Mf)





strand








MAPT-
25 mer
3959-4031
UACUCCAUACUGAGGGUGAAAUUAA
253


3959
sense
(Hs-Mf)





strand








MAPT-
25 mer
3960-4032
ACUCCAUACUGAGGGUGAAAUUAAG
254


3960
sense
(Hs-Mf)





strand








MAPT-
25 mer
3961-4033
CUCCAUACUGAGGGUGAAAAUAAGG
255


3961
sense
(Hs-Mf)





strand








MAPT-
25 mer
3965-4037
AUACUGAGGGUGAAAUUAAAGGAAG
256


3965
sense
(Hs-Mf)





strand








MAPT-
25 mer
3970-4042
GAGGGUGAAAUUAAGGGAAAGCAAA
257


3970
sense
(Hs-Mf)





strand








MAPT-
25 mer
4146-4218
GGUGUUUCUGCCUUGUUGAAAUGGA
258


4146
sense
(Hs-Mf)





strand








MAPT-
25 mer
4474-4545
CUGGAGCAGCUGAACAUAUACAUAG
259


4474
sense
(Hs-Mf)





strand








MAPT-
25 mer
4475-4546
UGGAGCAGCUGAACAUAUAAAUAGA
260


4475
sense
(Hs-Mf)





strand








MAPT-
25 mer
4477-4548
GAGCAGCUGAACAUAUACAAAGATG
261


4477
sense
(Hs-Mf)





strand








MAPT-
25 mer
4478-4549
AGCAGCUGAACAUAUACAUAGAUGT
262


4478
sense
(Hs-Mf)





strand








MAPT-
25 mer
4479-4550
GCAGCUGAACAUAUACAUAAAUGTT
263


4479
sense
(Hs-Mf)





strand








MAPT-
25 mer
4480-4551
CAGCUGAACAUAUACAUAGAUGUTG
264


4480
sense
(Hs-Mf)





strand








MAPT-
25 mer
4481-4552
AGCUGAACAUAUACAUAGAAGUUGC
265


4481
sense
(Hs-Mf)





strand








MAPT-
25 mer
4482-4553
GCUGAACAUAUACAUAGAUAUUGCC
266


4482
sense
(Hs-Mf)





strand








MAPT-
25 mer
4485-4556
GAACAUAUACAUAGAUGUUACCCTG
267


4485
sense
(Hs-Mf)





strand








MAPT-
25 mer
4486-4557
AACAUAUACAUAGAUGUUGACCUGC
268


4486
sense
(Hs-Mf)





strand








MAPT-
25 mer
4532 (Hs)
GAGUUGUAGUUGGAUUUGUAUGUTT
269


4532
sense






strand








MAPT-
25 mer
4533 (Hs)
AGUUGUAGUUGGAUUUGUCAGUUTA
270


4533
sense






strand








MAPT-
25 mer
4539-4610
AGUUGGAUUUGUCUGUUUAAGCUTG
271


4539
sense
(Hs-Mf)





strand








MAPT-
25 mer
4540-4611
GUUGGAUUUGUCUGUUUAUACUUGG
272


4540
sense
(Hs-Mf)





strand








MAPT-
25 mer
4541-4612
UUGGAUUUGUCUGUUUAUGAUUGGA
273


4541
sense
(Hs-Mf)





strand








MAPT-
25 mer
4543-4614
GGAUUUGUCUGUUUAUGCUAGGATT
274


4543
sense
(Hs-Mf)





strand








MAPT-
25 mer
4544-4615
GAUUUGUCUGUUUAUGCUUAGAUTC
275


4544
sense
(Hs-Mf)





strand








MAPT-
25 mer
4545-4616
AUUUGUCUGUUUAUGCUUGAAUUCA
276


4545
sense
(Hs-Mf)





strand








MAPT-
25 mer
4546-4617
UUUGUCUGUUUAUGCUUGGAUUCAC
277


4546
sense
(Hs-Mf)





strand








MAPT-
25 mer
4547-4618
UUGUCUGUUUAUGCUUGGAAUCACC
278


4547
sense
(Hs-Mf)





strand








MAPT-
25 mer
4548-4619
UGUCUGUUUAUGCUUGGAUACACCA
279


4548
sense
(Hs-Mf)





strand








MAPT-
25 mer
4549-4620
GUCUGUUUAUGCUUGGAUUAACCAG
280


4549
sense
(Hs-Mf)





strand








MAPT-
25 mer
4550-4621
UCUGUUUAUGCUUGGAUUCACCAGA
281


4550
sense
(Hs-Mf)





strand








MAPT-
25 mer
4551-4622
CUGUUUAUGCUUGGAUUCAACAGAG
282


4551
sense
(Hs-Mf)





strand








MAPT-
25 mer
4552-4623
UGUUUAUGCUUGGAUUCACAAGAGT
283


4552
sense
(Hs-Mf)





strand








MAPT-
25 mer
4554-4625
UUUAUGCUUGGAUUCACCAAAGUGA
284


4554
sense
(Hs-Mf)





strand








MAPT-
25 mer
4556-4627
UAUGCUUGGAUUCACCAGAAUGACT
285


4556
sense
(Hs-Mf)





strand








MAPT-
25 mer
4557-4628
AUGCUUGGAUUCACCAGAGAGACTA
286


4557
sense
(Hs-Mf)





strand








MAPT-
25 mer
4558-4629
UGCUUGGAUUCACCAGAGUAACUAT
287


4558
sense
(Hs-Mf)





strand








MAPT-
25 mer
4559-4630
GCUUGGAUUCACCAGAGUGACUATG
288


4559
sense
(Hs-Mf)





strand








MAPT-
25 mer
4560-4631
CUUGGAUUCACCAGAGUGAAUAUGA
289


4560
sense
(Hs-Mf)





strand








MAPT-
25 mer
4561-4632
UUGGAUUCACCAGAGUGACAAUGAT
290


4561
sense
(Hs-Mf)





strand








MAPT-
25 mer
4562-4633
UGGAUUCACCAGAGUGACUAUGATA
291


4562
sense
(Hs-Mf)





strand








MAPT-
25 mer
4563-4634
GGAUUCACCAGAGUGACUAAGAUAG
292


4563
sense
(Hs-Mf)





strand








MAPT-
25 mer
4564-4635
GAUUCACCAGAGUGACUAUAAUAGT
293


4564
sense
(Hs-Mf)





strand








MAPT-
25 mer
4615-4687
ACGCAUGUAUCUUGAAAUGAUUGTA
294


4615
sense
(Hs-Mf)





strand








MAPT-
25 mer
4616-4688
CGCAUGUAUCUUGAAAUGCAUGUAA
295


4616
sense
(Hs-Mf)





strand








MAPT-
25 mer
4617-4689
GCAUGUAUCUUGAAAUGCUAGUAAA
296


4617
sense
(Hs-Mf)





strand








MAPT-
25 mer
4618-4690
CAUGUAUCUUGAAAUGCUUAUAAAG
297


4618
sense
(Hs-Mf)





strand








MAPT-
25 mer
4619-4691
AUGUAUCUUGAAAUGCUUGAAAAGA
298


4619
sense
(Hs-Mf)





strand








MAPT-
25 mer
4620-4692
UGUAUCUUGAAAUGCUUGUAAAGAG
299


4620
sense
(Hs-Mf)





strand








MAPT-
25 mer
4621-4693
GUAUCUUGAAAUGCUUGUAAAGAGG
300


4621
sense
(Hs-Mf)





strand








MAPT-
25 mer
4622-4694
UAUCUUGAAAUGCUUGUAAAGAGGT
301


4622
sense
(Hs-Mf)





strand








MAPT-
25 mer
4623-4695
AUCUUGAAAUGCUUGUAAAAAGGTT
302


4623
sense
(Hs-Mf)





strand








MAPT-
25 mer
4625-4697
CUUGAAAUGCUUGUAAAGAAGUUTC
303


4625
sense
(Hs-Mf)





strand








MAPT-
25 mer
4627-4699
UGAAAUGCUUGUAAAGAGGAUUCTA
304


4627
sense
(Hs-Mf)





strand








MAPT-
25 mer
4628-4700
GAAAUGCUUGUAAAGAGGUAUCUAA
305


4628
sense
(Hs-Mf)





strand








MAPT-
25 mer
4629-4701
AAAUGCUUGUAAAGAGGUUACUAAC
306


4629
sense
(Hs-Mf)





strand








MAPT-
25 mer
4630-4702
AAUGCUUGUAAAGAGGUUUAUAACC
307


4630
sense
(Hs-Mf)





strand








MAPT-
25 mer
4632-4704
UGCUUGUAAAGAGGUUUCUAACCCA
308


4632
sense
(Hs-Mf)





strand








MAPT-
25 mer
4633-4705
GCUUGUAAAGAGGUUUCUAACCCAC
309


4633
sense
(Hs-Mf)





strand








MAPT-
25 mer
4825-4897
ACAGGAUUAGGACUGAAGCAAUGAT
310


4825
sense
(Hs-Mf)





strand








MAPT-
25 mer
4828-4900
GGAUUAGGACUGAAGCGAUAAUGTC
311


4828
sense
(Hs-Mf)





strand








MAPT-
25 mer
5682-5743
GAAGUUCUUGUGCCCUGCUAUUCAG
312


5682
sense
(Hs-Mf)





strand








MAPT-
25 mer
5958 (Hs)
AAGCUGCUGACUCACUUUAACAATA
313


5958
sense






strand








MAPT-
25 mer
5959 (Hs)
AGCUGCUGACUCACUUUAUAAAUAG
314


5959
sense






strand








MAPT-
25 mer
5961 (Hs)
CUGCUGACUCACUUUAUCAAUAGTT
315


5961
sense






strand








MAPT-
25 mer
5963 (Hs)
GCUGACUCACUUUAUCAAUAGUUCC
316


5963
sense






strand








MAPT-
25 mer
5964 (Hs)
CUGACUCACUUUAUCAAUAAUUCCA
317


5964
sense






strand








MAPT-
25 mer
5965 (Hs)
UGACUCACUUUAUCAAUAGUUCCAU
318


5965
sense






strand








MAPT-
25 mer
5966-6021
GACUCACUUUAUCAAUAGUACCATT
319


5966
sense
(Hs-Mf)





strand








MAPT-
25 mer
5967-6022
ACUCACUUUAUCAAUAGUUACAUTT
320


5967
sense
(Hs-Mf)





strand








MAPT-
25 mer
5968-6023
CUCACUUUAUCAAUAGUUCAAUUTA
321


5968
sense
(Hs-Mf)





strand








MAPT-
25 mer
6006-6061
GGUGAGACUGUAUCCUGUUAGCUAT
322


6006
sense
(Hs-Mf)





strand








MAPT-
25 mer
6007-6062
GUGAGACUGUAUCCUGUUUACUATT
323


6007
sense
(Hs-Mf)





strand








MAPT-
25 mer
6008-6063
UGAGACUGUAUCCUGUUUGAUAUTG
324


6008
sense
(Hs-Mf)





strand








MAPT-
25 mer
6009-6064
GAGACUGUAUCCUGUUUGCAAUUGC
325


6009
sense
(Hs-Mf)





strand








MAPT-
25 mer
6010-6065
AGACUGUAUCCUGUUUGCUAUUGCT
326


6010
sense
(Hs-Mf)





strand








MAPT-
25 mer
6011-6066
GACUGUAUCCUGUUUGCUAAUGCTT
327


6011
sense
(Hs-Mf)





strand








MAPT-
25 mer
6012-6067
ACUGUAUCCUGUUUGCUAUAGCUTG
328


6012
sense
(Hs-Mf)





strand








MAPT-
25 mer
6013-6068
CUGUAUCCUGUUUGCUAUUACUUGT
329


6013
sense
(Hs-Mf)





strand








MAPT-
25 mer
6014-6069
UGUAUCCUGUUUGCUAUUGAUUGTT
330


6014
sense
(Hs-Mf)





strand








MAPT-
25 mer
6015-6070
GUAUCCUGUUUGCUAUUGCAUGUTG
331


6015
sense
(Hs-Mf)





strand








MAPT-
25 mer
6017-6072
AUCCUGUUUGCUAUUGCUUAUUGTG
332


6017
sense
(Hs-Mf)





strand








MAPT-
25 mer
6119-6174
GCCUCGUAACCCUUUUCAUAAUUTC
333


6119
sense
(Hs-Mf)





strand








MAPT-
25 mer
6628-6689
GAGUUUGCCAUGUUGAGCAAGACTA
334


6628
sense
(Hs-Mf)





strand








MAPT-
25 mer
6629-6690
AGUUUGCCAUGUUGAGCAGAACUAT
335


6629
sense
(Hs-Mf)





strand








MAPT-
25 mer
6631-6692
UUUGCCAUGUUGAGCAGGAAUAUTT
336


6631
sense
(Hs-Mf)





strand








MAPT-
25 mer
6672-6733
CCAUGAUUUCUUCGGUAAUACUGAG
337


6672
sense
(Hs-Mf)





strand








MAPT-
25 mer
6731 (Hs)
GCUUUCUGUCUGUGAAUGUAUAUAT
338


6731
sense






strand








MAPT-
25 mer
6732 (Hs)
CUUUCUGUCUGUGAAUGUCAAUATA
339


6732
sense






strand








MAPT-
25 mer
6738-6799
GUCUGUGAAUGUCUAUAUAAUGUAT
340


6738
sense
(Hs-Mf)





strand








MAPT-
25 mer
6739-6800
UCUGUGAAUGUCUAUAUAGAGUATT
341


6739
sense
(Hs-Mf)





strand








MAPT-
25 mer
6740-6801
CUGUGAAUGUCUAUAUAGUAUAUTG
342


6740
sense
(Hs-Mf)





strand








MAPT-
25 mer
6741-6802
UGUGAAUGUCUAUAUAGUGAAUUGT
343


6741
sense
(Hs-Mf)





strand








MAPT-
25 mer
6742-6803
GUGAAUGUCUAUAUAGUGUAUUGTG
344


6742
sense
(Hs-Mf)





strand








MAPT-
25 mer
6743-6804
UGAAUGUCUAUAUAGUGUAAUGUGT
345


6743
sense
(Hs-Mf)





strand








MAPT-
25 mer
6745-6806
AAUGUCUAUAUAGUGUAUUAUGUGT
346


6745
sense
(Hs-Mf)





strand








MAPT-
25 mer
6748-6809
GUCUAUAUAGUGUAUUGUGAGUUTT
347


6748
sense
(Hs-Mf)





strand








MAPT-
25 mer
6749-6810
UCUAUAUAGUGUAUUGUGUAUUUTA
348


6749
sense
(Hs-Mf)





strand








MAPT-
25 mer
6750-6811
CUAUAUAGUGUAUUGUGUGAUUUAA
349


6750
sense
(Hs-Mf)





strand








MAPT-
25 mer
6751-6812
UAUAUAGUGUAUUGUGUGUAUUAAC
350


6751
sense
(Hs-Mf)





strand








MAPT-
25 mer
6752-6813
AUAUAGUGUAUUGUGUGUUAUAACA
351


6752
sense
(Hs-Mf)





strand








MAPT-
25 mer
6753-6814
UAUAGUGUAUUGUGUGUUUAAACAA
352


6753
sense
(Hs-Mf)





strand








MAPT-
25 mer
6754-6815
AUAGUGUAUUGUGUGUUUUAACAAA
353


6754
sense
(Hs-Mf)





strand








MAPT-
25 mer
6755-6816
UAGUGUAUUGUGUGUUUUAACAAAT
354


6755
sense
(Hs-Mf)





strand








MAPT-
25 mer
6756-6817
AGUGUAUUGUGUGUUUUAAAAAATG
355


6756
sense
(Hs-Mf)





strand








MAPT-
25 mer
6757-6818
GUGUAUUGUGUGUUUUAACAAAUGA
356


6757
sense
(Hs-Mf)





strand








MAPT-
25 mer
6758-6819
UGUAUUGUGUGUUUUAACAAAUGAT
357


6758
sense
(Hs-Mf)





strand








MAPT-
25 mer
6759-6820
GUAUUGUGUGUUUUAACAAAUGATT
358


6759
sense
(Hs-Mf)





strand








MAPT-
25 mer
6760-6821
UAUUGUGUGUUUUAACAAAAGAUTT
359


6760
sense
(Hs-Mf)





strand








MAPT-
25 mer
6761-6822
AUUGUGUGUUUUAACAAAUAAUUTA
360


6761
sense
(Hs-Mf)





strand








MAPT-
25 mer
6762-6823
UUGUGUGUUUUAACAAAUGAUUUAC
361


6762
sense
(Hs-Mf)





strand








MAPT-
25 mer
6763-6824
UGUGUGUUUUAACAAAUGAAUUACA
362


6763
sense
(Hs-Mf)





strand








MAPT-
25 mer
6764-6825
GUGUGUUUUAACAAAUGAUAUACAC
363


6764
sense
(Hs-Mf)





strand








MAPT-
25 mer
6765-6826
UGUGUUUUAACAAAUGAUUAACACT
364


6765
sense
(Hs-Mf)





strand








MAPT-
25 mer
6766-6827
GUGUUUUAACAAAUGAUUUACACTG
365


6766
sense
(Hs-Mf)





strand








MAPT-
25 mer
6767-6828
UGUUUUAACAAAUGAUUUAAACUGA
366


6767
sense
(Hs-Mf)





strand








MAPT-
25 mer
6768-6829
GUUUUAACAAAUGAUUUACACUGAC
367


6768
sense
(Hs-Mf)





strand








MAPT-
25 mer
6769-6830
UUUUAACAAAUGAUUUACAAUGACT
368


6769
sense
(Hs-Mf)





strand








MAPT-
25 mer
6772-6833
UAACAAAUGAUUUACACUGACUGTT
369


6772
sense
(Hs-Mf)





strand








MAPT-
25 mer
6773-6834
AACAAAUGAUUUACACUGAAUGUTG
370


6773
sense
(Hs-Mf)





strand








MAPT-
25 mer
6774-6835
ACAAAUGAUUUACACUGACAGUUGC
371


6774
sense
(Hs-Mf)





strand








MAPT-
25 mer
6775-6836
CAAAUGAUUUACACUGACUAUUGCT
372


6775
sense
(Hs-Mf)





strand








MAPT-
25 mer
6777-6838
AAUGAUUUACACUGACUGUAGCUGT
373


6777
sense
(Hs-Mf)





strand








MAPT-
25 mer
6778-6839
AUGAUUUACACUGACUGUUACUGTA
374


6778
sense
(Hs-Mf)





strand








MAPT-
25 mer
6779-6840
UGAUUUACACUGACUGUUGAUGUAA
375


6779
sense
(Hs-Mf)





strand








MAPT-
25 mer
6780-6841
GAUUUACACUGACUGUUGCAGUAAA
376


6780
sense
(Hs-Mf)





strand








MAPT-
25 mer
6781 (Hs)
AUUUACACUGACUGUUGCUAUAAAA
377


6781
sense






strand








MAPT-
25 mer
6789 (Hs)
UGACUGUUGCUGUAAAAGUAAAUTT
378


6789
sense






strand








MAPT-
25 mer
6792 (Hs)
CUGUUGCUGUAAAAGUGAAAUUGGA
379


6792
sense






strand








MAPT-
25 mer
6793 (Hs)
UGUUGCUGUAAAAGUGAAUAUGGAA
380


6793
sense






strand








MAPT-
25 mer
6795 (Hs)
UUGCUGUAAAAGUGAAUUUAGAAAT
381


6795
sense






strand








MAPT-
25 mer
6796 (Hs)
UGCUGUAAAAGUGAAUUUGAAAATA
382


6796
sense






strand








MAPT-
25 mer
6797 (Hs)
GCUGUAAAAGUGAAUUUGGAAAUAA
383


6797
sense






strand








MAPT-
25 mer
6798 (Hs)
CUGUAAAAGUGAAUUUGGAAAUAAA
384


6798
sense






strand








MAPT-
27 mer
2141-2218-
CUCCCUGCUGGUGCUUCAGGUUCUCAG
385


2141
antisense
966 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2142-2219-
CCUCCUGGCUGGUGCUUCAGGUUCUCA
386


2142
antisense
967 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2303-2380-
CUAAUUAGCCACACUUGGAGGUCACCU
387


2303
antisense
1128 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2347-2424-
UUUUAUUUCCACCUGGCCACCUCCUGG
388


2347
antisense
1172 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2349-2426-
GAUUUUACUUCCACCUGGCCACCUCCU
389


2349
antisense
1174 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2350-2427-
AGAUUUUACUUCCACCUGGCCACCUCC
390


2350
antisense
1175 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2351-2428-
CAGAUUUUACUUCCACCUGGCCACCUC
391


2351
antisense
1176 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2352-2429-
UCAGAUUUUACUUCCACCUGGCCACCU
392


2352
antisense
1177 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2353-2430-
CUCAGUUUUUACUUCCACCUGGCCACC
393


2353
antisense
1178 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2354-2431-
UCUCAUAUUUUACUUCCACCUGGCCAC
394


2354
antisense
1179 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2355-2432-
UUCUCUGAUUUUACUUCCACCUGGCCA
395


2355
antisense
1180 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2459-2536-
AGGUCUGCUUGUGGGUUUCAAUCUUUU
396


2459
antisense
1284 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2460-2537-
AAGGUUAGCUUGUGGGUUUCAAUCUUU
397


2460
antisense
1285 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2461-2538-
GAAGGUCAGCUUGUGGGUUUCAAUCUU
398


2461
antisense
1286 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2462-2539-
GGAAGUUCAGCUUGUGGGUUUCAAUCU
399


2462
antisense
1287 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2463-2540-
CGGAAUGUCAGCUUGUGGGUUUCAAUC
400


2463
antisense
1288 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2464-2541-
GCGGAUGGUCAGCUUGUGGGUUUCAAU
401


2464
antisense
1289 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2465-2542-
CGCGGUAGGUCAGCUUGUGGGUUUCAA
402


2465
antisense
1290 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2466-2543-
UCGCGUAAGGUCAGCUUGUGGGUUUCA
403


2466
antisense
1291 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2467-2544-
CUCGCUGAAGGUCAGCUUGUGGGUUUC
404


2467
antisense
1292 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2495-2572-
CCCCGUGGUCUGUCUUGGCUUUGGCGU
405


2495
antisense
1320 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
2496-2573-
GCCCCUUGGUCUGUCUUGGCUUUGGCG
406


2496
antisense
1321 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
3686-3758-
CAAGAUGCACAAGUCCUUACAAAGAGA
407


3686
antisense
2505 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
3687-3759-
CCAAGUGGCACAAGUCCUUACAAAGAG
408


3687
antisense
2506 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
3688-3760-
CCCAAUAGGCACAAGUCCUUACAAAGA
409


3688
antisense
2507 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
3691-3763-
UCUCCUAAGAGGCACAAGUCCUUACAA
410


3691
antisense
2510 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
3692-3764-
GUCUCUCAAGAGGCACAAGUCCUUACA
411


3692
antisense
2511 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
3693-3765-
CGUCUUCCAAGAGGCACAAGUCCUUAC
412


3693
antisense
2512 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4534-4605-
AUAAAUAGACAAAUCCAACUACAACUC
413


4534
antisense
3332 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4535-4606-
CAUAAUCAGACAAAUCCAACUACAACU
414


4535
antisense
3333 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4536-4607-
GCAUAUACAGACAAAUCCAACUACAAC
415


4536
antisense
3334 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4537-4608-
AGCAUUAACAGACAAAUCCAACUACAA
416


4537
antisense
3335 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4538-4609-
AAGCAUAAACAGACAAAUCCAACUACA
417


4538
antisense
3336 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4566-4637-
UCACUUUCAUAGUCACUCUGGUGAAUC
418


4566
antisense
3362 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4567-4638-
UUCACUAUCAUAGUCACUCUGGUGAAU
419


4567
antisense
3363 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4568-4639-
UUUCAUUAUCAUAGUCACUCUGGUGAA
420


4568
antisense
3364 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4569-4640-
UUUUCUCUAUCAUAGUCACUCUGGUGA
421


4569
antisense
3365 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4570-4641-
CUUUUUACUAUCAUAGUCACUCUGGUG
422


4570
antisense
3366 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4571-4642-
UCUUUUCACUAUCAUAGUCACUCUGGU
423


4571
antisense
3367 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4572-4643-
UUCUUUUCACUAUCAUAGUCACUCUGG
424


4572
antisense
3368 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4573-4644-
UUUCUUUUCACUAUCAUAGUCACUCUG
425


4573
antisense
3369 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4574-4645-
UUUUCUUUUCACUAUCAUAGUCACUCU
426


4574
antisense
3370 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4575-4646-
UUUUUUUUUUCACUAUCAUAGUCACUC
427


4575
antisense
3371 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4576-4647-
UUUUUUCUUUUCACUAUCAUAGUCACU
428


4576
antisense
3372 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4577-4648-
UUUUUUUCUUUUCACUAUCAUAGUCAC
429


4577
antisense
3373 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4578-4649-
UUUUUUUUCUUUUCACUAUCAUAGUCA
430


4578
antisense
3374 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4579-4650-
UUUUUUUUUCUUUUCACUAUCAUAGUC
431


4579
antisense
3375 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4580-4651-
UUUUUUUUUUCUUUUCACUAUCAUAGU
432


4580
antisense
3376 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4605-4677-
UCAAGUUACAUGCGUCCUUUUUUUUUU
433


4605
antisense
3439 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4606-4678-
UUCAAUAUACAUGCGUCCUUUUUUUUU
434


4606
antisense
3440 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4607-4679-
UUUCAUGAUACAUGCGUCCUUUUUUUU
435


4607
antisense
3441 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4608-4680-
AUUUCUAGAUACAUGCGUCCUUUUUUU
436


4608
antisense
3442 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4609-4681-
CAUUUUAAGAUACAUGCGUCCUUUUUU
437


4609
antisense
3443 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4610-4682-
GCAUUUCAAGAUACAUGCGUCCUUUUU
438


4610
antisense
3444 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4611-4683-
AGCAUUUCAAGAUACAUGCGUCCUUUU
439


4611
antisense
3445 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4612-4684-
AAGCAUUUCAAGAUACAUGCGUCCUUU
440


4612
antisense
3446 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4613-4685-
CAAGCUUUUCAAGAUACAUGCGUCCUU
441


4613
antisense
3447 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
4614-4686-
ACAAGUAUUUCAAGAUACAUGCGUCCU
442


4614
antisense
3448 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5969-6024-
UUAAAUGGAACUAUUGAUAAAGUGAGU
443


5969
antisense
4540 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5970-6025-
UUUAAUUGGAACUAUUGAUAAAGUGAG
444


5970
antisense
4541 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5971-6026-
AUUUAUAUGGAACUAUUGAUAAAGUGA
445


5971
antisense
4542 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5972-6027-
AAUUUUAAUGGAACUAUUGAUAAAGUG
446


5972
antisense
4543 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5973-6028-
CAAUUUAAAUGGAACUAUUGAUAAAGU
447


5973
antisense
4544 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5974-6029-
UCAAUUUAAAUGGAACUAUUGAUAAAG
448


5974
antisense
4545 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5975-6030-
GUCAAUUUAAAUGGAACUAUUGAUAAA
449


5975
antisense
4546 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5976-6031-
AGUCAUUUUAAAUGGAACUAUUGAUAA
450


5976
antisense
4547 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5977-6032-
AAGUCUAUUUAAAUGGAACUAUUGAUA
451


5977
antisense
4548 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5978-6033-
GAAGUUAAUUUAAAUGGAACUAUUGAU
452


5978
antisense
4549 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5979-6034-
UGAAGUCAAUUUAAAUGGAACUAUUGA
453


5979
antisense
4550 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5980-6035-
CUGAAUUCAAUUUAAAUGGAACUAUUG
454


5980
antisense
4551 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5981-6036-
ACUGAUGUCAAUUUAAAUGGAACUAUU
455


5981
antisense
4552 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5982-6037-
CACUGUAGUCAAUUUAAAUGGAACUAU
456


5982
antisense
4553 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5983-6038-
CCACUUAAGUCAAUUUAAAUGGAACUA
457


5983
antisense
4554 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5984-6039-
ACCACUGAAGUCAAUUUAAAUGGAACU
458


5984
antisense
4555 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
5985-6040-
CACCAUUGAAGUCAAUUUAAAUGGAAC
459


5985
antisense
4556 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6662-6723-
CCGAAUAAAUCAUGGGACUUGCAAGUG
460


6662
antisense
5230 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6663-6724-
ACCGAUGAAAUCAUGGGACUUGCAAGU
461


6663
antisense
5231 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6664-6725-
UACCGUAGAAAUCAUGGGACUUGCAAG
462


6664
antisense
5232 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6665-6726-
UUACCUAAGAAAUCAUGGGACUUGCAA
463


6665
antisense
5233 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6800-6861-
ACUUUUUUUCCAAAUUCACUUUUACAG
464


6800
antisense
5365 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6801-6862-
AACUUUAUUUCCAAAUUCACUUUUACA
465


6801
antisense
5366 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6802-6863-
UAACUUUAUUUCCAAAUUCACUUUUAC
466


6802
antisense
5367 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6803-6864-
AUAACUUUAUUUCCAAAUUCACUUUUA
467


6803
antisense
5368 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6804-6865-
AAUAAUUUUAUUUCCAAAUUCACUUUU
468


6804
antisense
5369 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6805-6866-
UAAUAUCUUUAUUUCCAAAUUCACUUU
469


6805
antisense
5370 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6806-6867-
GUAAUUACUUUAUUUCCAAAUUCACUU
470


6806
antisense
5371 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6807-6868-
AGUAAUAACUUUAUUUCCAAAUUCACU
471


6807
antisense
5372 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6808-6869-
GAGUAUUAACUUUAUUUCCAAAUUCAC
472


6808
antisense
5373 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6809-6870-
AGAGUUAUAACUUUAUUUCCAAAUUCA
473


6809
antisense
5374 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6810-6871-
CAGAGUAAUAACUUUAUUUCCAAAUUC
474


6810
antisense
5375 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6811-6872-
UCAGAUUAAUAACUUUAUUUCCAAAUU
475


6811
antisense
5376 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6812-6873-
AUCAGUGUAAUAACUUUAUUUCCAAAU
476


6812
antisense
5377 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6813-6874-
AAUCAUAGUAAUAACUUUAUUUCCAAA
477


6813
antisense
5378 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6814-6875-
UAAUCUGAGUAAUAACUUUAUUUCCAA
478


6814
antisense
5379 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6815-6876-
UUAAUUAGAGUAAUAACUUUAUUUCCA
479


6815
antisense
5380 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
6816-6877-
UUUAAUCAGAGUAAUAACUUUAUUUCC
480


6816
antisense
5381 (Hs-





strand
Mf-Mm)







MAPT-
27 mer
 363 (Hs)
UGAUCUUCCAUCACUUCGAACUCCUGG
481


363
antisense






strand








MAPT-
27 mer
 364 (Hs)
GUGAUUUUCCAUCACUUCGAACUCCUG
482


364
antisense






strand








MAPT-
27 mer
 365 (Hs)
CGUGAUCUUCCAUCACUUCGAACUCCU
483


365
antisense






strand








MAPT-
27 mer
 367 (Hs)
AGCGUUAUCUUCCAUCACUUCGAACUC
484


367
antisense






strand








MAPT-
27 mer
 369 (Hs)
CCAGCUUGAUCUUCCAUCACUUCGAAC
485


369
antisense






strand








MAPT-
27 mer
 374-226
ACGUCUCAGCGUGAUCUUCCAUCACUU
486


374
antisense
(Hs-Mf)





strand








MAPT-
27 mer
 395-247
CUUUCUUGUCCCCCAACCCGUACGUCC
487


395
antisense
(Hs-Mf)





strand








MAPT-
27 mer
 400-252
CUGAUUUUUCCUGUCCCCCAACCCGUA
488


400
antisense
(Hs-Mf)





strand








MAPT-
27 mer
 443-295
CGUCCUUGUCACCCUCUUGGUCUUGGU
489


443
antisense
(Hs-Mf)





strand








MAPT-
27 mer
 688-453
CACGUUACCAGCAGCUUCGUCUUCCAG
490


688
antisense
(Hs-Mf)





strand








MAPT-
27 mer
 689-454
UCACGUGACCAGCAGCUUCGUCUUCCA
491


689
antisense
(Hs-Mf)





strand








MAPT-
27 mer
 690-455
GUCACUUGACCAGCAGCUUCGUCUUCC
492


690
antisense
(Hs-Mf)





strand








MAPT-
27 mer
 693-458
UGGGUUACGUGACCAGCAGCUUCGUCU
493


693
antisense
(Hs-Mf)





strand








MAPT-
27 mer
 695-460
CUUGGUUCACGUGACCAGCAGCUUCGU
494


695
antisense
(Hs-Mf)





strand








MAPT-
27 mer
 696-461
UCUUGUGUCACGUGACCAGCAGCUUCG
495


696
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1475-1552
CGUCUUUGCUUUUACUGACCAUGCGAG
496


1475
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1476-1553
CCGUCUUUGCUUUUACUGACCAUGCGA
497


1476
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1479-1556
GUCCCUUCUUUGCUUUUACUGACCAUG
498


1479
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1480-1557
AGUCCUGUCUUUGCUUUUACUGACCAU
499


1480
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1481-1558
CAGUCUCGUCUUUGCUUUUACUGACCA
500


1481
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1484-1561
UUCCAUUCCCGUCUUUGCUUUUACUGA
501


1484
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1485-1562
CUUCCUGUCCCGUCUUUGCUUUUACUG
502


1485
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1492-1569
GUCAUUGCUUCCAGUCCCGUCUUUGCU
503


1492
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1494-1571
UUGUCUUCGCUUCCAGUCCCGUCUUUG
504


1494
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1495-1572
UUUGUUAUCGCUUCCAGUCCCGUCUUU
505


1495
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1498-1575
UUUUUUGUCAUCGCUUCCAGUCCCGUC
506


1498
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1499-1576
CUUUUUUGUCAUCGCUUCCAGUCCCGU
507


1499
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1500-1577
GCUUUUUUGUCAUCGCUUCCAGUCCCG
508


1500
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1502-1579
UGGCUUUUUUGUCAUCGCUUCCAGUCC
509


1502
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1503-1580
UUGGCUUUUUUGUCAUCGCUUCCAGUC
510


1503
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1504-1581
CUUGGUUUUUUUGUCAUCGCUUCCAGU
511


1504
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1505-1582
UCUUGUCUUUUUUGUCAUCGCUUCCAG
512


1505
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1506-1583
GUCUUUGCUUUUUUGUCAUCGCUUCCA
513


1506
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1507-1584
UGUCUUGGCUUUUUUGUCAUCGCUUCC
514


1507
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1508-1585
AUGUCUUGGCUUUUUUGUCAUCGCUUC
515


1508
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1509-1586
GAUGUUUUGGCUUUUUUGUCAUCGCUU
516


1509
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1733 (Hs)
GUGUGUCGAUCUUCGUUUUACCAUCAG
517


1733
antisense






strand








MAPT-
27 mer
1796-1873
UUUUUUCUGGAAUCCUGGUGGCGUUGG
518


1796
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1835-1912
UAGUCUCAGAGCUGGGUGGUGUCUUUG
519


1835
antisense
(Hs-Mf)





strand








MAPT-
27 mer
1912-1989
GCUGCUAUCCCCUGAUUUUGGAGGUUC
520


1912
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2094-2171
ACAUUUUUCAGGUCUGGCAUGGGCACG
521


2094
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2096-2173
UGACAUUCUUCAGGUCUGGCAUGGGCA
522


2096
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2097-2174
UUGACUUUCUUCAGGUCUGGCAUGGGC
523


2097
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2098 (Hs)
CUUGAUAUUCUUCAGGUCUGGCAUGGG
524


2098
antisense






strand








MAPT-
27 mer
2105 (Hs)
UCUUGUACUUGACAUUCUUCAGGUCUG
525


2105
antisense






strand








MAPT-
27 mer
2106 (Hs)
AUCUUUGACUUGACAUUCUUCAGGUCU
526


2106
antisense






strand








MAPT-
27 mer
2107 (Hs)
GAUCUUGGACUUGACAUUCUUCAGGUC
527


2107
antisense






strand








MAPT-
27 mer
2108 (Hs)
CGAUCUUGGACUUGACAUUCUUCAGGU
528


2108
antisense






strand








MAPT-
27 mer
2109 (Hs)
CCGAUUUUGGACUUGACAUUCUUCAGG
529


2109
antisense






strand








MAPT-
27 mer
2117-2194
CAGUGUAGCCGAUCUUGGACUUGACAU
530


2117
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2136 (Hs)
GGCUGUUGCUUCAGGUUCUCAGUGGAG
531


2136
antisense






strand








MAPT-
27 mer
2137 (Hs)
CGGCUUGUGCUUCAGGUUCUCAGUGGA
532


2137
antisense






strand








MAPT-
27 mer
2269-2346
GUCAAUUGGUUUGUAGACUAUUUGCAC
533


2269
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2270-2347
GGUCAUCUGGUUUGUAGACUAUUUGCA
534


2270
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2271-2348
AGGUCUACUGGUUUGUAGACUAUUUGC
535


2271
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2272-2349
CAGGUUAACUGGUUUGUAGACUAUUUG
536


2272
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2273-2350
UCAGGUCAACUGGUUUGUAGACUAUUU
537


2273
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2274-2351
CUCAGUUCAACUGGUUUGUAGACUAUU
538


2274
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2275-2352
GCUCAUGUCAACUGGUUUGUAGACUAU
539


2275
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2276-2353
UGCUCUGGUCAACUGGUUUGUAGACUA
540


2276
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2277-2354
UUGCUUAGGUCAACUGGUUUGUAGACU
541


2277
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2278-2355
CUUGCUCAGGUCAACUGGUUUGUAGAC
542


2278
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2279-2356
CCUUGUUCAGGUCAACUGGUUUGUAGA
543


2279
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2280-2357
ACCUUUCUCAGGUCAACUGGUUUGUAG
544


2280
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2281-2358
CACCUUGCUCAGGUCAACUGGUUUGUA
545


2281
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2282-2359
UCACCUUGCUCAGGUCAACUGGUUUGU
546


2282
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2283-2360
GUCACUUUGCUCAGGUCAACUGGUUUG
547


2283
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2284-2361
GGUCAUCUUGCUCAGGUCAACUGGUUU
548


2284
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2286-2363
GAGGUUACCUUGCUCAGGUCAACUGGU
549


2286
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2288-2365
UGGAGUUCACCUUGCUCAGGUCAACUG
550


2288
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2289-2366
UUGGAUGUCACCUUGCUCAGGUCAACU
551


2289
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2291-2368
ACUUGUAGGUCACCUUGCUCAGGUCAA
552


2291
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2294-2371
CACACUUGGAGGUCACCUUGCUCAGGU
553


2294
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2299-2376
UGAGCUACACUUGGAGGUCACCUUGCU
554


2299
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2300-2377
AUGAGUCACACUUGGAGGUCACCUUGC
555


2300
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2301-2378
AAUGAUCCACACUUGGAGGUCACCUUG
556


2301
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2308-2385
GUUGCUUAAUGAGCCACACUUGGAGGU
557


2308
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2316-2393
UGAUGUAUGUUGCCUAAUGAGCCACAC
558


2316
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2317-2394
AUGAUUGAUGUUGCCUAAUGAGCCACA
559


2317
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2319-2396
UUAUGUUGGAUGUUGCCUAAUGAGCCA
560


2319
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2320-2397
UUUAUUAUGGAUGUUGCCUAAUGAGCC
561


2320
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2322-2399
GGUUUUUGAUGGAUGUUGCCUAAUGAG
562


2322
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2323-2400
UGGUUUAUGAUGGAUGUUGCCUAAUGA
563


2323
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2324-2401
CUGGUUUAUGAUGGAUGUUGCCUAAUG
564


2324
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2326-2403
UCCUGUUUUAUGAUGGAUGUUGCCUAA
565


2326
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2330-2407
CACCUUCUGGUUUAUGAUGGAUGUUGC
566


2330
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2356-2433
CUUCUUAGAUUUUACUUCCACCUGGCC
567


2356
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2357-2434
GCUUCUCAGAUUUUACUUCCACCUGGC
568


2357
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2358-2435
AGCUUUUCAGAUUUUACUUCCACCUGG
569


2358
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2359-2436
AAGCUUCUCAGAUUUUACUUCCACCUG
570


2359
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2360-2437
CAAGCUUCUCAGAUUUUACUUCCACCU
571


2360
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2361-2438
UCAAGUUUCUCAGAUUUUACUUCCACC
572


2361
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2362-2439
GUCAAUCUUCUCAGAUUUUACUUCCAC
573


2362
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2363-2440
AGUCAUGCUUCUCAGAUUUUACUUCCA
574


2363
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2364-2441
AAGUCUAGCUUCUCAGAUUUUACUUCC
575


2364
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2365 (Hs)
GAAGUUAAGCUUCUCAGAUUUUACUUC
576


2365
antisense






strand








MAPT-
27 mer
2372 (Hs)
UGUCCUUGAAGUCAAGCUUCUCAGAUU
577


2372
antisense






strand








MAPT-
27 mer
2373 (Hs)
CUGUCUUUGAAGUCAAGCUUCUCAGAU
578


2373
antisense






strand








MAPT-
27 mer
2374 (Hs)
UCUGUUCUUGAAGUCAAGCUUCUCAGA
579


2374
antisense






strand








MAPT-
27 mer
2375 (Hs)
CUCUGUCCUUGAAGUCAAGCUUCUCAG
580


2375
antisense






strand








MAPT-
27 mer
2376 (Hs)
ACUCUUUCCUUGAAGUCAAGCUUCUCA
581


2376
antisense






strand








MAPT-
27 mer
2377 (Hs)
GACUCUGUCCUUGAAGUCAAGCUUCUC
582


2377
antisense






strand








MAPT-
27 mer
2378 (Hs)
GGACUUUGUCCUUGAAGUCAAGCUUCU
583


2378
antisense






strand








MAPT-
27 mer
2379 (Hs)
UGGACUCUGUCCUUGAAGUCAAGCUUC
584


2379
antisense






strand








MAPT-
27 mer
2380 (Hs)
CUGGAUUCUGUCCUUGAAGUCAAGCUU
585


2380
antisense






strand








MAPT-
27 mer
2381 (Hs)
ACUGGUCUCUGUCCUUGAAGUCAAGCU
586


2381
antisense






strand








MAPT-
27 mer
2382 (Hs)
GACUGUACUCUGUCCUUGAAGUCAAGC
587


2382
antisense






strand








MAPT-
27 mer
2390 (Hs)
CAAUCUUCGACUGGACUCUGUCCUUGA
588


2390
antisense






strand








MAPT-
27 mer
2391 (Hs)
CCAAUUUUCGACUGGACUCUGUCCUUG
589


2391
antisense






strand








MAPT-
27 mer
2414-2491
CGUGGUUGAUAUUGUCCAGGGACCCAA
590


2414
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2448-2525
UGGGUUUCAAUCUUUUUAUUUCCUCCG
591


2448
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2449-2526
GUGGGUUUCAAUCUUUUUAUUUCCUCC
592


2449
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2450-2527
UGUGGUUUUCAAUCUUUUUAUUUCCUC
593


2450
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2451-2528
UUGUGUGUUUCAAUCUUUUUAUUUCCU
594


2451
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2452-2529
CUUGUUGGUUUCAAUCUUUUUAUUUCC
595


2452
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2453-2530
GCUUGUGGGUUUCAAUCUUUUUAUUUC
596


2453
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2454-2531
AGCUUUUGGGUUUCAAUCUUUUUAUUU
597


2454
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2456-2533
UCAGCUUGUGGGUUUCAAUCUUUUUAU
598


2456
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2457-2534
GUCAGUUUGUGGGUUUCAAUCUUUUUA
599


2457
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2567 (Hs)
UGGAGUAGACAUUGCUGAGAUGCCGUG
600


2567
antisense






strand








MAPT-
27 mer
2598-2675
UGGGGUGAGUCUACCAUGUCGAUGCUG
601


2598
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2657-2734
CUGAUUACAAACCCUGCUUGGCCAGGG
602


2657
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2723-2800
AUUAUUCUUUUUUUUUCCACACUCUCU
603


2723
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2724-2801
CAUUAUUCUUUUUUUUUCCACACUCUC
604


2724
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2726-2803
GUCAUUAUUCUUUUUUUUUCCACACUC
605


2726
antisense
(Hs-Mf)





strand








MAPT-
27 mer
2784-2860-
GUGAUUAACCAAUUAACCGAACUGCGA
606


2784
antisense
1 mismatch





strand
(Hs-Mf)







MAPT-
27 mer
2963-3039
GAAAAUAGAAUCAAAAGGAAUUGCCUG
607


2963
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3110-3186
ACCAAUUUUCAAAUCCUUUGUUGCUGC
608


3110
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3114-3190
ACACAUCAAGUUUCAAAUCCUUUGUUG
609


3114
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3116-3192
GAACAUACCAAGUUUCAAAUCCUUUGU
610


3116
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3118-3194
ACGAAUACACCAAGUUUCAAAUCCUUU
611


3118
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3158-3234
UCACAUUCACACAAGGUUGACAUCGUC
612


3158
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3503-3576
UCUCAUGACAUCAAGGUCAGUCUUUUC
613


3503
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3589-3661
UCAAUUAAACAGGGUUUCUGUGGAGCA
614


3589
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3591-3663
ACUCAUUAAAACAGGGUUUCUGUGGAG
615


3591
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3592-3664
AACUCUAUAAAACAGGGUUUCUGUGGA
616


3592
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3593-3665
GAACUUAAUAAAACAGGGUUUCUGUGG
617


3593
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3594-3666
AGAACUCAAUAAAACAGGGUUUCUGUG
618


3594
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3595-3667
CAGAAUUCAAUAAAACAGGGUUUCUGU
619


3595
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3596-3668
UCAGAUCUCAAUAAAACAGGGUUUCUG
620


3596
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3597-3669
UUCAGUACUCAAUAAAACAGGGUUUCU
621


3597
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3598-3670
CUUCAUAACUCAAUAAAACAGGGUUUC
622


3598
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3599-3671
CCUUCUGAACUCAAUAAAACAGGGUUU
623


3599
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3600-3672
ACCUUUAGAACUCAAUAAAACAGGGUU
624


3600
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3601-3673
AACCUUCAGAACUCAAUAAAACAGGGU
625


3601
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3602-3674
CAACCUUCAGAACUCAAUAAAACAGGG
626


3602
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3603-3675
CCAACUUUCAGAACUCAAUAAAACAGG
627


3603
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3605-3677
UUCCAUCCUUCAGAACUCAAUAAAACA
628


3605
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3607-3679
AGUUCUAACCUUCAGAACUCAAUAAAA
629


3607
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3609-3681
GCAGUUCCAACCUUCAGAACUCAAUAA
630


3609
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3610-3682
AGCAGUUCCAACCUUCAGAACUCAAUA
631


3610
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3677-3749
CAAGUUCUUACAAAGAGAACUGGUUAG
632


3677
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3678-3750
ACAAGUCCUUACAAAGAGAACUGGUUA
633


3678
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3679-3751
CACAAUUCCUUACAAAGAGAACUGGUU
634


3679
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3680-3752
GCACAUGUCCUUACAAAGAGAACUGGU
635


3680
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3958-4030
UAAUUUCACCCUCAGUAUGGAGUAGGU
636


3958
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3959-4031
UUAAUUUCACCCUCAGUAUGGAGUAGG
637


3959
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3960-4032
CUUAAUUUCACCCUCAGUAUGGAGUAG
638


3960
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3961-4033
CCUUAUUUUCACCCUCAGUAUGGAGUA
639


3961
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3965-4037
CUUCCUUUAAUUUCACCCUCAGUAUGG
640


3965
antisense
(Hs-Mf)





strand








MAPT-
27 mer
3970-4042
UUUGCUUUCCCUUAAUUUCACCCUCAG
641


3970
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4146-4218
UCCAUUUCAACAAGGCAGAAACACCUA
642


4146
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4474-4545
CUAUGUAUAUGUUCAGCUGCUCCAGCA
643


4474
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4475-4546
UCUAUUUAUAUGUUCAGCUGCUCCAGC
644


4475
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4477-4548
CAUCUUUGUAUAUGUUCAGCUGCUCCA
645


4477
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4478-4549
ACAUCUAUGUAUAUGUUCAGCUGCUCC
646


4478
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4479-4550
AACAUUUAUGUAUAUGUUCAGCUGCUC
647


4479
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4480-4551
CAACAUCUAUGUAUAUGUUCAGCUGCU
648


4480
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4481-4552
GCAACUUCUAUGUAUAUGUUCAGCUGC
649


4481
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4482-4553
GGCAAUAUCUAUGUAUAUGUUCAGCUG
650


4482
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4485-4556
CAGGGUAACAUCUAUGUAUAUGUUCAG
651


4485
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4486-4557
GCAGGUCAACAUCUAUGUAUAUGUUCA
652


4486
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4532 (Hs)
AAACAUACAAAUCCAACUACAACUCAA
653


4532
antisense






strand








MAPT-
27 mer
4533 (Hs)
UAAACUGACAAAUCCAACUACAACUCA
654


4533
antisense






strand








MAPT-
27 mer
4539-4610
CAAGCUUAAACAGACAAAUCCAACUAC
655


4539
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4540-4611
CCAAGUAUAAACAGACAAAUCCAACUA
656


4540
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4541-4612
UCCAAUCAUAAACAGACAAAUCCAACU
657


4541
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4543-4614
AAUCCUAGCAUAAACAGACAAAUCCAA
658


4543
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4544-4615
GAAUCUAAGCAUAAACAGACAAAUCCA
659


4544
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4545-4616
UGAAUUCAAGCAUAAACAGACAAAUCC
660


4545
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4546-4617
GUGAAUCCAAGCAUAAACAGACAAAUC
661


4546
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4547-4618
GGUGAUUCCAAGCAUAAACAGACAAAU
662


4547
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4548-4619
UGGUGUAUCCAAGCAUAAACAGACAAA
663


4548
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4549-4620
CUGGUUAAUCCAAGCAUAAACAGACAA
664


4549
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4550-4621
UCUGGUGAAUCCAAGCAUAAACAGACA
665


4550
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4551-4622
CUCUGUUGAAUCCAAGCAUAAACAGAC
666


4551
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4552-4623
ACUCUUGUGAAUCCAAGCAUAAACAGA
667


4552
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4554-4625
UCACUUUGGUGAAUCCAAGCAUAAACA
668


4554
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4556-4627
AGUCAUUCUGGUGAAUCCAAGCAUAAA
669


4556
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4557-4628
UAGUCUCUCUGGUGAAUCCAAGCAUAA
670


4557
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4558-4629
AUAGUUACUCUGGUGAAUCCAAGCAUA
671


4558
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4559-4630
CAUAGUCACUCUGGUGAAUCCAAGCAU
672


4559
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4560-4631
UCAUAUUCACUCUGGUGAAUCCAAGCA
673


4560
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4561-4632
AUCAUUGUCACUCUGGUGAAUCCAAGC
674


4561
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4562-4633
UAUCAUAGUCACUCUGGUGAAUCCAAG
675


4562
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4563-4634
CUAUCUUAGUCACUCUGGUGAAUCCAA
676


4563
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4564-4635
ACUAUUAUAGUCACUCUGGUGAAUCCA
677


4564
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4615-4687
UACAAUCAUUUCAAGAUACAUGCGUCC
678


4615
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4616-4688
UUACAUGCAUUUCAAGAUACAUGCGUC
679


4616
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4617-4689
UUUACUAGCAUUUCAAGAUACAUGCGU
680


4617
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4618-4690
CUUUAUAAGCAUUUCAAGAUACAUGCG
681


4618
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4619-4691
UCUUUUCAAGCAUUUCAAGAUACAUGC
682


4619
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4620-4692
CUCUUUACAAGCAUUUCAAGAUACAUG
683


4620
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4621-4693
CCUCUUUACAAGCAUUUCAAGAUACAU
684


4621
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4622-4694
ACCUCUUUACAAGCAUUUCAAGAUACA
685


4622
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4623-4695
AACCUUUUUACAAGCAUUUCAAGAUAC
686


4623
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4625-4697
GAAACUUCUUUACAAGCAUUUCAAGAU
687


4625
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4627-4699
UAGAAUCCUCUUUACAAGCAUUUCAAG
688


4627
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4628-4700
UUAGAUACCUCUUUACAAGCAUUUCAA
689


4628
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4629-4701
GUUAGUAACCUCUUUACAAGCAUUUCA
690


4629
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4630-4702
GGUUAUAAACCUCUUUACAAGCAUUUC
691


4630
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4632-4704
UGGGUUAGAAACCUCUUUACAAGCAUU
692


4632
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4633-4705
GUGGGUUAGAAACCUCUUUACAAGCAU
693


4633
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4825-4897
AUCAUUGCUUCAGUCCUAAUCCUGUGC
694


4825
antisense
(Hs-Mf)





strand








MAPT-
27 mer
4828-4900
GACAUUAUCGCUUCAGUCCUAAUCCUG
695


4828
antisense
(Hs-Mf)





strand








MAPT-
27 mer
5682-5743
CUGAAUAGCAGGGCACAAGAACUUCAG
696


5682
antisense
(Hs-Mf)





strand








MAPT-
27 mer
5958 (Hs)
UAUUGUUAAAGUGAGUCAGCAGCUUGA
697


5958
antisense






strand








MAPT-
27 mer
5959 (Hs)
CUAUUUAUAAAGUGAGUCAGCAGCUUG
698


5959
antisense






strand








MAPT-
27 mer
5961 (Hs)
AACUAUUGAUAAAGUGAGUCAGCAGCU
699


5961
antisense






strand








MAPT-
27 mer
5963 (Hs)
GGAACUAUUGAUAAAGUGAGUCAGCAG
700


5963
antisense






strand








MAPT-
27 mer
5964 (Hs)
UGGAAUUAUUGAUAAAGUGAGUCAGCA
701


5964
antisense






strand








MAPT-
27 mer
5965 (Hs)
AUGGAACUAUUGAUAAAGUGAGUCAGC
702


5965
antisense






strand








MAPT-
27 mer
5966-6021
AAUGGUACUAUUGAUAAAGUGAGUCAG
703


5966
antisense
(Hs-Mf)





strand








MAPT-
27 mer
5967-6022
AAAUGUAACUAUUGAUAAAGUGAGUCA
704


5967
antisense
(Hs-Mf)





strand








MAPT-
27 mer
5968-6023
UAAAUUGAACUAUUGAUAAAGUGAGUC
705


5968
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6006-6061
AUAGCUAACAGGAUACAGUCUCACCAC
706


6006
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6007-6062
AAUAGUAAACAGGAUACAGUCUCACCA
707


6007
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6008-6063
CAAUAUCAAACAGGAUACAGUCUCACC
708


6008
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6009-6064
GCAAUUGCAAACAGGAUACAGUCUCAC
709


6009
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6010-6065
AGCAAUAGCAAACAGGAUACAGUCUCA
710


6010
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6011-6066
AAGCAUUAGCAAACAGGAUACAGUCUC
711


6011
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6012-6067
CAAGCUAUAGCAAACAGGAUACAGUCU
712


6012
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6013-6068
ACAAGUAAUAGCAAACAGGAUACAGUC
713


6013
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6014-6069
AACAAUCAAUAGCAAACAGGAUACAGU
714


6014
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6015-6070
CAACAUGCAAUAGCAAACAGGAUACAG
715


6015
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6017-6072
CACAAUAAGCAAUAGCAAACAGGAUAC
716


6017
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6119-6174
GAAAUUAUGAAAAGGGUUACGAGGCAG
717


6119
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6628-6689
UAGUCUUGCUCAACAUGGCAAACUCAU
718


6628
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6629-6690
AUAGUUCUGCUCAACAUGGCAAACUCA
719


6629
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6631-6692
AAAUAUUCCUGCUCAACAUGGCAAACU
720


6631
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6672-6733
CUCAGUAUUACCGAAGAAAUCAUGGGA
721


6672
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6731 (Hs)
AUAUAUACAUUCACAGACAGAAAGCUA
722


6731
antisense






strand








MAPT-
27 mer
6732 (Hs)
UAUAUUGACAUUCACAGACAGAAAGCU
723


6732
antisense






strand








MAPT-
27 mer
6738-6799
AUACAUUAUAUAGACAUUCACAGACAG
724


6738
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6739-6800
AAUACUCUAUAUAGACAUUCACAGACA
725


6739
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6740-6801
CAAUAUACUAUAUAGACAUUCACAGAC
726


6740
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6741-6802
ACAAUUCACUAUAUAGACAUUCACAGA
727


6741
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6742-6803
CACAAUACACUAUAUAGACAUUCACAG
728


6742
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6743-6804
ACACAUUACACUAUAUAGACAUUCACA
729


6743
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6745-6806
ACACAUAAUACACUAUAUAGACAUUCA
730


6745
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6748-6809
AAAACUCACAAUACACUAUAUAGACAU
731


6748
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6749-6810
UAAAAUACACAAUACACUAUAUAGACA
732


6749
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6750-6811
UUAAAUCACACAAUACACUAUAUAGAC
733


6750
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6751-6812
GUUAAUACACACAAUACACUAUAUAGA
734


6751
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6752-6813
UGUUAUAACACACAAUACACUAUAUAG
735


6752
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6753-6814
UUGUUUAAACACACAAUACACUAUAUA
736


6753
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6754-6815
UUUGUUAAAACACACAAUACACUAUAU
737


6754
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6755-6816
AUUUGUUAAAACACACAAUACACUAUA
738


6755
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6756-6817
CAUUUUUUAAAACACACAAUACACUAU
739


6756
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6757-6818
UCAUUUGUUAAAACACACAAUACACUA
740


6757
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6758-6819
AUCAUUUGUUAAAACACACAAUACACU
741


6758
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6759-6820
AAUCAUUUGUUAAAACACACAAUACAC
742


6759
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6760-6821
AAAUCUUUUGUUAAAACACACAAUACA
743


6760
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6761-6822
UAAAUUAUUUGUUAAAACACACAAUAC
744


6761
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6762-6823
GUAAAUCAUUUGUUAAAACACACAAUA
745


6762
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6763-6824
UGUAAUUCAUUUGUUAAAACACACAAU
746


6763
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6764-6825
GUGUAUAUCAUUUGUUAAAACACACAA
747


6764
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6765-6826
AGUGUUAAUCAUUUGUUAAAACACACA
748


6765
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6766-6827
CAGUGUAAAUCAUUUGUUAAAACACAC
749


6766
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6767-6828
UCAGUUUAAAUCAUUUGUUAAAACACA
750


6767
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6768-6829
GUCAGUGUAAAUCAUUUGUUAAAACAC
751


6768
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6769-6830
AGUCAUUGUAAAUCAUUUGUUAAAACA
752


6769
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6772-6833
AACAGUCAGUGUAAAUCAUUUGUUAAA
753


6772
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6773-6834
CAACAUUCAGUGUAAAUCAUUUGUUAA
754


6773
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6774-6835
GCAACUGUCAGUGUAAAUCAUUUGUUA
755


6774
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6775-6836
AGCAAUAGUCAGUGUAAAUCAUUUGUU
756


6775
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6777-6838
ACAGCUACAGUCAGUGUAAAUCAUUUG
757


6777
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6778-6839
UACAGUAACAGUCAGUGUAAAUCAUUU
758


6778
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6779-6840
UUACAUCAACAGUCAGUGUAAAUCAUU
759


6779
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6780-6841
UUUACUGCAACAGUCAGUGUAAAUCAU
760


6780
antisense
(Hs-Mf)





strand








MAPT-
27 mer
6781 (Hs)
UUUUAUAGCAACAGUCAGUGUAAAUCA
761


6781
antisense






strand








MAPT-
27 mer
6789 (Hs)
AAAUUUACUUUUACAGCAACAGUCAGU
762


6789
antisense






strand








MAPT-
27 mer
6792 (Hs)
UCCAAUUUCACUUUUACAGCAACAGUC
763


6792
antisense






strand








MAPT-
27 mer
6793 (Hs)
UUCCAUAUUCACUUUUACAGCAACAGU
764


6793
antisense






strand








MAPT-
27 mer
6795 (Hs)
AUUUCUAAAUUCACUUUUACAGCAACA
765


6795
antisense






strand








MAPT-
27 mer
6796 (Hs)
UAUUUUCAAAUUCACUUUUACAGCAAC
766


6796
antisense






strand








MAPT-
27 mer
6797 (Hs)
UUAUUUCCAAAUUCACUUUUACAGCAA
767


6797
antisense






strand








MAPT-
27 mer
6798 (Hs)
UUUAUUUCCAAAUUCACUUUUACAGCA
768


6798
antisense






strand








MAPT-
Unmodified
2456-2533
AAAAAGAUUGAAACCCACAAGCAGCCG
769


2456
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2567 (Hs)
CGGCAUCUCAGCAAUGUCUAGCAGCCGA
770


2567
36 mer

AAGGCUGC




sense






strand








MAPT-
Unmodified
2723-2800
AGAGUGUGGAAAAAAAAAGAGCAGCCG
771


2723
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
690-455
AAGACGAAGCUGCUGGUCAAGCAGCCG
772


0690
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
1494-1571
AAGACGGGACUGGAAGCGAAGCAGCCG
773


1494
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
1733 (Hs)
GAUGGUAAAACGAAGAUCGAGCAGCCG
774


1733
36 mer

AAAGGCUGC




sense






strand








MAPT-
Unmodified
2273-2350
AUAGUCUACAAACCAGUUGAGCAGCCG
775


2273
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2274-2351
UAGUCUACAAACCAGUUGAAGCAGCCG
776


2274
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2276-2353
GUCUACAAACCAGUUGACCAGCAGCCGA
777


2276
36 mer
(Hs-Mf)
AAGGCUGC




sense






strand








MAPT-
Unmodified
2301-2378
AGGUGACCUCCAAGUGUGGAGCAGCCG
778


2301
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2347-2424-
AGGAGGUGGCCAGGUGGAAAGCAGCCG
779


2347
36 mer
1172 (Hs-
AAAGGCUGC




sense
Mf-Mm)





strand








MAPT-
Unmodified
2357-2434
CAGGUGGAAGUAAAAUCUGAGCAGCCG
780


2357
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2358-2435
AGGUGGAAGUAAAAUCUGAAGCAGCCG
781


2358
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2364-2441
AAGUAAAAUCUGAGAAGCUAGCAGCCG
782


2364
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2378 (Hs)
AAGCUUGACUUCAAGGACAAGCAGCCG
783


2378
36 mer

AAAGGCUGC




sense






strand








MAPT-
Unmodified
2459-2536-
AAGAUUGAAACCCACAAGCAGCAGCCG
784


2459
36 mer
1284 (Hs-
AAAGGCUGC




sense
Mf-Mm)





strand








MAPT-
Unmodified
2461-2538-
GAUUGAAACCCACAAGCUGAGCAGCCG
785


2461
36 mer
1286 (Hs-
AAAGGCUGC




sense
Mf-Mm)





strand








MAPT-
Unmodified
2460-2537-
AGAUUGAAACCCACAAGCUAGCAGCCG
786


2460
36 mer
1285 (Hs-
AAAGGCUGC




sense
Mf-Mm)





strand








MAPT-
Unmodified
1479-1556
UGGUCAGUAAAAGCAAAGAAGCAGCCG
787


1479
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
1505-1582
GGAAGCGAUGACAAAAAAGAGCAGCCG
788


1505
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2096-2173
CCCAUGCCAGACCUGAAGAAGCAGCCGA
789


2096
36 mer
(Hs-Mf)
AAGGCUGC




sense






strand








MAPT-
Unmodified
2270-2347
CAAAUAGUCUACAAACCAGAGCAGCCG
790


2270
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2279-2356
UACAAACCAGUUGACCUGAAGCAGCCG
791


2279
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2281-2358
CAAACCAGUUGACCUGAGCAGCAGCCGA
792


2281
36 mer
(Hs-Mf)
AAGGCUGC




sense






strand








MAPT-
Unmodified
2284-2361
ACCAGUUGACCUGAGCAAGAGCAGCCG
793


2284
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2299-2376
CAAGGUGACCUCCAAGUGUAGCAGCCG
794


2299
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2376 (Hs)
AGAAGCUUGACUUCAAGGAAGCAGCCG
795


2376
36 mer

AAAGGCUGC




sense






strand








MAPT-
Unmodified
2379 (Hs)
AGCUUGACUUCAAGGACAGAGCAGCCG
796


2379
36 mer

AAAGGCUGC




sense






strand








MAPT-
Unmodified
2382 (Hs)
UUGACUUCAAGGACAGAGUAGCAGCCG
797


2382
36 mer

AAAGGCUGC




sense






strand








MAPT-
Unmodified
2449-2526
AGGAAAUAAAAAGAUUGAAAGCAGCCG
798


2449
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2450-2527
GGAAAUAAAAAGAUUGAAAAGCAGCCG
799


2450
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2451-2528
GAAAUAAAAAGAUUGAAACAGCAGCCG
800


2451
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2452-2529
AAAUAAAAAGAUUGAAACCAGCAGCCG
801


2452
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2453-2530
AAUAAAAAGAUUGAAACCCAGCAGCCG
802


2453
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
Unmodified
2454-2531
AUAAAAAGAUUGAAACCCAAGCAGCCG
803


2454
36 mer
(Hs-Mf)
AAAGGCUGC




sense






strand








MAPT-
unmodified
2456-2533
UUGUGGGUUUCAAUCUUUUUGG
804


2456
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2567 (Hs)
UAGACAUUGCUGAGAUGCCGGG
805


2567
32 mer






antisense






strand








MAPT-
unmodified
2723-2800
UCUUUUUUUUUCCACACUCUGG
806


2723
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
690-455
UUGACCAGCAGCUUCGUCUUGG
807


0690
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
1494-1571
UUCGCUUCCAGUCCCGUCUUGG
808


1494
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
1733 (Hs)
UCGAUCUUCGUUUUACCAUCGG
809


1733
32 mer






antisense






strand








MAPT-
unmodified
2273-2350
UCAACUGGUUUGUAGACUAUGG
810


2273
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2274-2351
UUCAACUGGUUUGUAGACUAGG
811


2274
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2276-2353
UGGUCAACUGGUUUGUAGACGG
812


2276
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2301-2378
UCCACACUUGGAGGUCACCUGG
813


2301
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2347-2424-
UUUCCACCUGGCCACCUCCUGG
814


2347
32 mer
1172 (Hs-





antisense
Mf-Mm)





strand








MAPT-
unmodified
2357-2434
UCAGAUUUUACUUCCACCUGGG
815


2357
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2358-2435
UUCAGAUUUUACUUCCACCUGG
816


2358
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2364-2441
UAGCUUCUCAGAUUUUACUUGG
817


2364
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2378 (Hs)
UUGUCCUUGAAGUCAAGCUUGG
818


2378
32 mer






antisense






strand








MAPT-
unmodified
2459-2536-
UGCUUGUGGGUUUCAAUCUUGG
819


2459
32 mer
1284 (Hs-





antisense
Mf-Mm)





strand








MAPT-
unmodified
2461-2538-
UCAGCUUGUGGGUUUCAAUCGG
820


2461
32 mer
1286 (Hs-





antisense
Mf-Mm)





strand








MAPT-
unmodified
2460-2537-
UAGCUUGUGGGUUUCAAUCUGG
821


2460
32 mer
1285 (Hs-





antisense
Mf-Mm)





strand








MAPT-
unmodified
1479-1556
UUCUUUGCUUUUACUGACCAGG
822


1479
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
1505-1582
UCUUUUUUGUCAUCGCUUCCGG
823


1505
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2096-2173
UUCUUCAGGUCUGGCAUGGGGG
824


2096
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2270-2347
UCUGGUUUGUAGACUAUUUGGG
825


2270
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2279-2356
UUCAGGUCAACUGGUUUGUAGG
826


2279
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2281-2358
UGCUCAGGUCAACUGGUUUGGG
827


2281
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2284-2361
UCUUGCUCAGGUCAACUGGUGG
828


2284
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2299-2376
UACACUUGGAGGUCACCUUGGG
829


2299
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2376 (Hs)
UUCCUUGAAGUCAAGCUUCUGG
830


2376
32 mer






antisense






strand








MAPT-
unmodified
2379 (Hs)
UCUGUCCUUGAAGUCAAGCUGG
831


2379
32 mer






antisense






strand








MAPT-
unmodified
2382 (Hs)
UACUCUGUCCUUGAAGUCAAGG
832


2382
32 mer






antisense






strand








MAPT-
unmodified
2449-2526
UUUCAAUCUUUUUAUUUCCUGG
833


2449
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2450-2527
UUUUCAAUCUUUUUAUUUCCGG
834


2450
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2451-2528
UGUUUCAAUCUUUUUAUUUCGG
835


2451
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2452-2529
UGGUUUCAAUCUUUUUAUUUGG
836


2452
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2453-2530
UGGGUUUCAAUCUUUUUAUUGG
837


2453
32 mer
(Hs-Mf)





antisense






strand








MAPT-
unmodified
2454-2531
UUGGGUUUCAAUCUUUUUAUGG
838


2454
32 mer
(Hs-Mf)





antisense






strand








MAPT-
Modified
2456-2533
[mAs][mA][fA][mA][fA][mG][mA][fU][mU][fG]
839


2456
36 mer
(Hs-Mf)
[mA][fA][fA][mC][fC][mC][fA][mC][mA][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2567 (Hs)
[mCs][mG][fG][mC][fA][mU][mC][fU][mC][fA]
840


2567
36 mer

[mG][fC][fA][mA][fU][mG][fU][mC][mU][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][G][mC][mU][mG][mC]






MAPT-
Modified
2723-2800
[mAs][mG][fA][mG][fU][mG][mU][fG][mG][fA]
841


2723
36 mer
(Hs-Mf)
[mA][fA][fA][mA][fA][mA][fA][mA][mG]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][adem




strand

A-GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
690-455
[mAs][mA][fG][mA][fC][mG][mA][fA][mG][fC]
842


0690
36 mer
(Hs-Mf)
[mU][fG][fC][mU][fG][mG][fU][mC][mA][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
1494-1571
[mAs][mA][fG][mA][fC][mG][mG][fG][mA][fC]
843


1494
36 mer
(Hs-Mf)
[mU][fG][fG][mA][fA][mG][fC][mG][mA]




sense

[mA][mG][mC][mA][mG][mC][mC][mA-G][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
1733 (Hs)
[mGs][mA][fU][mG][fG][mU][mA][fA][mA][fA]
844


1733
36 mer

[mC][fG][fA][mA][fG][mA][fU][mC][mG]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2273-2350
[mAs][mU][fA][mG][fU][mC][mU][fA][mC][fA]
845


2273
36 mer
(Hs-Mf)
[mA][fA][fC][mC][fA][mG][fU][mU][mG]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2274-2351
[mUs][mA][fG][mU][fC][mU][mA][fC][mA][fA]
846


2274
36 mer
(Hs-Mf)
[mA][fC][fC][mA][fG][mU][fU][mG][mA]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2276-2353
[mGs][mU][fC][mU][fA][mC][mA][fA][mA][fC]
847


2276
36 mer
(Hs-Mf)
[mC][fA][fG][mU][fU][mG][fA][mC][mC][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2301-2378
[mAs][mG][fG][mU][fG][mA][mC][fC][mU][fC]
848


2301
36 mer
(Hs-Mf)
[mC][fA][fA][mG][fU][mG][fU][mG][mG]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2347-2424-
[mAs][mG][fG][mA][fG][mG][mU][fG][mG][fC]
849


2347
36 mer
1172 (Hs-
[mC][fA][fG][mG][fU][mG][fG][mA][mA]




sense
Mf-Mm)
[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2357-2434
[mCs][mA][fG][mG][fU][mG][mG][fA][mA][fG]
850


2357
36 mer
(Hs-Mf)
[mU][fA][fA][mA][fA][mU][fC][mU][mG]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2358-2435
[mAs][mG][fG][mU][fG][mG][mA][fA][mG][fU]
851


2358
36 mer
(Hs-Mf)
[mA][fA][fA][mA][fU][mC][fU][mG][mA]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2364-2441
[mAs][mA][fG][mU][fA][mA][mA][fA][mU][fC]
852


2364
36 mer
(Hs-Mf)
[mU][fG][fA][mG][fA][mA][fG][mC][mU]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2378 (Hs)
[mAs][mA][fG][mC][fU][mU][mG][fA][mC][fU]
853


2378
36 mer

[mU][fC][fA][mA][fG][mG][fA][mC][mA]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2459-2536-
[mAs][mA][fG][mA][fU][mU][mG][fA][mA][fA]
854


2459
36 mer
1284 (Hs-
[mC][fC][fC][mA][fC][mA][fA][mG][mC][mA]




sense
Mf-Mm)
[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2461-2538-
[mGs][mA][fU][mU][fG][mA][mA][fA][mC][fC]
855


2461
36 mer
1286 (Hs-
[mC][fA][fC][mA][fA][mG][fC][mU][mG][mA]




sense
Mf-Mm)
[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2460-2537-
[mAs][mG][mA][mU][mU][mG][mA][A][fA][fC]
856


2460
36 mer
1285 (Hs-
[fC][mC][mA][mC][mA][mA][mG][mC][mU]




sense
Mf-Mm)
[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
1479-1556
[mUs][mG][fG][mU][fC][mA][mG][fU][mA][fA]
857


1479
36 mer
(Hs-Mf)
[mA][fA][fG][mC][fA][mA][fA][mG][mA]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
1505-1582
[mGs][mG][fA][mA][fG][mC][mG][fA][mU][fG]
858


1505
36 mer
(Hs-Mf)
[mA][fC][fA][mA][fA][mA][fA][mA][mG]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2096-2173
[mCs][mC][fC][mA][fU][mG][mC][fC][mA][fG]
859


2096
36 mer
(Hs-Mf)
[mA][fC][fC][mU][fG][mA][fA][mG][mA][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2270-2347
[mCs][mA][fA][mA][fU][mA][mG][fU][mC][fU]
860


2270
36 mer
(Hs-Mf)
[mA][fC][fA][mA][fA][mC][fC][mA][mG][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2279-2356
[mUs][mA][fC][mA][fA][mA][mC][fC][mA][fG]
861


2279
36 mer
(Hs-Mf)
[mU][fU][fG][mA][fC][mC][fU][mG][mA]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2281-2358
[mCs][mA][fA][mA][fC][mC][mA][fG][mU][fU]
862


2281
36 mer
(Hs-Mf)
[mG][fA][fC][mC][fU][mG][fA][mG][mC][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2284-2361
[mAs][mC][fC][mA][fG][mU][mU][fG][mA][fC]
863


2284
36 mer
(Hs-Mf)
[mC][fU][fG][mA][fG][mC][fA][mA][mG][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2299-2376
[mCs][mA][fA][mG][fG][mU][mG][fA][mC][fC]
864


2299
36 mer
(Hs-Mf)
[mU][fC][fC][mA][fA][mG][fU][mG][mU][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2376 (Hs)
[mAs][mG][fA][mA][fG][mC][mU][fU][mG][fA]
865


2376
36 mer

[mC][fU][fU][mC][fA][mA][fG][mG][mA]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2379 (Hs)
[mAs][mG][fC][mU][fU][mG][mA][fC][mU][fU]
866


2379
36 mer

[mC][fA][fA][mG][fG][mA][fC][mA][mG]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2382 (Hs)
[mUs][mU][fG][mA][fC][mU][mU][fC][mA][fA]
867


2382
36 mer

[mG][fG][fA][mC][fA][mG][fA][mG][mU]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2449-2526
[mAs][mG][fG][mA][fA][mA][mU][fA][mA][fA]
868


2449
36 mer
(Hs-Mf)
[mA][fA][fG][mA][fU][mU][fG][mA][mA]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2450-2527
[mGs][mG][fA][mA][fA][mU][mA][fA][mA][fA]
869


2450
36 mer
(Hs-Mf)
[mA][fG][fA][mU][fU][mG][fA][mA][mA]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2451-2528
[mGs][mA][fA][mA][fU][mA][mA][fA][mA][fA]
870


2451
36 mer
(Hs-Mf)
[mG][fA][fU][mU][fG][mA][fA][mA][mC]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2452-2529
[mAs][mA][fA][mU][fA][mA][mA][fA][mA][fG]
871


2452
36 mer
(Hs-Mf)
[mA][fU][fU][mG][fA][mA][fA][mC][mC]




sense

[mA][mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2453-2530
[mAs][mA][fU][mA][fA][mA][mA][fA][mG][fA]
872


2453
36 mer
(Hs-Mf)
[mU][fU][fG][mA][fA][mA][fC][mC][mC][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2454-2531
[mAs][mU][fA][mA][fA][mA][mA][fG][mA][fU]
873


2454
36 mer
(Hs-Mf)
[mU][fG][fA][mA][fA][mC][fC][mC][mA][mA]




sense

[mG][mC][mA][mG][mC][mC][mG][ademA-




strand

GalNAc][ademA-GalNAc][ademA-






GalNAc][mG][mG][mC][mU][mG][mC]






MAPT-
Modified
2456-2533
[MePhosphonate-4O-
874


2456
22 mer
(Hs-Mf)
mUs][fUs][fG][fU][fG][mG][fG][mU][mU][fU]




antisense

[mC][mA][mA][fU][mC][fU][mU][mU][fU]




strand

[mUs][mGs][mG]






MAPT-
Modified
2567 (Hs)
[MePhosphonate-4O-
875


2567
22 mer

mUs][fAs][fG][fA][fC][mA][fU][mU][mG][fC]




antisense

[mU][mG][mA][fG][mA][fU][mG][mC][fC][mGs]




strand

[mGs][mG]






MAPT-
Modified
2723-2800
[MePhosphonate-4O-
876


2723
22 mer
(Hs-Mf)
mUs][fCs][fU][fU][fU][mU][fU][mU][mU][fU]




antisense

[mU][mC][mC][fA][mC][fA][mC][mU][fC][mUs]




strand

[mGs][mG]






MAPT-
Modified
690-455
[MePhosphonate-4O-
877


0690
22 mer
(Hs-Mf)
mUs][fUs][fG][fA][fC][mC][fA][mG][mC][fA]




antisense

[mG][mC][mU][fU][mC][fG][mU][mC][fU][mUs]




strand

[mGs][mG]






MAPT-
Modified
1494-1571
[MePhosphonate-4O-
878


1494
22 mer
(Hs-Mf)
mUs][fUs][fC][fG][fC][mU][fU][mC][mC][fA]




antisense

[mG][mU][mC][fC][mC][fG][mU][mC][fU][mUs]




strand

[mGs][mG]






MAPT-
Modified
1733 (Hs)
[MePhosphonate-4O-
879


1733
22 mer

mUs][fCs][fG][fA][fU][mC][fU][mU][mC][fG]




antisense

[mU][mU][mU][fU][mA][fC][mC][mA][fU][mCs]




strand

[mGs][mG]






MAPT-
Modified
2273-2350
[MePhosphonate-4O-
880


2273
22 mer
(Hs-Mf)
mUs][fCs][fA][fA][fC][mU][fG][mG][mU][fU]




antisense

[mU][mG][mU][fA][mG][fA][mC][mU][fA][mUs]




strand

[mGs][mG]






MAPT-
Modified
2274-2351
[MePhosphonate-4O-
881


2274
22 mer
(Hs-Mf)
mUs][fUs][fC][fA][fA][mC][fU][mG][mG][fU]




antisense

[mU][mU][mG][fU][mA][fG][mA][mC][fU][mAs]




strand

[mGs][mG]






MAPT-
Modified
2276-2353
[MePhosphonate-4O-
882


2276
22 mer
(Hs-Mf)
mUs][fGs][fG][fU][fC][mA][fA][mC][mU][fG]




antisense

[mG][mU][mU][fU][mG][fU][mA][mG][fA][mCs]




strand

[mGs][mG]






MAPT-
Modified
2301-2378
[MePhosphonate-4O-
883


2301
22 mer
(Hs-Mf)
mUs][fCs][fC][fA][fC][mA][fC][mU][mU][fG]




antisense

[mG][mA][mG][fG][mU][fC][mA][mC][fC][mUs]




strand

[mGs][mG]






MAPT-
Modified
2347-2424-
[MePhosphonate-4O-
884


2347
22 mer
1172 (Hs-
mUs][fUs][fU][fC][fC][mA][fC][mC][mU][fG]




antisense
Mf-Mm)
[mG][mC][mC][fA][mC][fC][mU][mC][fC][mUs]




strand

[mGs][mG]






MAPT-
Modified
2357-2434
[MePhosphonate-4O-
885


2357
22 mer
(Hs-Mf)
mUs][fCs][fA][fG][fA][mU][fU][mU][mU][fA]




antisense

[mC][mU][mU][fC][mC][fA][mC][mC][fU][mGs]




strand

[mGs][mG]






MAPT-
Modified
2358-2435
[MePhosphonate-4O-
886


2358
22 mer
(Hs-Mf)
mUs][fUs][fC][fA][fG][mA][fU][mU][mU][fU]




antisense

[mA][mC][mU][fU][mC][fC][mA][mC][fC][mUs]




strand

[mGs][mG]






MAPT-
Modified
2364-2441
[MePhosphonate-4O-
887


2364
22 mer
(Hs-Mf)
mUs][fAs][fG][fC][fU][mU][fC][mU][mC][fA]




antisense

[mG][mA][mU][fU][mU][fU][mA][mC][fU][mUs]




strand

[mGs][mG]






MAPT-
Modified
2378 (Hs)
[MePhosphonate-4O-
888


2378
22 mer

mUs][fUs][fG][fU][fC][mC][fU][mU][mG][fA]




antisense

[mA][mG][mU][fC][mA][fA][mG][mC][fU][mUs]




strand

[mGs][mG]






MAPT-
Modified
2459-2536-
[MePhosphonate-4O-
889


2459
22 mer
1284 (Hs-
mUs][fGs][fC][fU][fU][mG][fU][mG][mG][fG]




antisense
Mf-Mm)
[mU][mU][mU][fC][mA][fA][mU][mC][fU][mUs]




strand

[mGs][mG]






MAPT-
Modified
2461-2538-
[MePhosphonate-4O-
890


2461
22 mer
1286 (Hs-
mUs][fCs][fA][fG][fC][mU][fU][mG][mU][fG]




antisense
Mf-Mm)
[mG][mG][mU][fU][mU][fC][mA][mA][fU][mCs]




strand

[mGs][mG]






MAPT-
Modified
2460-2537-
[MePhosphonate-4O-
891


2460
22 mer
1285 (Hs-
mUs][fAs][fGs][fC][fU][mU][fG][mU][mG][fG]




antisense
Mf-Mm)
[mG][mU][mU][fU][mC][mA][mA][mU][mC]




strand

[mUs][mGs][mG]






MAPT-
Modified
1479-1556
[MePhosphonate-4O-
892


1479
22 mer
(Hs-Mf)
mUs][fUs][fC][fU][fU][mU][fG][mC][mU][fU]




antisense

[mU][mU][mA][fC][mU][fG][mA][mC][fC][mAs]




strand

[mGs][mG]






MAPT-
Modified
1505-1582
[MePhosphonate-4O-
893


1505
22 mer
(Hs-Mf)
mUs][fCs][fU][fU][fU][mU][fU][mU][mG][fU]




antisense

[mC][mA][mU][fC][mG][fC][mU][mU][fC][mCs]




strand

[mGs][mG]






MAPT-
Modified
2096-2173
[MePhosphonate-4O-
894


2096
22 mer
(Hs-Mf)
mUs][fUs][fC][fU][fU][mC][fA][mG][mG][fU]




antisense

[mC][mU][mG][fG][mC][fA][mU][mG][fG][mGs]




strand

[mGs][mG]






MAPT-
Modified
2270-2347
[MePhosphonate-4O-
895


2270
22 mer
(Hs-Mf)
mUs][fCs][fU][fG][fG][mU][fU][mU][mG][fU]




antisense

[mA][mG][mA][fC][mU][fA][mU][mU][fU][mGs]




strand

[mGs][mG]






MAPT-
Modified
2279-2356
[MePhosphonate-4O-
896


2279
22 mer
(Hs-Mf)
mUs][fUs][fC][fA][fG][mG][fU][mC][mA][fA]




antisense

[mC][mU][mG][fG][mU][fU][mU][mG][fU][mAs]




strand

[mGs][mG]






MAPT-
Modified
2281-2358
[MePhosphonate-4O-
897


2281
22 mer
(Hs-Mf)
mUs][fGs][fC][fU][fC][mA][fG][mG][mU][fC]




antisense

[mA][mA][mC][fU][mG][fG][mU][mU][fU][mGs]




strand

[mGs][mG]






MAPT-
Modified
2284-2361
[MePhosphonate-4O-
898


2284
22 mer
(Hs-Mf)
mUs][fCs][fU][fU][fG][mC][fU][mC][mA][G]




antisense

[mG][mU][mC][fA][mA][fC][mU][mG][fG][mUs]




strand

[mGs][mG]






MAPT-
Modified
2299-2376
[MePhosphonate-4O-
899


2299
22 mer
(Hs-Mf)
mUs][fAs][fC][fA][fC][mU][fU][mG][mG][fA]




antisense

[mG][mG][mU][fC][mA][fC][mC][mU][fU][mGs]




strand

[mGs][mG]






MAPT-
Modified
2376 (Hs)
[MePhosphonate-4O-
900


2376
22 mer

mUs][fUs][fC][fC][fU][mU][fG][mA][mA][fG]




antisense

[mU][mC][mA][fA][mG][fC][mU][mU][fC][mUs]




strand

[mGs][mG]






MAPT-
Modified
2379 (Hs)
[MePhosphonate-4O-
901


2379
22 mer

mUs][fCs][fU][fG][fU][mC][fC][mU][mU][fG]




antisense

[mA][mA][mG][fU][mC][fA][mA][mG][fC][mUs]




strand

[mGs][mG]






MAPT-
Modified
2382 (Hs)
[MePhosphonate-4O-
902


2382
22 mer

mUs][fAs][fC][fU][fC][mU][fG][mU][mC][fC]




antisense

[mU][mU][mG][fA][mA][fG][mU][mC][fA][mAs]




strand

[mGs][mG]






MAPT-
Modified
2449-2526
[MePhosphonate-4O-
903


2449
22 mer
(Hs-Mf)
mUs][fUs][fU][fC][fA][mA][fU][mC][mU][fU]




antisense

[mU][mU][mU][fA][mU][fU][mU][mC][fC][mUs]




strand

[mGs][mG]






MAPT-
Modified
2450-2527
[MePhosphonate-4O-
904


2450
22 mer
(Hs-Mf)
mUs][fUs][fU][fU][fC][mA][fA][mU][mC][fU]




antisense

[mU][mU][mU][fU][mA][fU][mU][mU][fC][mCs]




strand

[mGs][mG]






MAPT-
Modified
2451-2528
[MePhosphonate-4O-
905


2451
22 mer
(Hs-Mf)
mUs][fGs][fU][fU][fU][mC][fA][mA][mU][fC]




antisense

[mU][mU][mU][fU][mU][fA][mU][mU][fU][mCs]




strand

[mGs][mG]






MAPT-
Modified
2452-2529
[MePhosphonate-4O-
906


2452
22 mer
(Hs-Mf)
mUs][fGs][fG][fU][fU][mU][fC][mA][mA][fU]




antisense

[mC][mU][mU][fU][mU][fU][mA][mU][fU][mUs]




strand

[mGs][mG]






MAPT-
Modified
2453-2530
[MePhosphonate-4O-
907


2453
22 mer
(Hs-Mf)
mUs][fGs][fG][fG][fU][mU][fU][mC][mA][fA]




antisense

[mU][mC][mU][fU][mU][fU][mU][mA][fU][mUs]




strand

[mGs][mG]






MAPT-
Modified
2454-2531
[MePhosphonate-4O-
908


2454
22 mer
(Hs-Mf)
mUs][fUs][fG][fG][fG][mU][fU][mU][mC][fA]




antisense

[mA][mU][mC][fU][mU][fU][mU][mU][fA][mUs]




strand

[mGs][mG]






Human
NM_001123066.3
N/A
ATGGCTGAGCCCCGCCAGGAGTTCGAAG
909


MAPT


TGATGGAAGATCACGCTGGGACGTACGG



RefSeq


GTTGGGGGACAGGAAAGATCAGGGGGGC






TACACCATGCACCAAGACCAAGAGGGTG






ACACGGACGCTGGCCTGAAAGAATCTCC






CCTGCAGACCCCCACTGAGGACGGATCT






GAGGAACCGGGCTCTGAAACCTCTGATG






CTAAGAGCACTCCAACAGCGGAAGATGT






GACAGCACCCTTAGTGGATGAGGGAGCT






CCCGGCAAGCAGGCTGCCGCGCAGCCCC






ACACGGAGATCCCAGAAGGAACCACAGC






TGAAGAAGCAGGCATTGGAGACACCCCC






AGCCTGGAAGACGAAGCTGCTGGTCACG






TGACCCAAGAGCCTGAAAGTGGTAAGGT






GGTCCAGGAAGGCTTCCTCCGAGAGCCA






GGCCCCCCAGGTCTGAGCCACCAGCTCA






TGTCCGGCATGCCTGGGGCTCCCCTCCTG






CCTGAGGGCCCCAGAGAGGCCACACGCC






AACCTTCGGGGACAGGACCTGAGGACAC






AGAGGGCGGCCGCCACGCCCCTGAGCTG






CTCAAGCACCAGCTTCTAGGAGACCTGC






ACCAGGAGGGGCCGCCGCTGAAGGGGGC






AGGGGGCAAAGAGAGGCCGGGGAGCAA






GGAGGAGGTGGATGAAGACCGCGACGTC






GATGAGTCCTCCCCCCAAGACTCCCCTCC






CTCCAAGGCCTCCCCAGCCCAAGATGGG






CGGCCTCCCCAGACAGCCGCCAGAGAAG






CCACCAGCATCCCAGGCTTCCCAGCGGA






GGGTGCCATCCCCCTCCCTGTGGATTTCC






TCTCCAAAGTTTCCACAGAGATCCCAGCC






TCAGAGCCCGACGGGCCCAGTGTAGGGC






GGGCCAAAGGGCAGGATGCCCCCCTGGA






GTTCACGTTTCACGTGGAAATCACACCCA






ACGTGCAGAAGGAGCAGGCGCACTCGGA






GGAGCATTTGGGAAGGGCTGCATTTCCA






GGGGCCCCTGGAGAGGGGCCAGAGGCCC






GGGGCCCCTCTTTGGGAGAGGACACAAA






AGAGGCTGACCTTCCAGAGCCCTCTGAA






AAGCAGCCTGCTGCTGCTCCGCGGGGGA






AGCCCGTCAGCCGGGTCCCTCAACTCAA






AGCTCGCATGGTCAGTAAAAGCAAAGAC






GGGACTGGAAGCGATGACAAAAAAGCCA






AGACATCCACACGTTCCTCTGCTAAAACC






TTGAAAAATAGGCCTTGCCTTAGCCCCAA






ACACCCCACTCCTGGTAGCTCAGACCCTC






TGATCCAACCCTCCAGCCCTGCTGTGTGC






CCAGAGCCACCTTCCTCTCCTAAATACGT






CTCTTCTGTCACTTCCCGAACTGGCAGTT






CTGGAGCAAAGGAGATGAAACTCAAGGG






GGCTGATGGTAAAACGAAGATCGCCACA






CCGCGGGGAGCAGCCCCTCCAGGCCAGA






AGGGCCAGGCCAACGCCACCAGGATTCC






AGCAAAAACCCCGCCCGCTCCAAAGACA






CCACCCAGCTCTGCGACTAAGCAAGTCC






AGAGAAGACCACCCCCTGCAGGGCCCAG






ATCTGAGAGAGGTGAACCTCCAAAATCA






GGGGATCGCAGCGGCTACAGCAGCCCCG






GCTCCCCAGGCACTCCCGGCAGCCGCTC






CCGCACCCCGTCCCTTCCAACCCCACCCA






CCCGGGAGCCCAAGAAGGTGGCAGTGGT






CCGTACTCCACCCAAGTCGCCGTCTTCCG






CCAAGAGCCGCCTGCAGACAGCCCCCGT






GCCCATGCCAGACCTGAAGAATGTCAAG






TCCAAGATCGGCTCCACTGAGAACCTGA






AGCACCAGCCGGGAGGCGGGAAGGTGCA






GATAATTAATAAGAAGCTGGATCTTAGC






AACGTCCAGTCCAAGTGTGGCTCAAAGG






ATAATATCAAACACGTCCCGGGAGGCGG






CAGTGTGCAAATAGTCTACAAACCAGTT






GACCTGAGCAAGGTGACCTCCAAGTGTG






GCTCATTAGGCAACATCCATCATAAACC






AGGAGGTGGCCAGGTGGAAGTAAAATCT






GAGAAGCTTGACTTCAAGGACAGAGTCC






AGTCGAAGATTGGGTCCCTGGACAATAT






CACCCACGTCCCTGGCGGAGGAAATAAA






AAGATTGAAACCCACAAGCTGACCTTCC






GCGAGAACGCCAAAGCCAAGACAGACCA






CGGGGCGGAGATCGTGTACAAGTCGCCA






GTGGTGTCTGGGGACACGTCTCCACGGC






ATCTCAGCAATGTCTCCTCCACCGGCAGC






ATCGACATGGTAGACTCGCCCCAGCTCG






CCACGCTAGCTGACGAGGTGTCTGCCTCC






CTGGCCAAGCAGGGTTTGTGA






Mouse
NM_001038609
N/A
ATGGCTGACCCTCGCCAGGAGTTTGACA
910


MAPT


CAATGGAAGACCATGCTGGAGATTACAC



RefSeq


TCTGCTCCAAGACCAAGAAGGAGACATG






GACCATGGCTTAAAAGAGTCTCCCCCAC






AGCCCCCCGCCGATGATGGAGCGGAGGA






ACCAGGGTCGGAGACCTCCGATGCTAAG






AGCACTCCAACTGCTGAAGACGTGACTG






CGCCCCTAGTGGATGAGAGAGCTCCCGA






CAAGCAGGCCGCTGCCCAGCCCCACACG






GAGATCCCAGAAGGAATTACAGCCGAAG






AAGCAGGCATCGGAGACACCCCGAACCA






GGAGGACCAAGCCGCTGGGCATGTGACT






CAAGCTCGTGTGGCCAGCAAAGACAGGA






CAGGAAATGACGAGAAGAAAGCCAAGG






GCGCTGATGGCAAAACCGGGGCGAAGAT






CGCCACACCTCGGGGAGCAGCCTCTCCG






GCCCAGAAGGGCACGTCCAACGCCACCA






GGATCCCGGCCAAGACCACGCCCAGCCC






TAAGACTCCTCCAGGGTCAGGTGAACCA






CCAAAATCCGGAGAACGAAGCGGCTACA






GCAGCCCCGGCTCTCCCGGAACGCCTGG






CAGTCGCTCGCGCACCCCATCCCTACCAA






CACCGCCCACCCGGGAGCCCAAGAAGGT






GGCAGTGGTCCGCACTCCCCCTAAGTCAC






CATCAGCTAGTAAGAGCCGCCTGCAGAC






TGCCCCTGTGCCCATGCCAGACCTAAAG






AATGTCAGGTCGAAGATTGGCTCTACTG






AGAACCTGAAGCACCAGCCAGGAGGTGG






CAAGGTGCAGATAATTAATAAGAAGCTG






GATCTTAGCAACGTCCAGTCCAAGTGTG






GCTCGAAGGATAATATCAAACACGTCCC






GGGTGGAGGCAGTGTGCAAATAGTCTAC






AAGCCGGTGGACCTGAGCAAAGTGACCT






CCAAGTGTGGCTCGTTAGGGAACATCCA






TCACAAGCCAGGAGGTGGCCAGGTGGAA






GTAAAATCAGAGAAGCTGGACTTCAAGG






ACAGAGTCCAGTCGAAGATTGGCTCCTT






GGATAATATCACCCACGTCCCTGGAGGA






GGGAATAAGAAGATTGAAACCCACAAGC






TGACCTTCAGGGAGAATGCCAAAGCCAA






GACAGACCATGGAGCAGAAATTGTGTAT






AAGTCACCCGTGGTGTCTGGGGACACAT






CTCCACGGCACCTCAGCAATGTGTCTTCC






ACGGGCAGCATCGACATGGTGGACTCAC






CACAGCTTGCCACACTAGCCGATGAAGT






GTCTGCTTCCTTGGCCAAGCAGGGTTTGT






GA






Monkey
XM_005584531
N/A
ATGGCTGAGCCCCGCCAGGAGTTCGATG
911


MAPT


TGATGGAAGATCACGCTGGGACGTACGG



RefSEQ


GTTGGGGGACAGGAAAGATCAAGAGGGC






TACACCATGCTCCAAGACCAAGAGGGTG






ACACGGACGCTGGCCTGAAAGAATCTCC






CCTGCAGACCCCCGCTGAGGATGGATCT






GAGGAACTGGGCTCTGAAACCTCTGATG






CTAAGAGCACTCCAACGGCGGAAGCTGA






GGAAGCAGGCATCGGAGACACCCCCAGC






CTGGAAGACGAAGCTGCTGGTCACGTGA






CCCAAGAGGAGTTGAGAGTTCCGGGCCA






GCAGAGGAAGGCACCTGAAAGGCCCCTG






GCCAATGAGATTAGTGCTCACGTCCAGC






CTGGACCCTGCAAAGAGGCCTCTGGGGT






CTCTGGGCTGTGCATGGGGGAGAAAGAG






CCAGAAGCTCCCATCCCACTGACCGCGA






GCCTTCCTCAGCACCGTCCCATTTGCTCA






GCGCCTCCTCCAACAGGAGGCCCTCGAG






AGCCCTCCCAGGAGTGGGGACGAAAAGG






TGGGGACTGGGCCGAGAAGGGTCCGACC






TTTCCGAAGTCCGCCACCCCTGCGTATCT






CCACACAGAGCCTGAAAGTGGTAAGGTG






GTCCAGGAAGTCTTCCTCGGAGAGCCAG






GCCCCCCAGGTCTGAGCCACCAGCTCGT






GTCCAGCATGCCTGGGGCTCCCCTCCTGC






CTGAGGGCCCCAGAGAGGCCACACGCCA






GCCTTCAGGGACAGGACCTGAGGACACA






GAGGGTGGCCAACACGCCCCTGAGCTGC






TCAAGCACCAGCTTCTGGGAGACCTGCA






CCAGGAGGGGCCGCCACTGAAGGGAGCC






GGGGGCAAAGAGAGGCTGGGGAGCAAG






GAGGAGGTGGATGAAGACCGCGACGTCG






ATGAGTCCTCCCCGCAAGACTCCCCTCCA






TCCAGGGTCTCCCCAGTCCAAGATGGGC






AGCCTCCCCAGACAGCCGCCAGAGAAGC






CACCAGCGTCCCAGGCTTCCCAGCGGAG






GGTGCCATTGCCCTCCCTGTGGATTTCCT






CTCCAGAGTTTCCACAGAGATCCCAGCCT






CTGAGCCCGAGGGGCCCAGTGCAGGGTG






GGCTGAAGGGCAGGACATGCCCCCTGAG






TTCACGTTCCACGTGGAAATCACACCCAA






CGTGCAGAAGGAGCAGGCGCACCCGGAG






GAGGATTCGGGAAGGGCTGCATTTCCAG






GGGCTCCTGGAGAGGAGCCAGAGGCCCG






GGGCCCCTCTTTGGGAGAGGACACAAAA






GAGGCTGAGCTTCCAGAGCCCACTGAAA






AGCAGCCTGCTGCTGCTCCGCGGGGAAA






ACCCGTCAGCCGGGTCCCTCAACTCAAA






GCTCGCATGGTCAGTAAAAGCAAAGACG






GGACTGGAAGCGATGACAAAAAAGCCAA






GACATCCACACGTTCCTCTGCTAAAACCT






TGAAAAATAGGCCTTGCCTTAGCCCCAA






ACACCCCACTCCTGGTAGCTCAGACCCTC






TGATCCAACCCTCCAGCCCTGCCGTGTGC






CCAGAGCCACCTTCCTCTCCTAAATACGT






CTCTTCTGTCACTCCCCGAACTGGCAGTT






CTGGAGCAAAGGAGATGAAACTCAAGGG






GGCTGATGGGAAAACGAAGATCGCCACA






CCCCGGGGAGCGGCCCCTCCAGGCCAGA






AGGGCCAAGCCAACGCCACCAGGATTCC






AGCAAAAACCCCGCCCGCCCCAAAGACA






CCACCCAGCTCTGCGACCAAGCAAGTGC






AGAGAAAACCACCCCCTGCAGAGCCCAC






ATCTGAGAGAGGTGAACCTCCAAAATCA






GGGGATCGCAGTGGCTACAGCAGCCCCG






GCTCCCCGGGCACTCCCGGCAGCCGCTC






CCGCACCCCGTCCCTTCCAACCCCTCCAG






CCCGGGAGCCCAAGAAGGTGGCGGTGGT






CCGTACTCCACCTAAGTCGCCGTCTTCCG






CCAAGAGCCGCCTGCAGACAGCCCCCGT






GCCCATGCCAGACCTGAAGAACGTCAAG






TCCAAGATCGGCTCCACCGAGAACCTGA






AGCACCAGCCGGGAGGCGGGAAGGTGCA






GATAATTAATAAGAAGCTGGATCTTAGC






AACGTCCAGTCCAAGTGTGGCTCAAAGG






ATAATATCAAACACGTCCCGGGAGGCGG






CAGTGTGCAAATAGTCTACAAACCAGTT






GACCTGAGCAAGGTGACCTCCAAGTGTG






GCTCATTAGGCAACATCCATCATAAACC






AGGAGGTGGCCAGGTGGAAGTAAAATCT






GAGAAGCTGGACTTCAAGGACAGAGTGC






AGTCGAAGATCGGGTCCCTGGACAATAT






CACCCATGTCCCTGGCGGAGGAAATAAA






AAGATTGAAACCCACAAGCTGACCTTCC






GCGAGAACGCCAAAGCCAAGACAGACCA






CGGGGCGGAAATCGTGTACAAGTCGCCG






GTGGTGTCTGGGGACACGTCTCCACGGC






ACCTCAGCAATGTCTCCTCCACCGGCAGC






ATCGACATGGTAGACTCGCCCCAGCTCG






CCACGCTAGCCGACGAGGTGTCTGCCTCC






CTGGCCAAGCAGGGTTTGTGA






MAPT-
19 mer
2141-2218-
GAGAACCUGAAGCACCAGC
912


2141
sense
966 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2142-2219-
AGAACCUGAAGCACCAGCC
913


2142
sense
967 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2303-2380-
GUGACCUCCAAGUGUGGCU
914


2303
sense
1128 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2347-2424-
AGGAGGUGGCCAGGUGGAA
915


2347
sense
1172 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2349-2426-
GAGGUGGCCAGGUGGAAGU
916


2349
sense
1174 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2350-2427-
AGGUGGCCAGGUGGAAGUA
917


2350
sense
1175 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2351-2428-
GGUGGCCAGGUGGAAGUAA
918


2351
sense
1176 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2352-2429-
GUGGCCAGGUGGAAGUAAA
919


2352
sense
1177 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2353-2430-
UGGCCAGGUGGAAGUAAAA
920


2353
sense
1178 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2354-2431-
GGCCAGGUGGAAGUAAAAU
921


2354
sense
1179 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2355-2432-
GCCAGGUGGAAGUAAAAUC
922


2355
sense
1180 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2459-2536-
AAGAUUGAAACCCACAAGC
923


2459
sense
1284 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2460-2537-
AGAUUGAAACCCACAAGCU
924


2460
sense
1285 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2461-2538-
GAUUGAAACCCACAAGCUG
925


2461
sense
1286 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2462-2539-
AUUGAAACCCACAAGCUGA
926


2462
sense
1287 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2463-2540-
UUGAAACCCACAAGCUGAC
927


2463
sense
1288 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2464-2541-
UGAAACCCACAAGCUGACC
928


2464
sense
1289 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2465-2542-
GAAACCCACAAGCUGACCU
929


2465
sense
1290 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2466-2543-
AAACCCACAAGCUGACCUU
930


2466
sense
1291 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2467-2544-
AACCCACAAGCUGACCUUC
931


2467
sense
1292 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2495-2572-
GCCAAAGCCAAGACAGACC
932


2495
sense
1320 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
2496-2573-
CCAAAGCCAAGACAGACCA
933


2496
sense
1321 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
3686-3758-
UCUUUGUAAGGACUUGUGC
934


3686
sense
2505 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
3687-3759-
CUUUGUAAGGACUUGUGCC
935


3687
sense
2506 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
3688-3760-
UUUGUAAGGACUUGUGCCU
936


3688
sense
2507 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
3691-3763-
GUAAGGACUUGUGCCUCUU
937


3691
sense
2510 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
3692-3764-
UAAGGACUUGUGCCUCUUG
938


3692
sense
2511 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
3693-3765-
AAGGACUUGUGCCUCUUGG
939


3693
sense
2512 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4534-4605-
GUUGUAGUUGGAUUUGUCU
940


4534
sense
3332 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4535-4606-
UUGUAGUUGGAUUUGUCUG
941


4535
sense
3333 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4536-4607-
UGUAGUUGGAUUUGUCUGU
942


4536
sense
3334 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4537-4608-
GUAGUUGGAUUUGUCUGUU
943


4537
sense
3335 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4538-4609-
UAGUUGGAUUUGUCUGUUU
944


4538
sense
3336 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4566-4637-
UUCACCAGAGUGACUAUGA
945


4566
sense
3362 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4567-4638-
UCACCAGAGUGACUAUGAU
946


4567
sense
3363 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4568-4639-
CACCAGAGUGACUAUGAUA
947


4568
sense
3364 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4569-4640-
ACCAGAGUGACUAUGAUAG
948


4569
sense
3365 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4570-4641-
CCAGAGUGACUAUGAUAGU
949


4570
sense
3366 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4571-4642-
CAGAGUGACUAUGAUAGUG
950


4571
sense
3367 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4572-4643-
AGAGUGACUAUGAUAGUGA
951


4572
sense
3368 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4573-4644-
GAGUGACUAUGAUAGUGAA
952


4573
sense
3369 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4574-4645-
AGUGACUAUGAUAGUGAAA
953


4574
sense
3370 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4575-4646-
GUGACUAUGAUAGUGAAAA
954


4575
sense
3371 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4576-4647-
UGACUAUGAUAGUGAAAAG
955


4576
sense
3372 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4577-4648-
GACUAUGAUAGUGAAAAGA
956


4577
sense
3373 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4578-4649-
ACUAUGAUAGUGAAAAGAA
957


4578
sense
3374 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4579-4650-
CUAUGAUAGUGAAAAGAAA
958


4579
sense
3375 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4580-4651-
UAUGAUAGUGAAAAGAAAA
959


4580
sense
3376 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4605-4677-
AAAAAAAAGGACGCAUGUA
960


4605
sense
3439 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4606-4678-
AAAAAAAGGACGCAUGUAU
961


4606
sense
3440 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4607-4679-
AAAAAAGGACGCAUGUAUC
962


4607
sense
3441 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4608-4680-
AAAAAGGACGCAUGUAUCU
963


4608
sense
3442 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4609-4681-
AAAAGGACGCAUGUAUCUU
964


4609
sense
3443 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4610-4682-
AAAGGACGCAUGUAUCUUG
965


4610
sense
3444 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4611-4683-
AAGGACGCAUGUAUCUUGA
966


4611
sense
3445 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4612-4684-
AGGACGCAUGUAUCUUGAA
967


4612
sense
3446 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4613-4685-
GGACGCAUGUAUCUUGAAA
968


4613
sense
3447 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
4614-4686-
GACGCAUGUAUCUUGAAAU
969


4614
sense
3448 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5969-6024-
UCACUUUAUCAAUAGUUCC
970


5969
sense
4540 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5970-6025-
CACUUUAUCAAUAGUUCCA
971


5970
sense
4541 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5971-6026-
ACUUUAUCAAUAGUUCCAU
972


5971
sense
4542 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5972-6027-
CUUUAUCAAUAGUUCCAUU
973


5972
sense
4543 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5973-6028-
UUUAUCAAUAGUUCCAUUU
974


5973
sense
4544 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5974-6029-
UUAUCAAUAGUUCCAUUUA
975


5974
sense
4545 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5975-6030-
UAUCAAUAGUUCCAUUUAA
976


5975
sense
4546 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5976-6031-
AUCAAUAGUUCCAUUUAAA
977


5976
sense
4547 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5977-6032-
UCAAUAGUUCCAUUUAAAU
978


5977
sense
4548 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5978-6033-
CAAUAGUUCCAUUUAAAUU
979


5978
sense
4549 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5979-6034-
AAUAGUUCCAUUUAAAUUG
980


5979
sense
4550 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5980-6035-
AUAGUUCCAUUUAAAUUGA
981


5980
sense
4551 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5981-6036-
UAGUUCCAUUUAAAUUGAC
982


5981
sense
4552 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5982-6037-
AGUUCCAUUUAAAUUGACU
983


5982
sense
4553 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5983-6038-
GUUCCAUUUAAAUUGACUU
984


5983
sense
4554 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5984-6039-
UUCCAUUUAAAUUGACUUC
985


5984
sense
4555 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
5985-6040-
UCCAUUUAAAUUGACUUCA
986


5985
sense
4556 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6662-6723-
CUUGCAAGUCCCAUGAUUU
987


6662
sense
5230 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6663-6724-
UUGCAAGUCCCAUGAUUUC
988


6663
sense
5231 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6664-6725-
UGCAAGUCCCAUGAUUUCU
989


6664
sense
5232 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6665-6726-
GCAAGUCCCAUGAUUUCUU
990


6665
sense
5233 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6800-6861-
GUAAAAGUGAAUUUGGAAA
991


6800
sense
5365 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6801-6862-
UAAAAGUGAAUUUGGAAAU
992


6801
sense
5366 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6802-6863-
AAAAGUGAAUUUGGAAAUA
993


6802
sense
5367 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6803-6864-
AAAGUGAAUUUGGAAAUAA
994


6803
sense
5368 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6804-6865-
AAGUGAAUUUGGAAAUAAA
995


6804
sense
5369 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6805-6866-
AGUGAAUUUGGAAAUAAAG
996


6805
sense
5370 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6806-6867-
GUGAAUUUGGAAAUAAAGU
997


6806
sense
5371 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6807-6868-
UGAAUUUGGAAAUAAAGUU
998


6807
sense
5372 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6808-6869-
GAAUUUGGAAAUAAAGUUA
999


6808
sense
5373 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6809-6870-
AAUUUGGAAAUAAAGUUAU
1000


6809
sense
5374 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6810-6871-
AUUUGGAAAUAAAGUUAUU
1001


6810
sense
5375 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6811-6872-
UUUGGAAAUAAAGUUAUUA
1002


6811
sense
5376 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6812-6873-
UUGGAAAUAAAGUUAUUAC
1003


6812
sense
5377 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6813-6874-
UGGAAAUAAAGUUAUUACU
1004


6813
sense
5378 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6814-6875-
GGAAAUAAAGUUAUUACUC
1005


6814
sense
5379 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6815-6876-
GAAAUAAAGUUAUUACUCU
1006


6815
sense
5380 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
6816-6877-
AAAUAAAGUUAUUACUCUG
1007


6816
sense
5381 (Hs-





strand
Mf-Mm)







MAPT-
19 mer
 363 (Hs)
AGGAGUUCGAAGUGAUGGA
1008


363
sense






strand








MAPT-
19 mer
 364 (Hs)
GGAGUUCGAAGUGAUGGAA
1009


364
sense






strand








MAPT-
19 mer
 365 (Hs)
GAGUUCGAAGUGAUGGAAG
1010


365
sense






strand








MAPT-
19 mer
 367 (Hs)
GUUCGAAGUGAUGGAAGAU
1011


367
sense






strand








MAPT-
19 mer
 369 (Hs)
UCGAAGUGAUGGAAGAUCA
1012


369
sense






strand








MAPT-
19 mer
 374-226
GUGAUGGAAGAUCACGCUG
1013


374
sense
(Hs-Mf)





strand








MAPT-
19 mer
 395-247
ACGUACGGGUUGGGGGACA
1014


395
sense
(Hs-Mf)





strand








MAPT-
19 mer
 400-252
CGGGUUGGGGGACAGGAAA
1015


400
sense
(Hs-Mf)





strand








MAPT-
19 mer
 443-295
CAAGACCAAGAGGGUGACA
1016


443
sense
(Hs-Mf)





strand








MAPT-
19 mer
 688-453
GGAAGACGAAGCUGCUGGU
1017


688
sense
(Hs-Mf)





strand








MAPT-
19 mer
 689-454
GAAGACGAAGCUGCUGGUC
1018


689
sense
(Hs-Mf)





strand








MAPT-
19 mer
 690-455
AAGACGAAGCUGCUGGUCA
1019


690
sense
(Hs-Mf)





strand








MAPT-
19 mer
 693-458
ACGAAGCUGCUGGUCACGU
1020


693
sense
(Hs-Mf)





strand








MAPT-
19 mer
 695-460
GAAGCUGCUGGUCACGUGA
1021


695
sense
(Hs-Mf)





strand








MAPT-
19 mer
 696-461
AAGCUGCUGGUCACGUGAC
1022


696
sense
(Hs-Mf)





strand








MAPT-
19 mer
1475-1552
CGCAUGGUCAGUAAAAGCA
1023


1475
sense
(Hs-Mf)





strand








MAPT-
19 mer
1476-1553
GCAUGGUCAGUAAAAGCAA
1024


1476
sense
(Hs-Mf)





strand








MAPT-
19 mer
1479-1556
UGGUCAGUAAAAGCAAAGA
1025


1479
sense
(Hs-Mf)





strand








MAPT-
19 mer
1480-1557
GGUCAGUAAAAGCAAAGAC
1026


1480
sense
(Hs-Mf)





strand








MAPT-
19 mer
1481-1558
GUCAGUAAAAGCAAAGACG
1027


1481
sense
(Hs-Mf)





strand








MAPT-
19 mer
1484-1561
AGUAAAAGCAAAGACGGGA
1028


1484
sense
(Hs-Mf)





strand








MAPT-
19 mer
1485-1562
GUAAAAGCAAAGACGGGAC
1029


1485
sense
(Hs-Mf)





strand








MAPT-
19 mer
1492-1569
CAAAGACGGGACUGGAAGC
1030


1492
sense
(Hs-Mf)





strand








MAPT-
19 mer
1494-1571
AAGACGGGACUGGAAGCGA
1031


1494
sense
(Hs-Mf)





strand








MAPT-
19 mer
1495-1572
AGACGGGACUGGAAGCGAU
1032


1495
sense
(Hs-Mf)





strand








MAPT-
19 mer
1498-1575
CGGGACUGGAAGCGAUGAC
1033


1498
sense
(Hs-Mf)





strand








MAPT-
19 mer
1499-1576
GGGACUGGAAGCGAUGACA
1034


1499
sense
(Hs-Mf)





strand








MAPT-
19 mer
1500-1577
GGACUGGAAGCGAUGACAA
1035


1500
sense
(Hs-Mf)





strand








MAPT-
19 mer
1502-1579
ACUGGAAGCGAUGACAAAA
1036


1502
sense
(Hs-Mf)





strand








MAPT-
19 mer
1503-1580
CUGGAAGCGAUGACAAAAA
1037


1503
sense
(Hs-Mf)





strand








MAPT-
19 mer
1504-1581
UGGAAGCGAUGACAAAAAA
1038


1504
sense
(Hs-Mf)





strand








MAPT-
19 mer
1505-1582
GGAAGCGAUGACAAAAAAG
1039


1505
sense
(Hs-Mf)





strand








MAPT-
19 mer
1506-1583
GAAGCGAUGACAAAAAAGC
1040


1506
sense
(Hs-Mf)





strand








MAPT-
19 mer
1507-1584
AAGCGAUGACAAAAAAGCC
1041


1507
sense
(Hs-Mf)





strand








MAPT-
19 mer
1508-1585
AGCGAUGACAAAAAAGCCA
1042


1508
sense
(Hs-Mf)





strand








MAPT-
19 mer
1509-1586
GCGAUGACAAAAAAGCCAA
1043


1509
sense
(Hs-Mf)





strand








MAPT-
19 mer
1733 (Hs)
GAUGGUAAAACGAAGAUCG
1044


1733
sense






strand








MAPT-
19 mer
1796-1873
AACGCCACCAGGAUUCCAG
1045


1796
sense
(Hs-Mf)





strand








MAPT-
19 mer
1835-1912
AAGACACCACCCAGCUCUG
1046


1835
sense
(Hs-Mf)





strand








MAPT-
19 mer
1912-1989
ACCUCCAAAAUCAGGGGAU
1047


1912
sense
(Hs-Mf)





strand








MAPT-
19 mer
2094-2171
UGCCCAUGCCAGACCUGAA
1048


2094
sense
(Hs-Mf)





strand








MAPT-
19 mer
2096-2173
CCCAUGCCAGACCUGAAGA
1049


2096
sense
(Hs-Mf)





strand








MAPT-
19 mer
2097-2174
CCAUGCCAGACCUGAAGAA
1050


2097
sense
(Hs-Mf)





strand








MAPT-
19 mer
2098 (Hs)
CAUGCCAGACCUGAAGAAU
1051


2098
sense






strand








MAPT-
19 mer
2105 (Hs)
GACCUGAAGAAUGUCAAGU
1052


2105
sense






strand








MAPT-
19 mer
2106 (Hs)
ACCUGAAGAAUGUCAAGUC
1053


2106
sense






strand








MAPT-
19 mer
2107 (Hs)
CCUGAAGAAUGUCAAGUCC
1054


2107
sense






strand








MAPT-
19 mer
2108 (Hs)
CUGAAGAAUGUCAAGUCCA
1055


2108
sense






strand








MAPT-
19 mer
2109 (Hs)
UGAAGAAUGUCAAGUCCAA
1056


2109
sense






strand








MAPT-
19 mer
2117-2194
GUCAAGUCCAAGAUCGGCU
1057


2117
sense
(Hs-Mf)





strand








MAPT-
19 mer
2136 (Hs)
CCACUGAGAACCUGAAGCA
1058


2136
sense






strand








MAPT-
19 mer
2137 (Hs)
CACUGAGAACCUGAAGCAC
1059


2137
sense






strand








MAPT-
19 mer
2269-2346
GCAAAUAGUCUACAAACCA
1060


2269
sense
(Hs-Mf)





strand








MAPT-
19 mer
2270-2347
CAAAUAGUCUACAAACCAG
1061


2270
sense
(Hs-Mf)





strand








MAPT-
19 mer
2271-2348
AAAUAGUCUACAAACCAGU
1062


2271
sense
(Hs-Mf)





strand








MAPT-
19 mer
2272-2349
AAUAGUCUACAAACCAGUU
1063


2272
sense
(Hs-Mf)





strand








MAPT-
19 mer
2273-2350
AUAGUCUACAAACCAGUUG
1064


2273
sense
(Hs-Mf)





strand








MAPT-
19 mer
2274-2351
UAGUCUACAAACCAGUUGA
1065


2274
sense
(Hs-Mf)





strand








MAPT-
19 mer
2275-2352
AGUCUACAAACCAGUUGAC
1066


2275
sense
(Hs-Mf)





strand








MAPT-
19 mer
2276-2353
GUCUACAAACCAGUUGACC
1067


2276
sense
(Hs-Mf)





strand








MAPT-
19 mer
2277-2354
UCUACAAACCAGUUGACCU
1068


2277
sense
(Hs-Mf)





strand








MAPT-
19 mer
2278-2355
CUACAAACCAGUUGACCUG
1069


2278
sense
(Hs-Mf)





strand








MAPT-
19 mer
2279-2356
UACAAACCAGUUGACCUGA
1070


2279
sense
(Hs-Mf)





strand








MAPT-
19 mer
2280-2357
ACAAACCAGUUGACCUGAG
1071


2280
sense
(Hs-Mf)





strand








MAPT-
19 mer
2281-2358
CAAACCAGUUGACCUGAGC
1072


2281
sense
(Hs-Mf)





strand








MAPT-
19 mer
2282-2359
AAACCAGUUGACCUGAGCA
1073


2282
sense
(Hs-Mf)





strand








MAPT-
19 mer
2283-2360
AACCAGUUGACCUGAGCAA
1074


2283
sense
(Hs-Mf)





strand








MAPT-
19 mer
2284-2361
ACCAGUUGACCUGAGCAAG
1075


2284
sense
(Hs-Mf)





strand








MAPT-
19 mer
2286-2363
CAGUUGACCUGAGCAAGGU
1076


2286
sense
(Hs-Mf)





strand








MAPT-
19 mer
2288-2365
GUUGACCUGAGCAAGGUGA
1077


2288
sense
(Hs-Mf)





strand








MAPT-
19 mer
2289-2366
UUGACCUGAGCAAGGUGAC
1078


2289
sense
(Hs-Mf)





strand








MAPT-
19 mer
2291-2368
GACCUGAGCAAGGUGACCU
1079


2291
sense
(Hs-Mf)





strand








MAPT-
19 mer
2294-2371
CUGAGCAAGGUGACCUCCA
1080


2294
sense
(Hs-Mf)





strand








MAPT-
19 mer
2299-2376
CAAGGUGACCUCCAAGUGU
1081


2299
sense
(Hs-Mf)





strand
2300-2377







MAPT-
19 mer

AAGGUGACCUCCAAGUGUG
1082


2300
sense
(Hs-Mf)





strand
2301-2378







MAPT-
19 mer

AGGUGACCUCCAAGUGUGG
1083


2301
sense
(Hs-Mf)





strand








MAPT-
19 mer
2308-2385
CUCCAAGUGUGGCUCAUUA
1084


2308
sense
(Hs-Mf)





strand








MAPT-
19 mer
2316-2393
GUGGCUCAUUAGGCAACAU
1085


2316
sense
(Hs-Mf)





strand








MAPT-
19 mer
2317-2394
UGGCUCAUUAGGCAACAUC
1086


2317
sense
(Hs-Mf)





strand








MAPT-
19 mer
2319-2396
GCUCAUUAGGCAACAUCCA
1087


2319
sense
(Hs-Mf)





strand








MAPT-
19 mer
2320-2397
CUCAUUAGGCAACAUCCAU
1088


2320
sense
(Hs-Mf)





strand








MAPT-
19 mer
2322-2399
CAUUAGGCAACAUCCAUCA
1089


2322
sense
(Hs-Mf)





strand








MAPT-
19 mer
2323-2400
AUUAGGCAACAUCCAUCAU
1090


2323
sense
(Hs-Mf)





strand








MAPT-
19 mer
2324-2401
UUAGGCAACAUCCAUCAUA
1091


2324
sense
(Hs-Mf)





strand








MAPT-
19 mer
2326-2403
AGGCAACAUCCAUCAUAAA
1092


2326
sense
(Hs-Mf)





strand








MAPT-
19 mer
2330-2407
AACAUCCAUCAUAAACCAG
1093


2330
sense
(Hs-Mf)





strand








MAPT-
19 mer
2356-2433
CCAGGUGGAAGUAAAAUCU
1094


2356
sense
(Hs-Mf)





strand








MAPT-
19 mer
2357-2434
CAGGUGGAAGUAAAAUCUG
1095


2357
sense
(Hs-Mf)





strand








MAPT-
19 mer
2358-2435
AGGUGGAAGUAAAAUCUGA
1096


2358
sense
(Hs-Mf)





strand








MAPT-
19 mer
2359-2436
GGUGGAAGUAAAAUCUGAG
1097


2359
sense
(Hs-Mf)





strand








MAPT-
19 mer
2360-2437
GUGGAAGUAAAAUCUGAGA
1098


2360
sense
(Hs-Mf)





strand








MAPT-
19 mer
2361-2438
UGGAAGUAAAAUCUGAGAA
1099


2361
sense
(Hs-Mf)





strand








MAPT-
19 mer
2362-2439
GGAAGUAAAAUCUGAGAAG
1100


2362
sense
(Hs-Mf)





strand








MAPT-
19 mer
2363-2440
GAAGUAAAAUCUGAGAAGC
1101


2363
sense
(Hs-Mf)





strand








MAPT-
19 mer
2364-2441
AAGUAAAAUCUGAGAAGCU
1102


2364
sense
(Hs-Mf)





strand








MAPT-
19 mer
2365 (Hs)
AGUAAAAUCUGAGAAGCUU
1103


2365
sense






strand








MAPT-
19 mer
2372 (Hs)
UCUGAGAAGCUUGACUUCA
1104


2372
sense






strand








MAPT-
19 mer
2373 (Hs)
CUGAGAAGCUUGACUUCAA
1105


2373
sense






strand








MAPT-
19 mer
2374 (Hs)
UGAGAAGCUUGACUUCAAG
1106


2374
sense






strand








MAPT-
19 mer
2375 (Hs)
GAGAAGCUUGACUUCAAGG
1107


2375
sense






strand








MAPT-
19 mer
2376 (Hs)
AGAAGCUUGACUUCAAGGA
1108


2376
sense






strand








MAPT-
19 mer
2377 (Hs)
GAAGCUUGACUUCAAGGAC
1109


2377
sense






strand








MAPT-
19 mer
2378 (Hs)
AAGCUUGACUUCAAGGACA
1110


2378
sense






strand








MAPT-
19 mer
2379 (Hs)
AGCUUGACUUCAAGGACAG
1111


2379
sense






strand








MAPT-
19 mer
2380 (Hs)
GCUUGACUUCAAGGACAGA
1112


2380
sense






strand








MAPT-
19 mer
2381 (Hs)
CUUGACUUCAAGGACAGAG
1113


2381
sense






strand








MAPT-
19 mer
2382 (Hs)
UUGACUUCAAGGACAGAGU
1114


2382
sense






strand








MAPT-
19 mer
2390 (Hs)
AAGGACAGAGUCCAGUCGA
1115


2390
sense






strand








MAPT-
19 mer
2391 (Hs)
AGGACAGAGUCCAGUCGAA
1116


2391
sense






strand








MAPT-
19 mer
2414-2491
GGGUCCCUGGACAAUAUCA
1117


2414
sense
(Hs-Mf)





strand








MAPT-
19 mer
2448-2525
GAGGAAAUAAAAAGAUUGA
1118


2448
sense
(Hs-Mf)





strand








MAPT-
19 mer
2449-2526
AGGAAAUAAAAAGAUUGAA
1119


2449
sense
(Hs-Mf)





strand








MAPT-
19 mer
2450-2527
GGAAAUAAAAAGAUUGAAA
1120


2450
sense
(Hs-Mf)





strand








MAPT-
19 mer
2451-2528
GAAAUAAAAAGAUUGAAAC
1121


2451
sense
(Hs-Mf)





strand








MAPT-
19 mer
2452-2529
AAAUAAAAAGAUUGAAACC
1122


2452
sense
(Hs-Mf)





strand








MAPT-
19 mer
2453-2530
AAUAAAAAGAUUGAAACCC
1123


2453
sense
(Hs-Mf)





strand








MAPT-
19 mer
2454-2531
AUAAAAAGAUUGAAACCCA
1124


2454
sense
(Hs-Mf)





strand








MAPT-
19 mer
2456-2533
AAAAAGAUUGAAACCCACA
1125


2456
sense
(Hs-Mf)





strand








MAPT-
19 mer
2457-2534
AAAAGAUUGAAACCCACAA
1126


2457
sense
(Hs-Mf)





strand








MAPT-
19 mer
2567 (Hs)
CGGCAUCUCAGCAAUGUCU
1127


2567
sense






strand








MAPT-
19 mer
2598-2675
GCAUCGACAUGGUAGACUC
1128


2598
sense
(Hs-Mf)





strand








MAPT-
19 mer
2657-2734
CUGGCCAAGCAGGGUUUGU
1129


2657
sense
(Hs-Mf)





strand








MAPT-
19 mer
2723-2800
AGAGUGUGGAAAAAAAAAG
1130


2723
sense
(Hs-Mf)





strand








MAPT-
19 mer
2724-2801
GAGUGUGGAAAAAAAAAGA
1131


2724
sense
(Hs-Mf)





strand








MAPT-
19 mer
2726-2803
GUGUGGAAAAAAAAAGAAU
1132


2726
sense
(Hs-Mf)





strand








MAPT-
19 mer
2784-2860-
GCAGUUCGGUUAAUUGGUU
1133


2784
sense
1 mismatch





strand
(Hs-Mf)







MAPT-
19 mer
2963-3039
GGCAAUUCCUUUUGAUUCU
1134


2963
sense
(Hs-Mf)





strand








MAPT-
19 mer
3110-3186
AGCAACAAAGGAUUUGAAA
1135


3110
sense
(Hs-Mf)





strand








MAPT-
19 mer
3114-3190
ACAAAGGAUUUGAAACUUG
1136


3114
sense
(Hs-Mf)





strand








MAPT-
19 mer
3116-3192
AAAGGAUUUGAAACUUGGU
1137


3116
sense
(Hs-Mf)





strand








MAPT-
19 mer
3118-3194
AGGAUUUGAAACUUGGUGU
1138


3118
sense
(Hs-Mf)





strand








MAPT-
19 mer
3158-3234
CGAUGUCAACCUUGUGUGA
1139


3158
sense
(Hs-Mf)





strand





MAPT-
19 mer
3503-3576
AAAGACUGACCUUGAUGUC
1140


3503
sense
(Hs-Mf)





strand








MAPT-
19 mer
3589-3661
CUCCACAGAAACCCUGUUU
1141


3589
sense
(Hs-Mf)





strand








MAPT-
19 mer
3591-3663
CCACAGAAACCCUGUUUUA
1142


3591
sense
(Hs-Mf)





strand








MAPT-
19 mer
3592-3664
CACAGAAACCCUGUUUUAU
1143


3592
sense
(Hs-Mf)





strand








MAPT-
19 mer
3593-3665
ACAGAAACCCUGUUUUAUU
1144


3593
sense
(Hs-Mf)





strand








MAPT-
19 mer
3594-3666
CAGAAACCCUGUUUUAUUG
1145


3594
sense
(Hs-Mf)





strand








MAPT-
19 mer
3595-3667
AGAAACCCUGUUUUAUUGA
1146


3595
sense
(Hs-Mf)





strand








MAPT-
19 mer
3596-3668
GAAACCCUGUUUUAUUGAG
1147


3596
sense
(Hs-Mf)





strand








MAPT-
19 mer
3597-3669
AAACCCUGUUUUAUUGAGU
1148


3597
sense
(Hs-Mf)





strand








MAPT-
19 mer
3598-3670
AACCCUGUUUUAUUGAGUU
1149


3598
sense
(Hs-Mf)





strand








MAPT-
19 mer
3599-3671
ACCCUGUUUUAUUGAGUUC
1150


3599
sense
(Hs-Mf)





strand








MAPT-
19 mer
3600-3672
CCCUGUUUUAUUGAGUUCU
1151


3600
sense
(Hs-Mf)





strand








MAPT-
19 mer
3601-3673
CCUGUUUUAUUGAGUUCUG
1152


3601
sense
(Hs-Mf)





strand








MAPT-
19 mer
3602-3674
CUGUUUUAUUGAGUUCUGA
1153


3602
sense
(Hs-Mf)





strand
3603-3675







MAPT-
19 mer

UGUUUUAUUGAGUUCUGAA
1154


3603
sense
(Hs-Mf)





strand








MAPT-
19 mer
3605-3677
UUUUAUUGAGUUCUGAAGG
1155


3605
sense
(Hs-Mf)





strand








MAPT-
19 mer
3607-3679
UUAUUGAGUUCUGAAGGUU
1156


3607
sense
(Hs-Mf)





strand








MAPT-
19 mer
3609-3681
AUUGAGUUCUGAAGGUUGG
1157


3609
sense
(Hs-Mf)





strand








MAPT-
19 mer
3610-3682
UUGAGUUCUGAAGGUUGGA
1158


3610
sense
(Hs-Mf)





strand








MAPT-
19 mer
3677-3749
AACCAGUUCUCUUUGUAAG
1159


3677
sense
(Hs-Mf)





strand








MAPT-
19 mer
3678-3750
ACCAGUUCUCUUUGUAAGG
1160


3678
sense
(Hs-Mf)





strand








MAPT-
19 mer
3679-3751
CCAGUUCUCUUUGUAAGGA
1161


3679
sense
(Hs-Mf)





strand








MAPT-
19 mer
3680-3752
CAGUUCUCUUUGUAAGGAC
1162


3680
sense
(Hs-Mf)





strand








MAPT-
19 mer
3958-4030
CUACUCCAUACUGAGGGUG
1163


3958
sense
(Hs-Mf)





strand








MAPT-
19 mer
3959-4031
UACUCCAUACUGAGGGUGA
1164


3959
sense
(Hs-Mf)





strand








MAPT-
19 mer
3960-4032
ACUCCAUACUGAGGGUGAA
1165


3960
sense
(Hs-Mf)





strand








MAPT-
19 mer
3961-4033
CUCCAUACUGAGGGUGAAA
1166


3961
sense
(Hs-Mf)





strand








MAPT-
19 mer
3965-4037
AUACUGAGGGUGAAAUUAA
1167


3965
sense
(Hs-Mf)





strand








MAPT-
19 mer
3970-4042
GAGGGUGAAAUUAAGGGAA
1168


3970
sense
(Hs-Mf)





strand








MAPT-
19 mer
4146-4218
GGUGUUUCUGCCUUGUUGA
1169


4146
sense
(Hs-Mf)





strand








MAPT-
19 mer
4474-4545
CUGGAGCAGCUGAACAUAU
1170


4474
sense
(Hs-Mf)





strand








MAPT-
19 mer
4475-4546
UGGAGCAGCUGAACAUAUA
1171


4475
sense
(Hs-Mf)





strand








MAPT-
19 mer
4477-4548
GAGCAGCUGAACAUAUACA
1172


4477
sense
(Hs-Mf)





strand








MAPT-
19 mer
4478-4549
AGCAGCUGAACAUAUACAU
1173


4478
sense
(Hs-Mf)





strand








MAPT-
19 mer
4479-4550
GCAGCUGAACAUAUACAUA
1174


4479
sense
(Hs-Mf)





strand








MAPT-
19 mer
4480-4551
CAGCUGAACAUAUACAUAG
1175


4480
sense
(Hs-Mf)





strand








MAPT-
19 mer
4481-4552
AGCUGAACAUAUACAUAGA
1176


4481
sense
(Hs-Mf)





strand








MAPT-
19 mer
4482-4553
GCUGAACAUAUACAUAGAU
1177


4482
sense
(Hs-Mf)





strand








MAPT-
19 mer
4485-4556
GAACAUAUACAUAGAUGUU
1178


4485
sense
(Hs-Mf)





strand








MAPT-
19 mer
4486-4557
AACAUAUACAUAGAUGUUG
1179


4486
sense
(Hs-Mf)





strand








MAPT-
19 mer
4532 (Hs)
GAGUUGUAGUUGGAUUUGU
1180


4532
sense






strand








MAPT-
19 mer
4533 (Hs)
AGUUGUAGUUGGAUUUGUC
1181


4533
sense






strand








MAPT-
19 mer
4539-4610
AGUUGGAUUUGUCUGUUUA
1182


4539
sense
(Hs-Mf)





strand








MAPT-
19 mer
4540-4611
GUUGGAUUUGUCUGUUUAU
1183


4540
sense
(Hs-Mf)





strand








MAPT-
19 mer
4541-4612
UUGGAUUUGUCUGUUUAUG
1184


4541
sense
(Hs-Mf)





strand








MAPT-
19 mer
4543-4614
GGAUUUGUCUGUUUAUGCU
1185


4543
sense
(Hs-Mf)





strand








MAPT-
19 mer
4544-4615
GAUUUGUCUGUUUAUGCUU
1186


4544
sense
(Hs-Mf)





strand








MAPT-
19 mer
4545-4616
AUUUGUCUGUUUAUGCUUG
1187


4545
sense
(Hs-Mf)





strand








MAPT-
19 mer
4546-4617
UUUGUCUGUUUAUGCUUGG
1188


4546
sense
(Hs-Mf)





strand








MAPT-
19 mer
4547-4618
UUGUCUGUUUAUGCUUGGA
1189


4547
sense
(Hs-Mf)





strand








MAPT-
19 mer
4548-4619
UGUCUGUUUAUGCUUGGAU
1190


4548
sense
(Hs-Mf)





strand








MAPT-
19 mer
4549-4620
GUCUGUUUAUGCUUGGAUU
1191


4549
sense
(Hs-Mf)





strand








MAPT-
19 mer
4550-4621
UCUGUUUAUGCUUGGAUUC
1192


4550
sense
(Hs-Mf)





strand








MAPT-
19 mer
4551-4622
CUGUUUAUGCUUGGAUUCA
1193


4551
sense
(Hs-Mf)





strand








MAPT-
19 mer
4552-4623
UGUUUAUGCUUGGAUUCAC
1194


4552
sense
(Hs-Mf)





strand








MAPT-
19 mer
4554-4625
UUUAUGCUUGGAUUCACCA
1195


4554
sense
(Hs-Mf)





strand








MAPT-
19 mer
4556-4627
UAUGCUUGGAUUCACCAGA
1196


4556
sense
(Hs-Mf)





strand








MAPT-
19 mer
4557-4628
AUGCUUGGAUUCACCAGAG
1197


4557
sense
(Hs-Mf)





strand








MAPT-
19 mer
4558-4629
UGCUUGGAUUCACCAGAGU
1198


4558
sense
(Hs-Mf)





strand








MAPT-
19 mer
4559-4630
GCUUGGAUUCACCAGAGUG
1199


4559
sense
(Hs-Mf)





strand








MAPT-
19 mer
4560-4631
CUUGGAUUCACCAGAGUGA
1200


4560
sense
(Hs-Mf)





strand








MAPT-
19 mer
4561-4632
UUGGAUUCACCAGAGUGAC
1201


4561
sense
(Hs-Mf)





strand








MAPT-
19 mer
4562-4633
UGGAUUCACCAGAGUGACU
1202


4562
sense
(Hs-Mf)





strand








MAPT-
19 mer
4563-4634
GGAUUCACCAGAGUGACUA
1203


4563
sense
(Hs-Mf)





strand








MAPT-
19 mer
4564-4635
GAUUCACCAGAGUGACUAU
1204


4564
sense
(Hs-Mf)





strand








MAPT-
19 mer
4615-4687
ACGCAUGUAUCUUGAAAUG
1205


4615
sense
(Hs-Mf)





strand








MAPT-
19 mer
4616-4688
CGCAUGUAUCUUGAAAUGC
1206


4616
sense
(Hs-Mf)





strand








MAPT-
19 mer
4617-4689
GCAUGUAUCUUGAAAUGCU
1207


4617
sense
(Hs-Mf)





strand








MAPT-
19 mer
4618-4690
CAUGUAUCUUGAAAUGCUU
1208


4618
sense
(Hs-Mf)





strand








MAPT-
19 mer
4619-4691
AUGUAUCUUGAAAUGCUUG
1209


4619
sense
(Hs-Mf)





strand








MAPT-
19 mer
4620-4692
UGUAUCUUGAAAUGCUUGU
1210


4620
sense
(Hs-Mf)





strand








MAPT-
19 mer
4621-4693
GUAUCUUGAAAUGCUUGUA
1211


4621
sense
(Hs-Mf)





strand








MAPT-
19 mer
4622-4694
UAUCUUGAAAUGCUUGUAA
1212


4622
sense
(Hs-Mf)





strand








MAPT-
19 mer
4623-4695
AUCUUGAAAUGCUUGUAAA
1213


4623
sense
(Hs-Mf)





strand








MAPT-
19 mer
4625-4697
CUUGAAAUGCUUGUAAAGA
1214


4625
sense
(Hs-Mf)





strand








MAPT-
19 mer
4627-4699
UGAAAUGCUUGUAAAGAGG
1215


4627
sense
(Hs-Mf)





strand








MAPT-
19 mer
4628-4700
GAAAUGCUUGUAAAGAGGU
1216


4628
sense
(Hs-Mf)





strand








MAPT-
19 mer
4629-4701
AAAUGCUUGUAAAGAGGUU
1217


4629
sense
(Hs-Mf)





strand








MAPT-
19 mer
4630-4702
AAUGCUUGUAAAGAGGUUU
1218


4630
sense
(Hs-Mf)





strand








MAPT-
19 mer
4632-4704
UGCUUGUAAAGAGGUUUCU
1219


4632
sense
(Hs-Mf)





strand








MAPT-
19 mer
4633-4705
GCUUGUAAAGAGGUUUCUA
1220


4633
sense
(Hs-Mf)





strand








MAPT-
19 mer
4825-4897
ACAGGAUUAGGACUGAAGC
1221


4825
sense
(Hs-Mf)





strand








MAPT-
19 mer
4828-4900
GGAUUAGGACUGAAGCGAU
1222


4828
sense
(Hs-Mf)





strand








MAPT-
19 mer
5682-5743
GAAGUUCUUGUGCCCUGCU
1223


5682
sense
(Hs-Mf)





strand








MAPT-
19 mer
5958 (Hs)
AAGCUGCUGACUCACUUUA
1224


5958
sense






strand








MAPT-
19 mer
5959 (Hs)
AGCUGCUGACUCACUUUAU
1225


5959
sense






strand








MAPT-
19 mer
5961 (Hs)
CUGCUGACUCACUUUAUCA
1226


5961
sense






strand








MAPT-
19 mer
5963 (Hs)
GCUGACUCACUUUAUCAAU
1227


5963
sense






strand








MAPT-
19 mer
5964 (Hs)
CUGACUCACUUUAUCAAUA
1228


5964
sense






strand








MAPT-
19 mer
5965 (Hs)
UGACUCACUUUAUCAAUAG
1229


5965
sense






strand








MAPT-
19 mer
5966-6021
GACUCACUUUAUCAAUAGU
1230


5966
sense
(Hs-Mf)





strand








MAPT-
19 mer
5967-6022
ACUCACUUUAUCAAUAGUU
1231


5967
sense
(Hs-Mf)





strand








MAPT-
19 mer
5968-6023
CUCACUUUAUCAAUAGUUC
1232


5968
sense
(Hs-Mf)





strand








MAPT-
19 mer
6006-6061
GGUGAGACUGUAUCCUGUU
1233


6006
sense
(Hs-Mf)





strand








MAPT-
19 mer
6007-6062
GUGAGACUGUAUCCUGUUU
1234


6007
sense
(Hs-Mf)





strand








MAPT-
19 mer
6008-6063
UGAGACUGUAUCCUGUUUG
1235


6008
sense
(Hs-Mf)





strand








MAPT-
19 mer
6009-6064
GAGACUGUAUCCUGUUUGC
1236


6009
sense
(Hs-Mf)





strand








MAPT-
19 mer
6010-6065
AGACUGUAUCCUGUUUGCU
1237


6010
sense
(Hs-Mf)





strand








MAPT-
19 mer
6011-6066
GACUGUAUCCUGUUUGCUA
1238


6011
sense
(Hs-Mf)





strand








MAPT-
19 mer
6012-6067
ACUGUAUCCUGUUUGCUAU
1239


6012
sense
(Hs-Mf)





strand








MAPT-
19 mer
6013-6068
CUGUAUCCUGUUUGCUAUU
1240


6013
sense
(Hs-Mf)





strand








MAPT-
19 mer
6014-6069
UGUAUCCUGUUUGCUAUUG
1241


6014
sense
(Hs-Mf)





strand








MAPT-
19 mer
6015-6070
GUAUCCUGUUUGCUAUUGC
1242


6015
sense
(Hs-Mf)





strand








MAPT-
19 mer
6017-6072
AUCCUGUUUGCUAUUGCUU
1243


6017
sense
(Hs-Mf)





strand








MAPT-
19 mer
6119-6174
GCCUCGUAACCCUUUUCAU
1244


6119
sense
(Hs-Mf)





strand








MAPT-
19 mer
6628-6689
GAGUUUGCCAUGUUGAGCA
1245


6628
sense
(Hs-Mf)





strand








MAPT-
19 mer
6629-6690
AGUUUGCCAUGUUGAGCAG
1246


6629
sense
(Hs-Mf)





strand








MAPT-
19 mer
6631-6692
UUUGCCAUGUUGAGCAGGA
1247


6631
sense
(Hs-Mf)





strand








MAPT-
19 mer
6672-6733
CCAUGAUUUCUUCGGUAAU
1248


6672
sense
(Hs-Mf)





strand








MAPT-
19 mer
6731 (Hs)
GCUUUCUGUCUGUGAAUGU
1249


6731
sense






strand








MAPT-
19 mer
6732 (Hs)
CUUUCUGUCUGUGAAUGUC
1250


6732
sense






strand








MAPT-
19 mer
6738-6799
GUCUGUGAAUGUCUAUAUA
1251


6738
sense
(Hs-Mf)





strand








MAPT-
19 mer
6739-6800
UCUGUGAAUGUCUAUAUAG
1252


6739
sense
(Hs-Mf)





strand








MAPT-
19 mer
6740-6801
CUGUGAAUGUCUAUAUAGU
1253


6740
sense
(Hs-Mf)





strand








MAPT-
19 mer
6741-6802
UGUGAAUGUCUAUAUAGUG
1254


6741
sense
(Hs-Mf)





strand








MAPT-
19 mer
6742-6803
GUGAAUGUCUAUAUAGUGU
1255


6742
sense
(Hs-Mf)





strand








MAPT-
19 mer
6743-6804
UGAAUGUCUAUAUAGUGUA
1256


6743
sense
(Hs-Mf)





strand








MAPT-
19 mer
6745-6806
AAUGUCUAUAUAGUGUAUU
1257


6745
sense
(Hs-Mf)





strand








MAPT-
19 mer
6748-6809
GUCUAUAUAGUGUAUUGUG
1258


6748
sense
(Hs-Mf)





strand








MAPT-
19 mer
6749-6810
UCUAUAUAGUGUAUUGUGU
1259


6749
sense
(Hs-Mf)





strand








MAPT-
19 mer
6750-6811
CUAUAUAGUGUAUUGUGUG
1260


6750
sense
(Hs-Mf)





strand








MAPT-
19 mer
6751-6812
UAUAUAGUGUAUUGUGUGU
1261


6751
sense
(Hs-Mf)





strand








MAPT-
19 mer
6752-6813
AUAUAGUGUAUUGUGUGUU
1262


6752
sense
(Hs-Mf)





strand








MAPT-
19 mer
6753-6814
UAUAGUGUAUUGUGUGUUU
1263


6753
sense
(Hs-Mf)





strand








MAPT-
19 mer
6754-6815
AUAGUGUAUUGUGUGUUUU
1264


6754
sense
(Hs-Mf)





strand








MAPT-
19 mer
6755-6816
UAGUGUAUUGUGUGUUUUA
1265


6755
sense
(Hs-Mf)





strand








MAPT-
19 mer
6756-6817
AGUGUAUUGUGUGUUUUAA
1266


6756
sense
(Hs-Mf)





strand








MAPT-
19 mer
6757-6818
GUGUAUUGUGUGUUUUAAC
1267


6757
sense
(Hs-Mf)





strand








MAPT-
19 mer
6758-6819
UGUAUUGUGUGUUUUAACA
1268


6758
sense
(Hs-Mf)





strand








MAPT-
19 mer
6759-6820
GUAUUGUGUGUUUUAACAA
1269


6759
sense
(Hs-Mf)





strand








MAPT-
19 mer
6760-6821
UAUUGUGUGUUUUAACAAA
1270


6760
sense
(Hs-Mf)





strand








MAPT-
19 mer
6761-6822
AUUGUGUGUUUUAACAAAU
1271


6761
sense
(Hs-Mf)





strand








MAPT-
19 mer
6762-6823
UUGUGUGUUUUAACAAAUG
1272


6762
sense
(Hs-Mf)





strand








MAPT-
19 mer
6763-6824
UGUGUGUUUUAACAAAUGA
1273


6763
sense
(Hs-Mf)





strand








MAPT-
19 mer
6764-6825
GUGUGUUUUAACAAAUGAU
1274


6764
sense
(Hs-Mf)





strand








MAPT-
19 mer
6765-6826
UGUGUUUUAACAAAUGAUU
1275


6765
sense
(Hs-Mf)





strand








MAPT-
19 mer
6766-6827
GUGUUUUAACAAAUGAUUU
1276


6766
sense
(Hs-Mf)





strand








MAPT-
19 mer
6767-6828
UGUUUUAACAAAUGAUUUA
1277


6767
sense
(Hs-Mf)





strand








MAPT-
19 mer
6768-6829
GUUUUAACAAAUGAUUUAC
1278


6768
sense
(Hs-Mf)





strand








MAPT-
19 mer
6769-6830
UUUUAACAAAUGAUUUACA
1279


6769
sense
(Hs-Mf)





strand








MAPT-
19 mer
6772-6833
UAACAAAUGAUUUACACUG
1280


6772
sense
(Hs-Mf)





strand








MAPT-
19 mer
6773-6834
AACAAAUGAUUUACACUGA
1281


6773
sense
(Hs-Mf)





strand








MAPT-
19 mer
6774-6835
ACAAAUGAUUUACACUGAC
1282


6774
sense
(Hs-Mf)





strand








MAPT-
19 mer
6775-6836
CAAAUGAUUUACACUGACU
1283


6775
sense
(Hs-Mf)





strand








MAPT-
19 mer
6777-6838
AAUGAUUUACACUGACUGU
1284


6777
sense
(Hs-Mf)





strand








MAPT-
19 mer
6778-6839
AUGAUUUACACUGACUGUU
1285


6778
sense
(Hs-Mf)





strand








MAPT-
19 mer
6779-6840
UGAUUUACACUGACUGUUG
1286


6779
sense
(Hs-Mf)





strand








MAPT-
19 mer
6780-6841
GAUUUACACUGACUGUUGC
1287


6780
sense
(Hs-Mf)





strand








MAPT-
19 mer
6781 (Hs)
AUUUACACUGACUGUUGCU
1288


6781
sense






strand








MAPT-
19 mer
6789 (Hs)
UGACUGUUGCUGUAAAAGU
1289


6789
sense






strand








MAPT-
19 mer
6792 (Hs)
CUGUUGCUGUAAAAGUGAA
1290


6792
sense






strand








MAPT-
19 mer
6793 (Hs)
UGUUGCUGUAAAAGUGAAU
1291


6793
sense






strand








MAPT-
19 mer
6795 (Hs)
UUGCUGUAAAAGUGAAUUU
1292


6795
sense






strand








MAPT-
19 mer
6796 (Hs)
UGCUGUAAAAGUGAAUUUG
1293


6796
sense






strand








MAPT-
19 mer
6797 (Hs)
GCUGUAAAAGUGAAUUUGG
1294


6797
sense






strand








MAPT-
19 mer
6798 (Hs)
CUGUAAAAGUGAAUUUGGA
1295


6798
sense






strand








MAPT-
19 mer
2141-2218-
GCUGGUGCUUCAGGUUCUC
1296


2141
anti-
966 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2142-2219-
GGCUGGUGCUUCAGGUUCU
1297


2142
anti-
967 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2303-2380-
AGCCACACUUGGAGGUCAC
1298


2303
anti-
1128 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2347-2424-
UUCCACCUGGCCACCUCCU
1299


2347
anti-
1172 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2349-2426-
ACUUCCACCUGGCCACCUC
1300


2349
anti-
1174 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2350-2427-
UACUUCCACCUGGCCACCU
1301


2350
anti-
1175 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2351-2428-
UUACUUCCACCUGGCCACC
1302


2351
anti-
1176 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2352-2429-
UUUACUUCCACCUGGCCAC
1303


2352
anti-
1177 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2353-2430-
UUUUACUUCCACCUGGCCA
1304


2353
anti-
1178 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2354-2431-
AUUUUACUUCCACCUGGCC
1305


2354
anti-
1179 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2355-2432-
GAUUUUACUUCCACCUGGC
1306


2355
anti-
1180 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2459-2536-
GCUUGUGGGUUUCAAUCUU
1307


2459
anti-
1284 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2460-2537-
AGCUUGUGGGUUUCAAUCU
1308


2460
anti-
1285 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2461-2538-
CAGCUUGUGGGUUUCAAUC
1309


2461
anti-
1286 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2462-2539-
UCAGCUUGUGGGUUUCAAU
1310


2462
anti-
1287 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2463-2540-
GUCAGCUUGUGGGUUUCAA
1311


2463
anti-
1288 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2464-2541-
GGUCAGCUUGUGGGUUUCA
1312


2464
anti-
1289 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2465-2542-
AGGUCAGCUUGUGGGUUUC
1313


2465
anti-
1290 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2466-2543-
AAGGUCAGCUUGUGGGUUU
1314


2466
anti-
1291 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2467-2544-
GAAGGUCAGCUUGUGGGUU
1315


2467
anti-
1292 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2495-2572-
GGUCUGUCUUGGCUUUGGC
1316


2495
anti-
1320 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
2496-2573-
UGGUCUGUCUUGGCUUUGG
1317


2496
anti-
1321 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
3686-3758-
GCACAAGUCCUUACAAAGA
1318


3686
anti-
2505 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
3687-3759-
GGCACAAGUCCUUACAAAG
1319


3687
anti-
2506 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
3688-3760-
AGGCACAAGUCCUUACAAA
1320


3688
anti-
2507 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
3691-3763-
AAGAGGCACAAGUCCUUAC
1321


3691
anti-
2510 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
3692-3764-
CAAGAGGCACAAGUCCUUA
1322


3692
anti-
2511 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
3693-3765-
CCAAGAGGCACAAGUCCUU
1323


3693
anti-
2512 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4534-4605-
AGACAAAUCCAACUACAAC
1324


4534
anti-
3332 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4535-4606-
CAGACAAAUCCAACUACAA
1325


4535
anti-
3333 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4536-4607-
ACAGACAAAUCCAACUACA
1326


4536
anti-
3334 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4537-4608-
AACAGACAAAUCCAACUAC
1327


4537
anti-
3335 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4538-4609-
AAACAGACAAAUCCAACUA
1328


4538
anti-
3336 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4566-4637-
UCAUAGUCACUCUGGUGAA
1329


4566
anti-
3362 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4567-4638-
AUCAUAGUCACUCUGGUGA
1330


4567
anti-
3363 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4568-4639-
UAUCAUAGUCACUCUGGUG
1331


4568
anti-
3364 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4569-4640-
CUAUCAUAGUCACUCUGGU
1332


4569
anti-
3365 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4570-4641-
ACUAUCAUAGUCACUCUGG
1333


4570
anti-
3366 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4571-4642-
CACUAUCAUAGUCACUCUG
1334


4571
anti-
3367 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4572-4643-
UCACUAUCAUAGUCACUCU
1335


4572
anti-
3368 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4573-4644-
UUCACUAUCAUAGUCACUC
1336


4573
anti-
3369 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4574-4645-
UUUCACUAUCAUAGUCACU
1337


4574
anti-
3370 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4575-4646-
UUUUCACUAUCAUAGUCAC
1338


4575
anti-
3371 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4576-4647-
CUUUUCACUAUCAUAGUCA
1339


4576
anti-
3372 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4577-4648-
UCUUUUCACUAUCAUAGUC
1340


4577
anti-
3373 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4578-4649-
UUCUUUUCACUAUCAUAGU
1341


4578
anti-
3374 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4579-4650-
UUUCUUUUCACUAUCAUAG
1342


4579
anti-
3375 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4580-4651-
UUUUCUUUUCACUAUCAUA
1343


4580
anti-
3376 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4605-4677-
UACAUGCGUCCUUUUUUUU
1344


4605
anti-
3439 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4606-4678-
AUACAUGCGUCCUUUUUUU
1345


4606
anti-
3440 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4607-4679-
GAUACAUGCGUCCUUUUUU
1346


4607
anti-
3441 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4608-4680-
AGAUACAUGCGUCCUUUUU
1347


4608
anti-
3442 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4609-4681-
AAGAUACAUGCGUCCUUUU
1348


4609
anti-
3443 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4610-4682-
CAAGAUACAUGCGUCCUUU
1349


4610
anti-
3444 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4611-4683-
UCAAGAUACAUGCGUCCUU
1350


4611
anti-
3445 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4612-4684-
UUCAAGAUACAUGCGUCCU
1351


4612
anti-
3446 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4613-4685-
UUUCAAGAUACAUGCGUCC
1352


4613
anti-
3447 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
4614-4686-
AUUUCAAGAUACAUGCGUC
1353


4614
anti-
3448 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5969-6024-
GGAACUAUUGAUAAAGUGA
1354


5969
anti-
4540 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5970-6025-
UGGAACUAUUGAUAAAGUG
1355


5970
anti-
4541 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5971-6026-
AUGGAACUAUUGAUAAAGU
1356


5971
anti-
4542 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5972-6027-
AAUGGAACUAUUGAUAAAG
1357


5972
anti-
4543 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5973-6028-
AAAUGGAACUAUUGAUAAA
1358


5973
anti-
4544 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5974-6029-
UAAAUGGAACUAUUGAUAA
1359


5974
anti-
4545 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5975-6030-
UUAAAUGGAACUAUUGAUA
1360


5975
anti-
4546 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5976-6031-
UUUAAAUGGAACUAUUGAU
1361


5976
anti-
4547 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5977-6032-
AUUUAAAUGGAACUAUUGA
1362


5977
anti-
4548 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5978-6033-
AAUUUAAAUGGAACUAUUG
1363


5978
anti-
4549 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5979-6034-
CAAUUUAAAUGGAACUAUU
1364


5979
anti-
4550 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5980-6035-
UCAAUUUAAAUGGAACUAU
1365


5980
anti-
4551 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5981-6036-
GUCAAUUUAAAUGGAACUA
1366


5981
anti-
4552 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5982-6037-
AGUCAAUUUAAAUGGAACU
1367


5982
anti-
4553 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5983-6038-
AAGUCAAUUUAAAUGGAAC
1368


5983
anti-
4554 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5984-6039-
GAAGUCAAUUUAAAUGGAA
1369


5984
anti-
4555 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
5985-6040-
UGAAGUCAAUUUAAAUGGA
1370


5985
anti-
4556 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6662-6723-
AAAUCAUGGGACUUGCAAG
1371


6662
anti-
5230 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6663-6724-
GAAAUCAUGGGACUUGCAA
1372


6663
anti-
5231 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6664-6725-
AGAAAUCAUGGGACUUGCA
1373


6664
anti-
5232 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6665-6726-
AAGAAAUCAUGGGACUUGC
1374


6665
anti-
5233 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6800-6861-
UUUCCAAAUUCACUUUUAC
1375


6800
anti-
5365 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6801-6862-
AUUUCCAAAUUCACUUUUA
1376


6801
anti-
5366 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6802-6863-
UAUUUCCAAAUUCACUUUU
1377


6802
anti-
5367 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6803-6864-
UUAUUUCCAAAUUCACUUU
1378


6803
anti-
5368 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6804-6865-
UUUAUUUCCAAAUUCACUU
1379


6804
anti-
5369 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6805-6866-
CUUUAUUUCCAAAUUCACU
1380


6805
anti-
5370 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6806-6867-
ACUUUAUUUCCAAAUUCAC
1381


6806
anti-
5371 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6807-6868-
AACUUUAUUUCCAAAUUCA
1382


6807
anti-
5372 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6808-6869-
UAACUUUAUUUCCAAAUUC
1383


6808
anti-
5373 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6809-6870-
AUAACUUUAUUUCCAAAUU
1384


6809
anti-
5374 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6810-6871-
AAUAACUUUAUUUCCAAAU
1385


6810
anti-
5375 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6811-6872-
UAAUAACUUUAUUUCCAAA
1386


6811
anti-
5376 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6812-6873-
GUAAUAACUUUAUUUCCAA
1387


6812
anti-
5377 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6813-6874-
AGUAAUAACUUUAUUUCCA
1388


6813
anti-
5378 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6814-6875-
GAGUAAUAACUUUAUUUCC
1389


6814
anti-
5379 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6815-6876-
AGAGUAAUAACUUUAUUUC
1390


6815
anti-
5380 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
6816-6877-
CAGAGUAAUAACUUUAUUU
1391


6816
anti-
5381 (Hs-





sense
Mf-Mm)





strand








MAPT-
19 mer
 363 (Hs)
UCCAUCACUUCGAACUCCU
1392


363
anti-






sense






strand








MAPT-
19 mer
 364 (Hs)
UUCCAUCACUUCGAACUCC
1393


364
anti-






sense






strand








MAPT-
19 mer
 365 (Hs)
CUUCCAUCACUUCGAACUC
1394


365
anti-






sense






strand








MAPT-
19 mer
 367 (Hs)
AUCUUCCAUCACUUCGAAC
1395


367
anti-






sense






strand








MAPT-
19 mer
 369 (Hs)
UGAUCUUCCAUCACUUCGA
1396


369
anti-






sense






strand








MAPT-
19 mer
 374-226
CAGCGUGAUCUUCCAUCAC
1397


374
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
 395-247
UGUCCCCCAACCCGUACGU
1398


395
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
 400-252
UUUCCUGUCCCCCAACCCG
1399


400
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
 443-295
UGUCACCCUCUUGGUCUUG
1400


443
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
 688-453
ACCAGCAGCUUCGUCUUCC
1401


688
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
 689-454
GACCAGCAGCUUCGUCUUC
1402


689
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
 690-455
UGACCAGCAGCUUCGUCUU
1403


690
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
 693-458
ACGUGACCAGCAGCUUCGU
1404


693
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
 695-460
UCACGUGACCAGCAGCUUC
1405


695
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
 696-461
GUCACGUGACCAGCAGCUU
1406


696
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1475-1552
UGCUUUUACUGACCAUGCG
1407


1475
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1476-1553
UUGCUUUUACUGACCAUGC
1408


1476
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1479-1556
UCUUUGCUUUUACUGACCA
1409


1479
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1480-1557
GUCUUUGCUUUUACUGACC
1410


1480
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1481-1558
CGUCUUUGCUUUUACUGAC
1411


1481
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1484-1561
UCCCGUCUUUGCUUUUACU
1412


1484
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1485-1562
GUCCCGUCUUUGCUUUUAC
1413


1485
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1492-1569
GCUUCCAGUCCCGUCUUUG
1414


1492
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1494-1571
UCGCUUCCAGUCCCGUCUU
1415


1494
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1495-1572
AUCGCUUCCAGUCCCGUCU
1416


1495
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1498-1575
GUCAUCGCUUCCAGUCCCG
1417


1498
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1499-1576
UGUCAUCGCUUCCAGUCCC
1418


1499
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1500-1577
UUGUCAUCGCUUCCAGUCC
1419


1500
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1502-1579
UUUUGUCAUCGCUUCCAGU
1420


1502
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1503-1580
UUUUUGUCAUCGCUUCCAG
1421


1503
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1504-1581
UUUUUUGUCAUCGCUUCCA
1422


1504
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1505-1582
CUUUUUUGUCAUCGCUUCC
1423


1505
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1506-1583
GCUUUUUUGUCAUCGCUUC
1424


1506
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1507-1584
GGCUUUUUUGUCAUCGCUU
1425


1507
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1508-1585
UGGCUUUUUUGUCAUCGCU
1426


1508
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1509-1586
UUGGCUUUUUUGUCAUCGC
1427


1509
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1733 (Hs)
CGAUCUUCGUUUUACCAUC
1428


1733
anti-






sense






strand








MAPT-
19 mer
1796-1873
CUGGAAUCCUGGUGGCGUU
1429


1796
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1835-1912
CAGAGCUGGGUGGUGUCUU
1430


1835
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
1912-1989
AUCCCCUGAUUUUGGAGGU
1431


1912
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2094-2171
UUCAGGUCUGGCAUGGGCA
1432


2094
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2096-2173
UCUUCAGGUCUGGCAUGGG
1433


2096
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2097-2174
UUCUUCAGGUCUGGCAUGG
1434


2097
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2098 (Hs)
AUUCUUCAGGUCUGGCAUG
1435


2098
anti-






sense






strand








MAPT-
19 mer
2105 (Hs)
ACUUGACAUUCUUCAGGUC
1436


2105
anti-






sense






strand








MAPT-
19 mer
2106 (Hs)
GACUUGACAUUCUUCAGGU
1437


2106
anti-






sense






strand








MAPT-
19 mer
2107 (Hs)
GGACUUGACAUUCUUCAGG
1438


2107
anti-






sense






strand








MAPT-
19 mer
2108 (Hs)
UGGACUUGACAUUCUUCAG
1439


2108
anti-






sense






strand








MAPT-
19 mer
2109 (Hs)
UUGGACUUGACAUUCUUCA
1440


2109
anti-






sense






strand








MAPT-
19 mer
2117-2194
AGCCGAUCUUGGACUUGAC
1441


2117
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2136 (Hs)
UGCUUCAGGUUCUCAGUGG
1442


2136
anti-






sense






strand








MAPT-
19 mer
2137 (Hs)
GUGCUUCAGGUUCUCAGUG
1443


2137
anti-






sense






strand








MAPT-
19 mer
2269-2346
UGGUUUGUAGACUAUUUGC
1444


2269
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2270-2347
CUGGUUUGUAGACUAUUUG
1445


2270
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2271-2348
ACUGGUUUGUAGACUAUUU
1446


2271
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2272-2349
AACUGGUUUGUAGACUAUU
1447


2272
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2273-2350
CAACUGGUUUGUAGACUAU
1448


2273
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2274-2351
UCAACUGGUUUGUAGACUA
1449


2274
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2275-2352
GUCAACUGGUUUGUAGACU
1450


2275
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2276-2353
GGUCAACUGGUUUGUAGAC
1451


2276
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2277-2354
AGGUCAACUGGUUUGUAGA
1452


2277
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2278-2355
CAGGUCAACUGGUUUGUAG
1453


2278
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2279-2356
UCAGGUCAACUGGUUUGUA
1454


2279
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2280-2357
CUCAGGUCAACUGGUUUGU
1455


2280
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2281-2358
GCUCAGGUCAACUGGUUUG
1456


2281
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2282-2359
UGCUCAGGUCAACUGGUUU
1457


2282
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2283-2360
UUGCUCAGGUCAACUGGUU
1458


2283
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2284-2361
CUUGCUCAGGUCAACUGGU
1459


2284
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2286-2363
ACCUUGCUCAGGUCAACUG
1460


2286
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2288-2365
UCACCUUGCUCAGGUCAAC
1461


2288
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2289-2366
GUCACCUUGCUCAGGUCAA
1462


2289
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2291-2368
AGGUCACCUUGCUCAGGUC
1463


2291
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2294-2371
UGGAGGUCACCUUGCUCAG
1464


2294
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2299-2376
ACACUUGGAGGUCACCUUG
1465


2299
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2300-2377
CACACUUGGAGGUCACCUU
1466


2300
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2301-2378
CCACACUUGGAGGUCACCU
1467


2301
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2308-2385
UAAUGAGCCACACUUGGAG
1468


2308
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2316-2393
AUGUUGCCUAAUGAGCCAC
1469


2316
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2317-2394
GAUGUUGCCUAAUGAGCCA
1470


2317
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2319-2396
UGGAUGUUGCCUAAUGAGC
1471


2319
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2320-2397
AUGGAUGUUGCCUAAUGAG
1472


2320
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2322-2399
UGAUGGAUGUUGCCUAAUG
1473


2322
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2323-2400
AUGAUGGAUGUUGCCUAAU
1474


2323
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2324-2401
UAUGAUGGAUGUUGCCUAA
1475


2324
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2326-2403
UUUAUGAUGGAUGUUGCCU
1476


2326
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2330-2407
CUGGUUUAUGAUGGAUGUU
1477


2330
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2356-2433
AGAUUUUACUUCCACCUGG
1478


2356
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2357-2434
CAGAUUUUACUUCCACCUG
1479


2357
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2358-2435
UCAGAUUUUACUUCCACCU
1480


2358
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2359-2436
CUCAGAUUUUACUUCCACC
1481


2359
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2360-2437
UCUCAGAUUUUACUUCCAC
1482


2360
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2361-2438
UUCUCAGAUUUUACUUCCA
1483


2361
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2362-2439
CUUCUCAGAUUUUACUUCC
1484


2362
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2363-2440
GCUUCUCAGAUUUUACUUC
1485


2363
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2364-2441
AGCUUCUCAGAUUUUACUU
1486


2364
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2365 (Hs)
AAGCUUCUCAGAUUUUACU
1487


2365
anti-






sense






strand








MAPT-
19 mer
2372 (Hs)
UGAAGUCAAGCUUCUCAGA
1488


2372
anti-






sense






strand








MAPT-
19 mer
2373 (Hs)
UUGAAGUCAAGCUUCUCAG
1489


2373
anti-






sense






strand








MAPT-
19 mer
2374 (Hs)
CUUGAAGUCAAGCUUCUCA
1490


2374
anti-






sense






strand








MAPT-
19 mer
2375 (Hs)
CCUUGAAGUCAAGCUUCUC
1491


2375
anti-






sense






strand








MAPT-
19 mer
2376 (Hs)
UCCUUGAAGUCAAGCUUCU
1492


2376
anti-






sense






strand








MAPT-
19 mer
2377 (Hs)
GUCCUUGAAGUCAAGCUUC
1493


2377
anti-






sense






strand








MAPT-
19 mer
2378 (Hs)
UGUCCUUGAAGUCAAGCUU
1494


2378
anti-






sense






strand








MAPT-
19 mer
2379 (Hs)
CUGUCCUUGAAGUCAAGCU
1495


2379
anti-






sense






strand








MAPT-
19 mer
2380 (Hs)
UCUGUCCUUGAAGUCAAGC
1496


2380
anti-






sense






strand








MAPT-
19 mer
2381 (Hs)
CUCUGUCCUUGAAGUCAAG
1497


2381
anti-






sense






strand








MAPT-
19 mer
2382 (Hs)
ACUCUGUCCUUGAAGUCAA
1498


2382
anti-






sense






strand








MAPT-
19 mer
2390 (Hs)
UCGACUGGACUCUGUCCUU
1499


2390
anti-






sense






strand








MAPT-
19 mer
2391 (Hs)
UUCGACUGGACUCUGUCCU
1500


2391
anti-






sense






strand








MAPT-
19 mer
2414-2491
UGAUAUUGUCCAGGGACCC
1501


2414
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2448-2525
UCAAUCUUUUUAUUUCCUC
1502


2448
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2449-2526
UUCAAUCUUUUUAUUUCCU
1503


2449
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2450-2527
UUUCAAUCUUUUUAUUUCC
1504


2450
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2451-2528
GUUUCAAUCUUUUUAUUUC
1505


2451
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2452-2529
GGUUUCAAUCUUUUUAUUU
1506


2452
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2453-2530
GGGUUUCAAUCUUUUUAUU
1507


2453
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2454-2531
UGGGUUUCAAUCUUUUUAU
1508


2454
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2456-2533
UGUGGGUUUCAAUCUUUUU
1509


2456
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2457-2534
UUGUGGGUUUCAAUCUUUU
1510


2457
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer

AGACAUUGCUGAGAUGCCG
1511


2567
anti-
2567 (Hs)





sense






strand








MAPT-
19 mer
2598-2675
GAGUCUACCAUGUCGAUGC
1512


2598
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2657-2734
ACAAACCCUGCUUGGCCAG
1513


2657
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2723-2800
CUUUUUUUUUCCACACUCU
1514


2723
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2724-2801
UCUUUUUUUUUCCACACUC
1515


2724
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2726-2803
AUUCUUUUUUUUUCCACAC
1516


2726
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
2784-2860-
AACCAAUUAACCGAACUGC
1517


2784
anti-
1 mismatch





sense
(Hs-Mf)





strand








MAPT-
19 mer
2963-3039
AGAAUCAAAAGGAAUUGCC
1518


2963
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3110-3186
UUUCAAAUCCUUUGUUGCU
1519


3110
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3114-3190
CAAGUUUCAAAUCCUUUGU
1520


3114
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3116-3192
ACCAAGUUUCAAAUCCUUU
1521


3116
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3118-3194
ACACCAAGUUUCAAAUCCU
1522


3118
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3158-3234
UCACACAAGGUUGACAUCG
1523


3158
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3503-3576
GACAUCAAGGUCAGUCUUU
1524


3503
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3589-3661
AAACAGGGUUUCUGUGGAG
1525


3589
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3591-3663
UAAAACAGGGUUUCUGUGG
1526


3591
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3592-3664
AUAAAACAGGGUUUCUGUG
1527


3592
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3593-3665
AAUAAAACAGGGUUUCUGU
1528


3593
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3594-3666
CAAUAAAACAGGGUUUCUG
1529


3594
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3595-3667
UCAAUAAAACAGGGUUUCU
1530


3595
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3596-3668
CUCAAUAAAACAGGGUUUC
1531


3596
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3597-3669
ACUCAAUAAAACAGGGUUU
1532


3597
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3598-3670
AACUCAAUAAAACAGGGUU
1533


3598
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3599-3671
GAACUCAAUAAAACAGGGU
1534


3599
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3600-3672
AGAACUCAAUAAAACAGGG
1535


3600
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3601-3673
CAGAACUCAAUAAAACAGG
1536


3601
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3602-3674
UCAGAACUCAAUAAAACAG
1537


3602
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3603-3675
UUCAGAACUCAAUAAAACA
1538


3603
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3605-3677
CCUUCAGAACUCAAUAAAA
1539


3605
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3607-3679
AACCUUCAGAACUCAAUAA
1540


3607
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3609-3681
CCAACCUUCAGAACUCAAU
1541


3609
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3610-3682
UCCAACCUUCAGAACUCAA
1542


3610
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3677-3749
CUUACAAAGAGAACUGGUU
1543


3677
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3678-3750
CCUUACAAAGAGAACUGGU
1544


3678
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3679-3751
UCCUUACAAAGAGAACUGG
1545


3679
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3680-3752
GUCCUUACAAAGAGAACUG
1546


3680
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3958-4030
CACCCUCAGUAUGGAGUAG
1547


3958
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3959-4031
UCACCCUCAGUAUGGAGUA
1548


3959
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3960-4032
UUCACCCUCAGUAUGGAGU
1549


3960
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3961-4033
UUUCACCCUCAGUAUGGAG
1550


3961
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3965-4037
UUAAUUUCACCCUCAGUAU
1551


3965
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
3970-4042
UUCCCUUAAUUUCACCCUC
1552


3970
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4146-4218
UCAACAAGGCAGAAACACC
1553


4146
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4474-4545
AUAUGUUCAGCUGCUCCAG
1554


4474
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4475-4546
UAUAUGUUCAGCUGCUCCA
1555


4475
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4477-4548
UGUAUAUGUUCAGCUGCUC
1556


4477
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4478-4549
AUGUAUAUGUUCAGCUGCU
1557


4478
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4479-4550
UAUGUAUAUGUUCAGCUGC
1558


4479
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4480-4551
CUAUGUAUAUGUUCAGCUG
1559


4480
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4481-4552
UCUAUGUAUAUGUUCAGCU
1560


4481
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4482-4553
AUCUAUGUAUAUGUUCAGC
1561


4482
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4485-4556
AACAUCUAUGUAUAUGUUC
1562


4485
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4486-4557
CAACAUCUAUGUAUAUGUU
1563


4486
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4532 (Hs)
ACAAAUCCAACUACAACUC
1564


4532
anti-






sense






strand








MAPT-
19 mer
4533 (Hs)
GACAAAUCCAACUACAACU
1565


4533
anti-






sense






strand








MAPT-
19 mer
4539-4610
UAAACAGACAAAUCCAACU
1566


4539
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4540-4611
AUAAACAGACAAAUCCAAC
1567


4540
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4541-4612
CAUAAACAGACAAAUCCAA
1568


4541
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4543-4614
AGCAUAAACAGACAAAUCC
1569


4543
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4544-4615
AAGCAUAAACAGACAAAUC
1570


4544
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4545-4616
CAAGCAUAAACAGACAAAU
1571


4545
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4546-4617
CCAAGCAUAAACAGACAAA
1572


4546
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4547-4618
UCCAAGCAUAAACAGACAA
1573


4547
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4548-4619
AUCCAAGCAUAAACAGACA
1574


4548
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4549-4620
AAUCCAAGCAUAAACAGAC
1575


4549
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4550-4621
GAAUCCAAGCAUAAACAGA
1576


4550
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4551-4622
UGAAUCCAAGCAUAAACAG
1577


4551
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4552-4623
GUGAAUCCAAGCAUAAACA
1578


4552
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4554-4625
UGGUGAAUCCAAGCAUAAA
1579


4554
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4556-4627
UCUGGUGAAUCCAAGCAUA
1580


4556
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4557-4628
CUCUGGUGAAUCCAAGCAU
1581


4557
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4558-4629
ACUCUGGUGAAUCCAAGCA
1582


4558
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4559-4630
CACUCUGGUGAAUCCAAGC
1583


4559
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4560-4631
UCACUCUGGUGAAUCCAAG
1584


4560
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4561-4632
GUCACUCUGGUGAAUCCAA
1585


4561
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4562-4633
AGUCACUCUGGUGAAUCCA
1586


4562
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4563-4634
UAGUCACUCUGGUGAAUCC
1587


4563
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4564-4635
AUAGUCACUCUGGUGAAUC
1588


4564
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4615-4687
CAUUUCAAGAUACAUGCGU
1589


4615
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4616-4688
GCAUUUCAAGAUACAUGCG
1590


4616
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4617-4689
AGCAUUUCAAGAUACAUGC
1591


4617
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4618-4690
AAGCAUUUCAAGAUACAUG
1592


4618
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4619-4691
CAAGCAUUUCAAGAUACAU
1593


4619
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4620-4692
ACAAGCAUUUCAAGAUACA
1594


4620
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4621-4693
UACAAGCAUUUCAAGAUAC
1595


4621
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4622-4694
UUACAAGCAUUUCAAGAUA
1596


4622
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4623-4695
UUUACAAGCAUUUCAAGAU
1597


4623
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4625-4697
UCUUUACAAGCAUUUCAAG
1598


4625
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4627-4699
CCUCUUUACAAGCAUUUCA
1599


4627
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4628-4700
ACCUCUUUACAAGCAUUUC
1600


4628
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4629-4701
AACCUCUUUACAAGCAUUU
1601


4629
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4630-4702
AAACCUCUUUACAAGCAUU
1602


4630
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4632-4704
AGAAACCUCUUUACAAGCA
1603


4632
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4633-4705
UAGAAACCUCUUUACAAGC
1604


4633
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4825-4897
GCUUCAGUCCUAAUCCUGU
1605


4825
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
4828-4900
AUCGCUUCAGUCCUAAUCC
1606


4828
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
5682-5743
AGCAGGGCACAAGAACUUC
1607


5682
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
5958 (Hs)
UAAAGUGAGUCAGCAGCUU
1608


5958
anti-






sense






strand








MAPT-
19 mer
5959 (Hs)
AUAAAGUGAGUCAGCAGCU
1609


5959
anti-






sense






strand








MAPT-
19 mer
5961 (Hs)
UGAUAAAGUGAGUCAGCAG
1610


5961
anti-






sense






strand








MAPT-
19 mer
5963 (Hs)
AUUGAUAAAGUGAGUCAGC
1611


5963
anti-






sense






strand








MAPT-
19 mer
5964 (Hs)
UAUUGAUAAAGUGAGUCAG
1612


5964
anti-






sense






strand








MAPT-
19 mer
5965 (Hs)
CUAUUGAUAAAGUGAGUCA
1613


5965
anti-






sense






strand








MAPT-
19 mer
5966-6021
ACUAUUGAUAAAGUGAGUC
1614


5966
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
5967-6022
AACUAUUGAUAAAGUGAGU
1615


5967
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
5968-6023
GAACUAUUGAUAAAGUGAG
1616


5968
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6006-6061
AACAGGAUACAGUCUCACC
1617


6006
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6007-6062
AAACAGGAUACAGUCUCAC
1618


6007
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6008-6063
CAAACAGGAUACAGUCUCA
1619


6008
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6009-6064
GCAAACAGGAUACAGUCUC
1620


6009
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6010-6065
AGCAAACAGGAUACAGUCU
1621


6010
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6011-6066
UAGCAAACAGGAUACAGUC
1622


6011
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6012-6067
AUAGCAAACAGGAUACAGU
1623


6012
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6013-6068
AAUAGCAAACAGGAUACAG
1624


6013
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6014-6069
CAAUAGCAAACAGGAUACA
1625


6014
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6015-6070
GCAAUAGCAAACAGGAUAC
1626


6015
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6017-6072
AAGCAAUAGCAAACAGGAU
1627


6017
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6119-6174
AUGAAAAGGGUUACGAGGC
1628


6119
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6628-6689
UGCUCAACAUGGCAAACUC
1629


6628
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6629-6690
CUGCUCAACAUGGCAAACU
1630


6629
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6631-6692
UCCUGCUCAACAUGGCAAA
1631


6631
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6672-6733
AUUACCGAAGAAAUCAUGG
1632


6672
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6731 (Hs)
ACAUUCACAGACAGAAAGC
1633


6731
anti-






sense






strand








MAPT-
19 mer
6732 (Hs)
GACAUUCACAGACAGAAAG
1634


6732
anti-






sense






strand








MAPT-
19 mer
6738-6799
UAUAUAGACAUUCACAGAC
1635


6738
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6739-6800
CUAUAUAGACAUUCACAGA
1636


6739
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6740-6801
ACUAUAUAGACAUUCACAG
1637


6740
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6741-6802
CACUAUAUAGACAUUCACA
1638


6741
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6742-6803
ACACUAUAUAGACAUUCAC
1639


6742
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6743-6804
UACACUAUAUAGACAUUCA
1640


6743
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6745-6806
AAUACACUAUAUAGACAUU
1641


6745
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6748-6809
CACAAUACACUAUAUAGAC
1642


6748
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6749-6810
ACACAAUACACUAUAUAGA
1643


6749
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6750-6811
CACACAAUACACUAUAUAG
1644


6750
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6751-6812
ACACACAAUACACUAUAUA
1645


6751
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6752-6813
AACACACAAUACACUAUAU
1646


6752
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6753-6814
AAACACACAAUACACUAUA
1647


6753
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6754-6815
AAAACACACAAUACACUAU
1648


6754
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6755-6816
UAAAACACACAAUACACUA
1649


6755
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6756-6817
UUAAAACACACAAUACACU
1650


6756
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6757-6818
GUUAAAACACACAAUACAC
1651


6757
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6758-6819
UGUUAAAACACACAAUACA
1652


6758
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6759-6820
UUGUUAAAACACACAAUAC
1653


6759
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6760-6821
UUUGUUAAAACACACAAUA
1654


6760
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6761-6822
AUUUGUUAAAACACACAAU
1655


6761
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6762-6823
CAUUUGUUAAAACACACAA
1656


6762
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6763-6824
UCAUUUGUUAAAACACACA
1657


6763
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6764-6825
AUCAUUUGUUAAAACACAC
1658


6764
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6765-6826
AAUCAUUUGUUAAAACACA
1659


6765
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6766-6827
AAAUCAUUUGUUAAAACAC
1660


6766
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6767-6828
UAAAUCAUUUGUUAAAACA
1661


6767
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6768-6829
GUAAAUCAUUUGUUAAAAC
1662


6768
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6769-6830
UGUAAAUCAUUUGUUAAAA
1663


6769
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6772-6833
CAGUGUAAAUCAUUUGUUA
1664


6772
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6773-6834
UCAGUGUAAAUCAUUUGUU
1665


6773
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6774-6835
GUCAGUGUAAAUCAUUUGU
1666


6774
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6775-6836
AGUCAGUGUAAAUCAUUUG
1667


6775
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6777-6838
ACAGUCAGUGUAAAUCAUU
1668


6777
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6778-6839
AACAGUCAGUGUAAAUCAU
1669


6778
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6779-6840
CAACAGUCAGUGUAAAUCA
1670


6779
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6780-6841
GCAACAGUCAGUGUAAAUC
1671


6780
anti-
(Hs-Mf)





sense






strand








MAPT-
19 mer
6781 (Hs)
AGCAACAGUCAGUGUAAAU
1672


6781
anti-






sense






strand








MAPT-
19 mer
6789 (Hs)
ACUUUUACAGCAACAGUCA
1673


6789
anti-






sense






strand








MAPT-
19 mer
6792 (Hs)
UUCACUUUUACAGCAACAG
1674


6792
anti-






sense






strand








MAPT-
19 mer
6793 (Hs)
AUUCACUUUUACAGCAACA
1675


6793
anti-






sense






strand








MAPT-
19 mer
6795 (Hs)
AAAUUCACUUUUACAGCAA
1676


6795
anti-






sense






strand








MAPT-
19 mer
6796 (Hs)
CAAAUUCACUUUUACAGCA
1677


6796
anti-






sense






strand








MAPT-
19 mer
6797 (Hs)
CCAAAUUCACUUUUACAGC
1678


6797
anti-






sense






strand








MAPT-
19 mer
6798 (Hs)
UCCAAAUUCACUUUUACAG
1679


6798
anti-






sense






strand








Stem
N/A
N/A
GCAGCCGAAAGGCUGC
1680


loop









MAPT-
20 mer
2357-2434
CAGGUGGAAGUAAAAUCUGA
1681


2357
sense
(Hs-Mf)





strand








MAPT-
20 mer
2357-2434
[ademCs-C16][mA][fG][mG][fU][mG][mG]
1682


2357
sense
(Hs-Mf)
[fA][mA][fG][mU][fA][fA][mA][fA][mU][fC]




strand

[mUs][mGs][mA]






Forward
3′ assay

GAAGATTGGGTCCCTGGA
1683


Primer









Reverse
3′ assay

TGTCTTGGCTTTGGCGTT
1684


Primer









Probe
3′ assay

6FAM- CGG AAG GTC /ZEN/ AGC TTG TGG
1685





GTT TCA






Forward
5′ assay

CACCACAGCCACCTTCTC
1686


Primer









Reverse
5′ assay

CTTCCATCACTTCGAACTCCT
1687


Primer









Probe
5′ assay

CGT CCT CGC /ZEN/ CTC TGT CGA CTA
1688








Claims
  • 1. An RNAi oligonucleotide for reducing MAPT gene expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand is 15 to 50 nucleotides in length, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a MAPT mRNA target sequence of any one of SEQ ID NOs: 912-1295, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.
  • 2.-3. (canceled)
  • 4. The RNAi oligonucleotide claim 1, wherein the antisense strand is 15 to 30 nucleotides in length, optionally wherein the antisense strand is 22 nucleotides in length, and wherein antisense strand and the sense strand form a duplex region of at least 19 nucleotides in length, optionally at least 20 nucleotides in length.
  • 5.-8. (canceled)
  • 9. The RNAi oligonucleotide of claim 1, wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length.
  • 10. The RNAi oligonucleotide of claim 9, wherein L is a triloop or a tetraloop, optionally wherein the tetraloop comprises the sequence 5′-GAAA-3′.
  • 11.-12. (canceled)
  • 13. The RNAi oligonucleotide of claim 9, wherein the S1 and S2 are 1-10 nucleotides in length and have the same length, optionally wherein the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1680).
  • 14.-16. (canceled)
  • 17. The RNAi oligonucleotide of claim 1, wherein the oligonucleotide comprises a blunt end, optionally the blunt end comprises the 3′ end of the sense strand, and optionally wherein the sense strand is 20-22 nucleotides.
  • 18.-20. (canceled)
  • 21. The RNAi oligonucleotide of claim 1, wherein the antisense strand comprises a 3′ overhang sequence of one or more nucleotides in length, optionally wherein the 3′ overhang sequence is 2 nucleotides in length, and optionally wherein the 3′ overhang is selected from AA, GG, AG, and GA.
  • 22.-26. (canceled)
  • 27. The RNAi oligonucleotide of claim 1, wherein the oligonucleotide comprises at least one modified nucleotide.
  • 28. The RNAi oligonucleotide of claim 27, wherein the modified nucleotide comprises a 2′-modification, optionally wherein the 2′-modification is a modification selected from 2′-fluoro and 2′-O-methyl.
  • 29.-35. (canceled)
  • 36. The RNAi oligonucleotide of claim 28, wherein: (i) the sense strand comprises 36 nucleotides with positions 1-36 from 5′ to 3′, wherein each of positions 3, 5, 8, 10, 12, 13, 15, and 17 comprise a 2′-fluoro modification, the antisense strand comprises 22 nucleotides with positions 1-22 from 5′ to 3′, and wherein each of positions 2, 3, 4, 5, 7, 10 14, 16, and 19 comprise a 2′-fluoro modification, and the remaining nucleotides of the sense strand and the antisense strand comprise a 2′-O-methyl modification; or(ii) the sense strand comprises 20 nucleotides with positions 1-20 from 5′ to 3′, wherein each of positions 3, 5, 8, 10, 12, 13, 15, and 17 comprise a 2′-fluoro modification, and the remaining nucleotides comprise a 2′-O-methyl modification, the antisense strand comprises 22 nucleotides with positions 1-22 from 5′ to 3′, and wherein each of positions 2, 3, 4, 5, 7, 10 14, 16, and 19 comprise a 2′-fluoro modification, and the remaining nucleotides of the sense strand and the antisense strand comprise a 2′-O-methyl modification.
  • 37.-39. (canceled)
  • 40. The RNAi oligonucleotide of claim 1, wherein the oligonucleotide comprises at least one modified internucleotide linkage, optionally wherein the at least one modified internucleotide linkage is a phosphorothioate linkage.
  • 41. (canceled)
  • 42. The RNAi oligonucleotide of claim 40, wherein the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5′ to 3′: optionally wherein the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, and wherein positions are numbered 1-22 from 5′ to 3′.
  • 43. (canceled)
  • 44. The RNAi oligonucleotide of claim 40, wherein the sense strand comprises a phosphorothioate linkage between positions 1 and 2, and wherein positions are numbered 1-2 from 5′ to 3′, optionally wherein the sense strand is 20 nucleotides in length, wherein the sense strand comprises a phosphorothioate linkage between positions between positions 1 and 2, between positions 18 and 19 and between positions 19 and 20, and wherein positions are numbered 1-20 from 5′ to 3′.
  • 45. (canceled)
  • 46. The RNAi oligonucleotide of claim 1, wherein the antisense strand comprises a phosphate analog at 4′-carbon of the sugar of the 5′-nucleotide, optionally wherein the phosphate analog is oxymethyl phosphonate, vinyl phosphonate or malonyl phosphonate, further optionally wherein the phosphate analog is a 4′-phosphate analog comprising 4′-oxymethylphosphonate.
  • 47. (canceled)
  • 48. The RNAi oligonucleotide of claim 1, wherein at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands.
  • 49.-52. (canceled)
  • 53. The RNAi oligonucleotide of claim 48, wherein each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety, optionally wherein the GalNac moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety, or a tetravalent GalNAc moiety.
  • 54.-55. (canceled)
  • 56. The RNAi oligonucleotide of claim 48, wherein the one or more targeting ligands is a lipid moiety, optionally wherein the lipid moiety is conjugated to the 2′ carbon of the ribose ring of the 5′ terminal nucleotide of the sense strand, optionally wherein the lipid moiety is a hydrocarbon chain, and the hydrocarbon chain is a C8-C30 hydrocarbon chain.
  • 57.-64. (canceled)
  • 65. The RNAi oligonucleotide of claim 1, wherein the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 769-803 and 1681; or SEQ ID NOs: 1130, 1095, 1096, 1119, 1120, and 1124.
  • 66. The RNAi oligonucleotide of claim 65, wherein the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 804-838.
  • 67. The RNAi oligonucleotide of claim 1, wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of: a) SEQ ID NOs: 769 and 804, respectively;b) SEQ ID NOs: 770 and 805, respectively;c) SEQ ID NOs: 771 and 806, respectively;d) SEQ ID NOs: 772 and 807, respectively;e) SEQ ID NOs: 773 and 808, respectively;f) SEQ ID NOs: 774 and 809, respectively;g) SEQ ID NOs: 775 and 810, respectively;h) SEQ ID NOs: 776 and 811, respectively;i) SEQ ID NOs: 777 and 812, respectively;j) SEQ ID NOs: 778 and 813, respectively;k) SEQ ID NOs: 779 and 814, respectively;l) SEQ ID NOs: 780 and 815, respectively;m) SEQ ID NOs: 781 and 816, respectively;n) SEQ ID NOs: 782 and 817, respectively;o) SEQ ID NOs: 783 and 818, respectively;p) SEQ ID NOs: 784 and 819, respectively;q) SEQ ID NOs: 785 and 820, respectively;r) SEQ ID NOs: 786 and 821, respectively;s) SEQ ID NOs: 787 and 822, respectively;t) SEQ ID NOs: 788 and 823, respectively;u) SEQ ID NOs: 789 and 824, respectively;v) SEQ ID NOs: 790 and 825, respectively;w) SEQ ID NOs: 791 and 826, respectively;x) SEQ ID NOs: 792 and 827, respectively;y) SEQ ID NOs: 793 and 828, respectively;z) SEQ ID NOs: 794 and 829, respectively;aa) SEQ ID NOs: 795 and 830, respectively;bb) SEQ ID NOs: 796 and 831, respectively;cc) SEQ ID NOs: 797 and 832, respectively;dd) SEQ ID NOs: 798 and 833, respectively;ee) SEQ ID NOs: 799 and 834, respectively;ff) SEQ ID NOs: 800 and 835, respectively;gg) SEQ ID NOs: 801 and 836, respectively;hh) SEQ ID NOs: 802 and 837, respectively;ii) SEQ ID NOs: 803 and 838, respectively; andjj) SEQ ID NOs: 1681 and 815, respectively.
  • 68.-83. (canceled)
  • 84. The RNAi oligonucleotide of claim 1, wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of: a) SEQ ID NOs: 839 and 874, respectively;b) SEQ ID NOs: 840 and 875, respectively;c) SEQ ID NOs: 841 and 876, respectively;d) SEQ ID NOs: 842 and 877, respectively;e) SEQ ID NOs: 843 and 878, respectively;f) SEQ ID NOs: 844 and 879, respectively;g) SEQ ID NOs: 845 and 880, respectively;h) SEQ ID NOs: 846 and 881, respectively;i) SEQ ID NOs: 847 and 882, respectively;j) SEQ ID NOs: 848 and 883, respectively;k) SEQ ID NOs: 849 and 884, respectively;l) SEQ ID NOs: 850 and 885, respectively;m) SEQ ID NOs: 851 and 886, respectively;n) SEQ ID NOs: 852 and 887, respectively;o) SEQ ID NOs: 853 and 888, respectively;p) SEQ ID NOs: 854 and 889, respectively;q) SEQ ID NOs: 855 and 890, respectively;r) SEQ ID NOs: 856 and 891, respectively;s) SEQ ID NOs: 857 and 892, respectively;t) SEQ ID NOs: 858 and 893, respectively;u) SEQ ID NOs: 859 and 894, respectively;v) SEQ ID NOs: 860 and 895, respectively;w) SEQ ID NOs: 861 and 896, respectively;x) SEQ ID NOs: 862 and 897, respectively;y) SEQ ID NOs: 863 and 898, respectively;z) SEQ ID NOs: 864 and 899, respectively;aa) SEQ ID NOs: 865 and 900, respectively;bb) SEQ ID NOs: 866 and 901, respectively;cc) SEQ ID NOs: 867 and 902, respectively;dd) SEQ ID NOs: 868 and 903, respectively;ee) SEQ ID NOs: 869 and 904, respectively;ff) SEQ ID NOs: 870 and 905, respectively;gg) SEQ ID NOs: 871 and 906, respectively;hh) SEQ ID NOs: 872 and 907, respectively;ii) SEQ ID NOs: 873 and 908, respectively; andjj) SEQ ID NOs: 1682 and 885, respectively.
  • 85.-93. (canceled)
  • 94. The RNAi oligonucleotide of claim 1, wherein: (i) the sense strand comprises the sequence and all of the modifications of 5′-[mAs][mG][fA][mG][fJ][mG][mU][fG][mG][fA][mA][fA][fA][mA][fA][mA][fA][mA][mG][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 841), wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fCs][fU][fU][fU][mU][fU][mU][mU][fU][mU][mC][mC][fA][mC][fA][mC][mU][fC][mUs][mGs][mG]-3′ (SEQ ID NO: 876);(ii) the sense strand comprises the sequence and all of the modifications of 5′-[mCs][mA][fG][mG][fU][mG][mG][fA][mA][fG][mU][fA][fA][mA][fA][mU][fC][mU][mG][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 850), wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fCs][fA][fG][fA][mU][fU][mU][mU][fA][mC][mU][mU][fC][mC][fA][mC][mC][fU][mGs][mGs][mG]-3′ (SEQ ID NO: 885);(iii) wherein the sense strand comprises the sequence and all of the modifications of 5′-[mAs][mG][fG][mU][fG][mG][mA][fA][mG][fU][mA][fA][fA][mA][fU][mC][fU][mG][mA][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 851), wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fUs][fC][fA][fG][mA][fU][mU][mU][fU][mA][mC][mU][fU][mC][fC][mA][mC][fC][mUs][mGs][mG]-3′ (SEQ ID NO: 886);(iv) the sense strand comprises the sequence and all of the modifications of 5′-[mAs][mG][fG][mA][fA][mA][mU][fA][mA][fA][mA][fA][fG][mA][fU][mU][fG][mA][mA][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 868), wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fUs][fU][fC][fA][mA][fU][mC][mU][fU][mU][mU][mU][fA][mU][fU][mU][mC][fC][mUs][mGs][mG]-3′ (SEQ ID NO: 903);(v) the sense strand comprises the sequence and all of the modifications of 5′-[mGs][mG][fA][mA][fA][mU][mA][fA][mA][fA][mA][fG][fA][mU][fU][mG][fA][mA][mA][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 869), wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fUs][fU][fU][fC][mA][fA][mU][mC][fU][mU][mU][mU][fU][mA][fU][mU][mU][fC][mCs][mGs][mG]-3′ (SEQ ID NO: 904);(vi) the sense strand comprises the sequence and all of the modifications of 5′-[mAs][mU][fA][mA][fA][mA][mA][fG][mA][fU][mU][fG][fA][mA][fA][mC][fC][mC[mA][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC]][mU][mG][mC]-3′ (SEQ ID NO: 873), wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fUs][fG][fG][fG][mU][fU][mU][mC][fA][mA][mU][mC][fU][mU][fU][mU][mU][fA][mUs][mGs][mG]-3′ (SEQ ID NO: 908); or(vii) the sense strand comprises the sequence and all of the modifications of 5′-[ademCs-C16][mA][fG][mG][fU][mG][mG][fA][mA][fG][mU][fA][fA][mA][fA][mU][fC][mUs][mGs][mA]-3′ (SEQ ID NO: 1682), wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs][fCs][fA][fG][fA][mU][fU][mU][mU][fA][mC][mU][mU][fC][mC][fA][mC][mC][fU][mGs][mGs][mG]-3′ (SEQ ID NO: 885), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate; [ademA-GalNAc]=
  • 95.-100. (canceled)
  • 101. A pharmaceutical composition comprising the RNAi oligonucleotide of claim 1, and a pharmaceutically acceptable carrier, delivery agent or excipient.
  • 102. A method for treating a subject having a disease, disorder, or condition associated with MAPT gene expression, the method comprising administering to the subject a therapeutically effective amount of the RNAi oligonucleotide of claim 1, thereby treating the subject.
  • 103. (canceled)
  • 104. A method for reducing MAPT gene expression in a cell, a population of cells, or a subject, the method comprising the step of: i. contacting the cell or the population of cells with the RNAi oligonucleotide of claim 1; orii. administering to the subject the RNAi oligonucleotide of claim 1.
CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) from U.S. Provisional Application No. 63/364,609, filed May 12, 2022, which is incorporated herein by reference in its entirety.

Provisional Applications (1)
Number Date Country
63364609 May 2022 US