Xanthine dehydrogenase (XDH) iRNA compositions and methods of use thereof

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of xanthine dehydrogenase (XDH) in a cell,

wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand comprises at least 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of nucleotides 2691-2722 of SEQ ID NO: 1, and the antisense strand comprises a nucleotide sequence selected from the group consisting of

5′-AAAUACTCUGAGAGAGAUCCUGG-3′(SEQ ID NO:485);

5′-AUAATACUCUGAGAGAGAUCCUG-3′(SEQ ID NO:486);

5′-AAUAAUACUCUGAGAGAGAUCCU-3′(SEQ ID NO:487);

5′-ACAUAAUACUCUGAGAGAGAUCC-3′(SEQ ID NO:488);

5′-ACCAUAAUACUCUGAGAGAGAUC-3′(SEQ ID NO:489);

5′-AUCCAUAAUACUCUGAGAGAGAU-3′(SEQ ID NO:490);

5′-AUUCCAUAAUACUCUGAGAGAGA-3′(SEQ ID NO:491);

5′-AGUUCCAUAAUACUCUGAGAGAG-3′(SEQ ID NO:492);

5′-ACGUUCCAUAAUACUCUGAGAGA-3′(SEQ ID NO:493);

5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494); and

5′-AGCUCGUUCCAUAAUACUCUGAG-3′(SEQ ID NO:495),

wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides,

wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus, and

wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus.

2. The dsRNA agent of claim 1 , wherein at least one of the modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxythimidine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, a nucleotide comprising a 5′-phosphate mimic, a nucleotide comprising a 2′-phosphate, a thermally destabilizing nucleotide, a glycol modified nucleotide (GNA), and a 2-O—(N-methylacetamide) modified nucleotide; and combinations thereof.

3. The dsRNA agent of claim 1 , wherein the sense strand and the antisense strand are each independently 19-25 nucleotides in length.

4. The dsRNA agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.

5. The dsRNA agent of claim 1 , further comprising a ligand.

6. The dsRNA agent of claim 5 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.

7. The dsRNA agent of claim 6 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

8. The dsRNA agent of claim 7 , wherein the ligand is

9. The dsRNA agent of claim 8 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic

and, wherein X is O or S.

10. The dsRNA agent of claim 1 , wherein the sense strand and the antisense strand comprise nucleotide sequences selected from the group consisting of

5′-AGGAUCUCUCUCAGAGUAUUU-3′(SEQ ID NO:126) and 5′-AAAUACTCUGAGAGAGAUCCUGG-3′(SEQ ID NO:485);

5′-GGAUCUCUCUCAGAGUAUUAU-3′(SEQ ID NO:127) and 5′-AUAATACUCUGAGAGAGAUCCUG-3′(SEQ ID NO:486);

5′-GAUCUCUCUCAGAGUAUUAUU-3′(SEQ ID NO:128) and 5′-AAUAAUACUCUGAGAGAGAUCCU-3′(SEQ ID NO:487);

5′-AUCUCUCUCAGAGUAUUAUGU-3′(SEQ ID NO:129) and 5′-ACAUAAUACUCUGAGAGAGAUCC-3′(SEQ ID NO:488);

5′-UCUCUCUCAGAGUAUUAUGGU-3′(SEQ ID NO:130) and 5′-ACCAUAAUACUCUGAGAGAGAUC-3′(SEQ ID NO:489);

5′-CUCUCUCAGAGUAUUAUGGAU-3′(SEQ ID NO:131) and 5′-AUCCAUAAUACUCUGAGAGAGAU-3′(SEQ ID NO:490);

5′-UCUCUCAGAGUAUUAUGGAAU-3′(SEQ ID NO:132) and 5′-AUUCCAUAAUACUCUGAGAGAGA-3′(SEQ ID NO:491);

5′-CUCUCAGAGUAUUAUGGAACU-3′(SEQ ID NO:133) and 5′-AGUUCCAUAAUACUCUGAGAGAG-3′(SEQ ID NO:492);

5′-UCUCAGAGUAUUAUGGAACGU-3′(SEQ ID NO:134) and 5′-ACGUUCCAUAAUACUCUGAGAGA-3′(SEQ ID NO:493);

5′-UCAGAGUAUUAUGGAACGAGU-3′(SEQ ID NO:135) and 5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494); and

5′-CAGAGUAUUAUGGAACGAGCU-3′(SEQ ID NO:136) and 5′-AGCUCGUUCCAUAAUACUCUGAG-3′(SEQ ID NO:495).

11. The dsRNA agent of claim 10 , wherein the sense strand and the antisense strand comprise nucleotide sequences selected from the group consisting of

5′-asgsgaucUfcUfCfUfcagaguauuu-3′(SEQ ID NO:844) and 5′-asAfsaudAc(Tgn)cugagaGfaGfauccusgsg-3′(SEQ ID NO:1203);

5′-gsgsaucuCfuCfUfCfagaguauuau-3′(SEQ ID NO:845) and 5′-asUfsaadTa(C2p)ucugagAfgAfgauccsusg-3 ‘(SEQ ID NO:1204);

5’-gsasucucUfcUfCfAfgaguauuauu-3′(SEQ ID NO:846) and 5′-asAfsuaaUfacucugaGfaGfagaucscsu-3 ‘(SEQ ID NO:1205);

5’-asuscucuCfuCfAfGfaguauuaugu-3′(SEQ ID NO:847) and 5′-asCfsauaAfuacucugAfgAfgagauscsc-3′(SEQ ID NO:1206);

5′-uscsucucUfcAfGfAfguauuauggu-3′(SEQ ID NO:848) and 5′-asCfscauAfauacucuGfaGfagagasusc-3 ‘(SEQ ID NO:1207);

5’-csuscucuCfaGfAfGfuauuauggau-3′(SEQ ID NO:849) and 5′-asUfsccaUfaauacucUfgAfgagagsasu-3′(SEQ ID NO:1208);

5′-uscsucucAfgAfGfUfauuauggaau-3′(SEQ ID NO:850) and 5′-asUfsuccAfuaauacuCfuGfagagasgsa-3′(SEQ ID NO:1209);

5′-csuscucaGfaGfUfAfuuauggaacu-3′(SEQ ID NO:851) and 5′-asGfsuudCc(Agn)uaauacUfcUfgagagsasg-3′(SEQ ID NO:1210);

5′-uscsucagAfgUfAfUfuauggaacgu-3′(SEQ ID NO:852); and 5′-asCfsguuCfcauaauaCfuCfugagasgsa-3′(SEQ ID NO:1211);

5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212); and

5′-csasgaguAfuUfAfUfggaacgagcu-3′(SEQ ID NO:854) and 5′-asGfscucGfuuccauaAfuAfcucugsasg-3′(SEQ ID NO:1213);

wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; s is a phosphorothioate linkage; dA is 2′-deoxyadenosine-3′-phosphate; (Tgn) is a thymidine-glycol nucleic acid (GNA)S-Isomer; dT is 2′-deoxythimidine-3′-phosphate; (C2p) is cytidine-2′-phosphate; and (Agn) is an adenosine-glycol nucleic acid (GNA)S-Isomer.

12. A pharmaceutical composition for inhibiting expression of a gene encoding xanthine dehydrogenase (XDH) comprising the dsRNA agent of claim 1 .

13. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of xanthine dehydrogenase (XDH) in a cell,

wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand comprises at least 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of nucleotides 2701-2721 of SEQ ID NO: 1, and the antisense strand comprises at least 19 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2,

wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides,

wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus, and

wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus.

14. The dsRNA agent of claim 13 , wherein at least one of the modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxythimidine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, a nucleotide comprising a 5′-phosphate mimic, a nucleotide comprising a 2′-phosphate, a thermally destabilizing nucleotide, a glycol modified nucleotide (GNA), and a 2-O—(N-methylacetamide) modified nucleotide; and combinations thereof.

15. The dsRNA agent of claim 13 , wherein the sense strand and the antisense strand are each independently 19-25 nucleotides in length.

16. The dsRNA agent of claim 15 , further comprising a ligand.

17. The dsRNA agent of claim 16 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.

18. The dsRNA agent of claim 17 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.

19. The dsRNA agent of claim 18 , wherein the ligand is

20. The dsRNA agent of claim 19 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic

and, wherein X is O or S.

21. The dsRNA agent of claim 13 , wherein the antisense strand comprises the nucleotide sequence 5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494).

22. The dsRNA agent of claim 21 , wherein the sense strand comprises the nucleotide sequence 5′-UCAGAGUAUUAUGGAACGAGU-3′(SEQ ID NO:135) and the antisense strand comprise the nucleotide sequence 5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494).

23. The dsRNA agent of claim 22 , wherein the sense strand comprises the nucleotide sequence 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and the antisense strand comprises the nucleotide sequence 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212),

wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; and s is a phosphorothioate linkage.

24. The dsRNA agent of claim 23 , further comprising a ligand.

25. The dsRNA agent of claim 24 , wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic

wherein X is O.

26. A pharmaceutical composition for inhibiting expression of a gene encoding xanthine dehydrogenase (XDH) comprising the dsRNA agent of claim 13 .

27. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of xanthine dehydrogenase (XDH) in a cell,

wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand comprises the nucleotide sequence 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and the antisense strand comprises the nucleotide sequence 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212),

wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; and s is a phosphorothioate linkage; and

wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic

wherein X is O.

28. The dsRNA agent of claim 27 , wherein the sense strand consists of the nucleotide sequence 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and the antisense strand consists of the nucleotide sequence 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212).

29. A pharmaceutical composition for inhibiting expression of a gene encoding xanthine dehydrogenase (XDH) comprising the dsRNA agent of claim 27 .