Angiopoietin-like 3 (ANGPTL3) iRNA compositions and methods of use thereof

1. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), wherein said dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, the antisense strand comprising a region of complementarity to an mRNA encoding ANGPTL3 which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the complement of nucleotides 1051-1098 of SEQ ID NO:1.

2. The dsRNA agent of claim 1 , wherein said dsRNA agent comprises at least one modified nucleotide.

3. The dsRNA agent of claim 2 , wherein at least one of said modified nucleotides is selected from the group consisting of a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group.

4. The dsRNA agent of claim 1 , wherein the region of complementarity is at least 17 nucleotides in length.

5. The dsRNA agent of claim 1 , wherein each strand is no more than 30 nucleotides in length.

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

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

8. A cell containing the dsRNA agent of claim 1 .

9. A pharmaceutical composition for inhibiting expression of an ANGPTL3 gene comprising the dsRNA agent of claim 1 .

10. A method of inhibiting ANGPTL3 expression in a cell, the method comprising:

(a) contacting the cell with the dsRNA agent of claim 1 ; and

(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of an ANGPTL3gene, thereby inhibiting expression of the ANGPTL3 gene in the cell.

11. The method of claim 10 , wherein said cell is within a subject.

12. A method of treating a subject having a disorder that would benefit from reduction in ANGPTL3 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby treating said subject.

13. The method of claim 12 , wherein the disorder is a disorder of lipid metabolism.

14. A method of inhibiting the expression of ANGPTL3 in a subject, the method comprising administering to said subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby inhibiting the expression of ANGPTL3 in said subject.

15. The dsRNA agent of claim 1 , wherein the double-stranded region is 17-25 nucleotide pairs in length.

16. The dsRNA agent of claim 1 , wherein the double-stranded region is 21-23 nucleotide pairs in length.

17. The dsRNA agent of claim 1 , wherein each strand is 19-30 nucleotides in length.

18. The dsRNA agent of claim 1 , wherein the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides.

19. The dsRNA agent of claim 1 , wherein the region of complementarity is between 19 and 21 nucleotides in length.

20. The dsRNA agent of claim 3 , wherein said modified nucleotide is a 2′-O-methyl or a 2′-fluoro modified nucleotide.

21. The dsRNA agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 2 nucleotides.

22. The dsRNA agent of claim 7 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.

23. The dsRNA agent of claim 22 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

24. The dsRNA agent of claim 22 , wherein the ligand is

25. The dsRNA agent of claim 1 , wherein said dsRNA agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

26. The dsRNA agent of claim 25 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of one strand.

27. The dsRNA agent of claim 1 , wherein the region of complementarity comprises any one of the antisense nucleotide sequences selected from the group consisting of

5′-UUGUCUUUCCAGUCUUCCAACUC-3′ (SEQ ID NO:562);

5′-AAUAUAAUGUUUGUUGUCUUUCC-3′ (SEQ ID NO:449);

5′-UUCAAUAUAAUGUUUGUUGUCUU-3′ (SEQ ID NO:498);

5′-AUUCAAUAUAAUGUUUGUUGUCU-3′ (SEQ ID NO:480);

5′-UAUUCAAUAUAAUGUUUGUUGUC-3′ (SEQ ID NO:575);

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

5′-AAUAUUCAAUAUAAUGUUUGUUG-3′ (SEQ ID NO:495);

5′-AAGAAUAUUCAAUAUAAUGUUUG-3′ (SEQ ID NO:582);

5′-AAAGAAUAUUCAAUAUAAUGUUU-3′ (SEQ ID NO:533); and

5′-AAAAGAAUAUUCAAUAUAAUGUU-3′ (SEQ ID NO:459).

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

5′-GUUGGAAGACUGGAAAGACAA-3′ (SEQ ID NO:377) and

5′-UUGUCUUUCCAGUCUUCCAACUC-3′ (SEQ ID NO:562);

5′-AAAGACAACAAACAUUAUAUU-3′ (SEQ ID NO:264) and

5′-AAUAUAAUGUUUGUUGUCUUUCC-3′ (SEQ ID NO:449);

5′-GACAACAAACAUUAUAUUGAA-3′ (SEQ ID NO:313) and

5′-UUCAAUAUAAUGUUUGUUGUCUU-3′ (SEQ ID NO:498);

5′-ACAACAAACAUUAUAUUGAAU-3′ (SEQ ID NO:295) and

5′-AUUCAAUAUAAUGUUUGUUGUCU-3′ (SEQ ID NO:480);

5′-CAACAAACAUUAUAUUGAAUA-3′ (SEQ ID NO:390) and

5′-UAUUCAAUAUAAUGUUUGUUGUC-3′ (SEQ ID NO:575);

5′-AACAAACAUUAUAUUGAAUA-3′ (SEQ ID NO:301) and

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

5′-ACAAACAUUAUAUUGAAUAUU-3′ (SEQ ID NO:310) and

5′-AAUAUUCAAUAUAAUGUUUGUUG-3′ (SEQ ID NO:495);

5′-AACAUUAUAUUGAAUAUUCUU-3′ (SEQ ID NO:397) and

5′-AAGAAUAUUCAAUAUAAUGUUUG-3′ (SEQ ID NO:582);

5′-ACAUUAUAUUGAAUAUUCUUU-3′ (SEQ ID NO:348) and

5′-AAAGAAUAUUCAAUAUAAUGUUU-3′ (SEQ ID NO:533); and

5′-CAUUAUAUUGAAUAUUCUUUU-3′ (SEQ ID NO:274) and

5′-AAAAGAAUAUUCAAUAUAAUGUU-3′ (SEQ ID NO:459).

29. The dsRNA agent of claim 28 , wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of

5′-GfuUfgGfaAfgAfCfUfgGfaAfaGfaCfaAf (SEQ ID NO: 747) and

5′-uUfgUfcUfuUfcCfaguCfuUfcCfaAfcsUfsc (SEQ ID NO:932);

5′-AfaAfgAfcAfaCfAfAfaCfaUfuAfuAfuUf (SEQ ID NO:634) and

5′-aAfuAfuAfaUfgUfuugUfuGfuCfuUfusCfsc (SEQ ID NO:819);

5′-GfaCfaAfcAfaAfCfAfuUfaUfaUfuGfaAf (SEQ ID NO:683) and

5′-uUfcAfaUfaUfaAfuguUfuGfuUfgUfcsUfsu (SEQ ID NO:868);

5′-AfcAfaCfaAfaCfAfUfuAfuAfuUfgAfaUf (SEQ ID NO:665) and

5′-aUfuCfaAfuAfuAfaugUfuUfgUfuGfusCfsu (SEQ ID NO:850);

5′-CfaAfcAfaAfcAfUfUfaUfaUfuGfaAfuAf (SEQ ID NO:760) and

5′-uAfuUfcAfaUfaUfaauGfuUfuGfuUfgsUfsc (SEQ ID NO:945);

5′-AfaCfaAfaCfaUfUfAfuAfuUfgAfaUfaUf (SEQ ID NO:671) and

5′-aUfaUfuCfaAfuAfuaaUfgUfuUfgUfusGfsu (SEQ ID NO:856);

5′-AfcAfaAfcAfuUfAfUfaUfuGfaAfuAfuUf (SEQ ID NO:680) and

5′-aAfuAfuUfcAfaUfauaAfuGfuUfuGfusUfsg (SEQ ID NO:865);

5′-AfaCfaUfuAfuAfUfUfgAfaUfaUfuCfuUf (SEQ ID NO:767) and

5′-aAfgAfaUfaUfuCfaauAfuAfaUfgUfusUfsg (SEQ ID NO:952);

5′-AfcAfuUfaUfaUfUfGfaAfuAfuUfcUfuUf (SEQ ID NO:718) and

5′-aAfaGfaAfuAfuUfcaaUfaUfaAfuGfusUfsu (SEQ ID NO:903); and

5′-CfaUfuAfuAfuUfGfAfaUfaUfuCfuUfuUf (SEQ ID NO:644) and

5′-aAfaAfgAfaUfaUfucaAfuAfuAfaUfgsUfsu (SEQ ID NO:829),

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

30. The pharmaceutical composition of claim 9 , further comprising a lipid formulation.

31. The pharmaceutical composition of claim 9 , wherein the dsRNA agent is present in a buffered solution.