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

1. A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5′- AAUAAAAAGAAGGAGCUUAAUUG - 3′ (SEQ ID NO:468).

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

3. The dsRNA 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 2′-fluoro 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 of claim 1 , wherein the region of complementarity is at least 17 nucleotides in length.

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

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

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

8. A cell containing the dsRNA of claim 1 .

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

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

(a) contacting the cell with the dsRNA 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 ANGPTL3 gene, 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 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 of claim 1 , thereby inhibiting the expression of ANGPTL3 in said subject.

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

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

17. The dsRNA of claim 16 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

18. The dsRNA of claim 17 , wherein the ligand is

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

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

21. The dsRNA of claim 20 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of one strand.

22. The dsRNA of claim 20 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 5′-terminus of one strand.

23. The dsRNA of claim 20 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the both the 5′- and 3′-terminus of one strand.

24. The dsRNA of claim 1 , wherein the region of complementarity consists of one of the antisense nucleotide sequences selected from the group consisting of

(SEQ ID NO: 468)

5′-AAUAAAAAGAAGGAGCUUAAUUG-3′;

(SEQ ID NO: 450

5′-AAAAAGAAGGAGCUUAAUUGUGA-3′;

(SEQ ID NO: 452) 

5′-AAAGAAGGAGCUUAAUUGUGAAC-3′;

(SEQ ID NO: 455) 

5′-UAAAAAGAAGGAGCUUAAUUGUG-3′;

(SEQ ID NO: 458) 

5′-AUAAAAAGAAGGAGCUUAAUUGU-3′;

and

(SEQ ID NO: 125) 

5′-AAGAAGGAGCUUAAUUGUG-3′.

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

(SEQ ID NO: 283)

5′-AUUAAGCUCCUUCUUUUUAUU-3′

and

(SEQ ID NO: 468) 

5′-AAUAAAAAGAAGGAGCUUAAUUG-3′;

(SEQ ID NO: 265)

5′-ACAAUUAAGCUCCUUCUUUUU-3′

and

(SEQ ID NO: 450 

5′-AAAAAGAAGGAGCUUAAUUGUGA-3′;

(SEQ ID NO: 267) 

5′-UCACAAUUAAGCUCCUUCUUU-3′

and

(SEQ ID NO: 452)

5′-AAAGAAGGAGCUUAAUUGUGAAC-3′;

(SEQ ID NO: 270) 

5′-CAAUUAAGCUCCUUCUUUUUA-3′

and

(SEQ ID NO: 455)

5′-UAAAAAGAAGGAGCUUAAUUGUG-3′;

(SEQ ID NO: 273) 

5′-AAUUAAGCUCCUUCUUUUUAU-3′

and

(SEQ ID NO: 458)

5′-AUAAAAAGAAGGAGCUUAAUUGU-3′;

and

(SEQ ID NO: 63) 

5′-CACAAUUAAGCUCCUUCUU-3′

and

(SEQ ID NO: 125)

5′-AAGAAGGAGCUUAAUUGUG-3′.

26. The dsRNA of claim 25 , wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of

(SEQ ID NO: 653)

5′-AfuUfaAfgCfuCfCfUfuCfuUfuUfuAfuUf-3′

and

(SEQ ID NO: 838)

5′-aAfuAfaAfaAfgAfaggAfgCfuUfaAfusUfsg-3′;

(SEQ ID NO: 635) 

5′-AfcAfaUfuAfaGfCfUfcCfuUfcUfuUfuUf-3′

and

(SEQ ID NO: 820) 

5′-aAfaAfaGfaAfgGfagcUfuAfaUfuGfusGfsa-3′;

(SEQ ID NO: 637) 

5′-UfcAfcAfaUfuAfAfGfcUfcCfuUfcUfuUf-3′

and

(SEQ ID NO: 822)

5′-aAfaGfaAfgGfaGfcuuAfaUfuGfuGfasAfsc-3′;

(SEQ ID NO: 640) 

5′-AfcCfcAfgCfaAfCfUfcUfcAfaGfuUfuUf-3′

and

(SEQ ID NO: 825)

5′-aAfaAfcUfuGfaGfaguUfgCfuGfgGfusCfsu-3′;

(SEQ ID NO: 643) 

5′-AfaUfuAfaGfcUfCfCfuUfcUfuUfuUfaUf-3′

and

(SEQ ID NO: 828) 

5′-aUfaAfaAfaGfaAfggaGfcUfuAfaUfusGfsu-3′;

and

(SEQ ID NO: 187)

5′-cAcAAuuAAGcuccuucuudTsdT-3′

and

(SEQ ID NO: 249)

5′-AAGAAGGAGCUuAAUUGUGdTsdT-3′,

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

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

28. The method of claim 12 , wherein the subject is a human.

29. The method of claim 13 , wherein the disorder of lipid metabolism is hyperlipidemia or hypertriglyceridemia.

30. The method of claim 14 , wherein the subject is a human.

31. The method of claim 30 , wherein the human subject suffers from a disorder of lipid metabolism.

32. The method of claim 31 , wherein the disorder of lipid metabolism is hyperlipidemia or hypertriglyceridemia.

33. The method of claim 12 or 14 , wherein the administration of the dsRNA to the subject causes a decrease in one or more serum lipid and/or a decrease in ANGPTL3 protein accumulation.

34. The method of claim 12 or 14 , wherein the dsRNA is administered to the subject at a dose of about 0.01 mg/kg to about 10 mg/kg or about 5 mg/kg to about 50 mg/kg.