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), comprising a sense strand and an antisense strand,

wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from the nucleotide sequence of 5′-AAAGACUGAUCAAAUAUGUUGAG-3′(nucleotides 274-296 of SEQ ID NO:1),

wherein each strand is independently 17-25 nucleotides in length,

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

wherein the antisense strand comprises at least seven 2′-fluoro modified nucleotides, and

wherein a ligand comprising an N-acetylgalactosamine (GalNAc) derivative is conjugated to at least one strand of the dsRNA agent.

2. The dsRNA agent of claim 1 , wherein at least one of the seven 2′-fluoro modified nucleotides is a 2′-fluoro modified guanosine nucleotide.

3. The dsRNA agent of claim 1 , wherein at least four of the seven 2′-fluoro modified nucleotides are 2-fluoro modified uridine nucleotides.

4. The dsRNA agent of claim 1 , wherein the antisense strand comprises at least ten 2′-O-methyl modified nucleotides.

5. The dsRNA gent of claim 1 , wherein the sense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence 5′-AACAUAUUUGAUCAGUCUUUU-3′ (SEQ ID NO: 303).

6. The dsRNA agent of claim 5 , wherein the sense strand comprises at least one 2′-fluoro modified nucleotide.

7. The dsRNA agent of claim 6 , wherein the at least one 2′-fluoro modified nucleotide is a 2-fluoro modified uridine nucleotide.

8. The dsRNA agent of claim 1 , wherein the sense strand comprises at least six 2′-O-methyl modified nucleotides.

9. The dsRNA agent of claim 8 , wherein at least three of the six 2′-O-methyl modified nucleotides are 2′-O-methyl modified adenosine nucleotides.

10. The dsRNA agent of claim 8 , wherein at least two of the six 2′-O-methyl modified nucleotides are 2′-O-methyl modified uridine nucleotides.

11. The dsRNA agent of claim 10 , wherein one of the 2′-O-methyl modified uridine nucleotides is at position 12 of the sense strand, counting from the 5′-end of the sense strand.

12. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), comprising a sense strand and an antisense strand,

wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from the nucleotide sequence of 5′-AAGACUGAUCAAAUAUGUUGAGU-3′(nucleotides 273-295 of SEQ ID NO:1),

wherein each strand is independently 17-25 nucleotides in length, wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides,

wherein the antisense strand comprises at least nine 2′-fluoro modified nucleotides, and

wherein a ligand comprising an N-acetylgalactosamine (GalNAc) derivative is conjugated to at least one strand of the dsRNA agent.

13. The dsRNA agent of claim 12 , wherein the sense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence 5′-UCAACAUAUUUGAUCAGUCUU-3′ (SEQ ID NO: 358).

14. The dsRNA agent of claim 13 , wherein the sense strand comprises at least seven 2′-O-methyl modified nucleotides.

15. The dsRNA agent of claim 14 , wherein the seven 2′-O-methyl modified nucleotides are at positions 2, 4, 6, 12, 14, 16, and 18 of the sense strand, counting from the 5′-end of the sense strand.

16. The dsRNA agent of claim 15 , wherein the 2′-O-methyl modified nucleotide at positions 2 of the sense strand, counting from the 5′-end of the sense strand is a 2′-O-methyl modified cytosine nucleotide.

17. The dsRNA agent of claim 15 , wherein the 2′-O-methyl modified nucleotide at position 6 of the sense strand, counting from the 5′-end of the sense strand is a 2′-O-methyl modified adenosine nucleotide.

18. The dsRNA agent of claim 1 , wherein each strand is independently 19-25 nucleotides in length.

19. The dsRNA agent of claim 1 , wherein the dsRNA agent comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

20. The dsRNA agent of claim 1 , wherein the GalNAc (N-acetylgalactosamine) derivative is attached through a bivalent or trivalent branched linker.

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

(SEQ ID NO: 387)

5′-CAUAUUUGAUCAGUCUUUUUA-3′

and

(SEQ ID NO: 572)

5′-UAAAAAGACUGAUCAAAUAUGUU-3′;

(SEQ ID NO: 287)

5′-ACAUAUUUGAUCAGUCUUUUU-3′

and

(SEQ ID NO: 472)

5′-AAAAAGACUGAUCAAAUAUGUUG-3′;

(SEQ ID NO: 303)

5′-AACAUAUUUGAUCAGUCUUUU-3′

and

(SEQ ID NO: 488)

5′-AAAAGACUGAUCAAAUAUGUUGA-3′;

(SEQ ID NO: 39)

5′-ACAUAUUUGAUCAGUCUUU-3′

and

(SEQ ID NO: 101)

5′-AAAGACUGAUCAAAUAUGU-3′;

(SEQ ID NO: 294)

5′-CAACAUAUUUGAUCAGUCUUU-3′

and

(SEQ ID NO: 479)

5′-AAAGACUGAUCAAAUAUGUUGAG-3′;

(SEQ ID NO: 358)

5′-UCAACAUAUUUGAUCAGUCUU-3′

and

(SEQ ID NO: 543)

5′-AAGACUGAUCAAAUAUGUUGAGU-3′;

and

(SEQ ID NO: 64)

5′-CAACAUAUUUGAUCAGUCU-3′

and

(SEQ ID NO: 126)

5′-AGACUGAUCAAAUAUGUUG-3′.

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

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

24. The pharmaceutical composition of claim 23 , wherein the dsRNA agent is present in a buffered solution.

25. The dsRNA agent of claim 12 , wherein each strand is independently 19-25 nucleotides in length.

26. The dsRNA agent of claim 12 , wherein the dsRNA agent comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

27. The dsRNA agent of claim 12 , wherein the GalNAc (N-acetylgalactosamine) derivative is attached through a bivalent or trivalent branched linker.

28. A cell containing the dsRNA agent of claim 12 .

29. A pharmaceutical composition for inhibiting expression of an ANGPTL3 gene, comprising the dsRNA agent of claim 12 .

30. The pharmaceutical composition of claim 29 , wherein the dsRNA agent is present in a buffered solution.