Insulin-like growth factor binding protein, acid labile subunit (IGFALS) compositions and methods of use thereof

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of an insulin-like growth factor binding protein, acid labile subunit (IGFALS) gene, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein said antisense strand comprises at least 17 contiguous nucleotides of the nucleotide sequence of 5′-AGUGAGUUGUUCCUGAGGCUGAG-3′ (SEQ ID NO: 135), and wherein the dsRNA agent comprises at least one modified nucleotide.

2. The dsRNA agent of claim 1 , wherein the nucleotide sequence of the antisense strand is 5′-AGUGAGUUGUUCCUGAGGCUGAG-3′ (SEQ ID NO: 135).

3. The dsRNA agent of claim 2 , wherein the nucleotide sequence of the antisense strand is 5′-AGUGAGUUGUUCCUGAGGCUGAG-3′ (SEQ ID NO: 135) and the nucleotide sequence of the sense strand is 5′-CAGCCUCAGGAACAACUCACU-3′ (SEQ ID NO: 78).

4. The dsRNA agent of claim 1 , wherein substantially all of the nucleotides of said sense strand or substantially all of the nucleotides of said antisense strand comprise a nucleotide modification.

5. The dsRNA agent of claim 1 , wherein all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand comprise a nucleotide modification.

6. The dsRNA agent of claim 4 , wherein at least one of the nucleotides comprising a nucleotide modification comprises a nucleotide modification selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxy-thymine (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 a basic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxyl-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, and a nucleotide comprising a 5′-phosphate mimic.

7. The dsRNA agent of claim 1 , wherein the antisense strand is 19-21 nucleotides in length.

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

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

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

11. The dsRNA agent of claim 10 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.

12. The dsRNA agent of claim 10 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

13. The dsRNA agent of claim 12 , wherein the ligand is

14. The dsRNA agent of claim 12 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic

and, wherein X is O or S.

15. The dsRNA agent of claim 14 , wherein the X is O.

16. The dsRNA agent of claim 1 , wherein the double stranded region is 17-23 nucleotide pairs in length.

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

18. The dsRNA agent of claim 1 , wherein the at least one modified nucleotide comprises a nucleotide modification selected from the group consisting of LNA, HNA, CeNA, 2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-C-allyl, 2′-fluoro, 2′-deoxy, 2′-hydroxyl, and combinations thereof.

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

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

21. The dsRNA agent of claim 1 , wherein the sense strand comprises the nucleotide sequence of 5′-csasgccuCfaGfGfAfacaacucacuL96-3′ (SEQ ID NO: 184) and the antisense strand comprises the nucleotide sequence of 5′-asGfsugaGfuUfGfuuccUfgAfggcugsasg-3′ (SEQ ID NO: 241),

wherein Af is 2′-fluoroadenosine-3′-phosphate, Cf is 2′-fluorocytidine-3′-phosphate, Gf is 2′-fluoroguanosine-3′-phosphate, and Uf is 2′-fluorouridine-3′-phosphate;

wherein a is 2′-O-methyladenosine-3′-phosphate, c is 2′-O-methylcytidine-3′-phosphate, g is 2′-O-methylguanosine-3′-phosphate, and u is 2′-O-methyluridine-3′-phosphate;

wherein s is a phosphorothioate linkage; and

wherein L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol.

22. The dsRNA agent of claim 1 , wherein the sense strand consists of the nucleotide sequence of 5′-csasgccuCfaGfGfAfacaacucacuL96-3′ (SEQ ID NO: 184) and the antisense strand consists of the nucleotide sequence of 5′-asGfsugaGfuUfGfuuccUfgAfggcugsasg-3′ (SEQ ID NO: 241),

wherein Af is 2′-fluoroadenosine-3′-phosphate, Cf is 2′-fluorocytidine-3′-phosphate, Gf is 2′-fluoroguanosine-3′-phosphate, and Uf is 2′-fluorouridine-3′-phosphate;

wherein a is 2′-O-methyladenosine-3′-phosphate, c is 2′-O-methylcytidine-3′-phosphate, g is 2′-O-methylguanosine-3′-phosphate, and u is 2′-O-methyluridine-3′-phosphate;

wherein s is a phosphorothioate linkage; and

wherein L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol.