Insulin-like growth factor binding protein, acid labile subunit (IGFALS) and insulin-like growth factor 1 (IGF-1) iRNA compositions and methods of use thereof
The present invention relates to RNAi agents, e.g., double stranded RNAi agents, targeting the insulin-like growth factor binding protein, acid labile subunit (IGFALS) gene or the insulin-like growth factor 1 (IGF-1) gene, methods of using such double stranded RNAi agents to inhibit expression of an IGFALS gene or an IGF-1 gene, and methods of treating subjects having an IGF system-associated disorder.
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 sense strand comprises the nucleotide sequence 5′-UUCUGGCUGGACGUCUCGCAA-3′ (SEQ ID NO:74) and the antisense strand comprises the nucleotide sequence 5′-UUGCGAGACGUCCAGCCAGAAGG-3′ (SEQ ID NO:131); and wherein the dsRNA agent comprises at least one modified nucleotide.
2. 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.
3. 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.
4. The dsRNA agent of claim 2 , wherein at least one of said modified nucleotides 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 abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxly-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.
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 further comprising a ligand.
7. The dsRNA agent of claim 6 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.
8. The dsRNA agent of claim 6 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
9. The dsRNA agent of claim 1 , wherein the modifications on the nucleotides are 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.
10. The dsRNA agent of claim 1 , wherein said agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.
11. A pharmaceutical composition comprising the dsRNA agent of claim 1 and a pharmaceutically acceptable carrier.
12. The dsRNA agent of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-ususcuggCfuGfGfAfcgucucgcaaL96-3′ (SEQ ID NO:181) and the antisense strand comprises the nucleotide sequence 5′-usUfsgcgAfgAfCfguccAfgCfcagaasgsg-3′ (SEQ ID NO:238),
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; and wherein s is a phosphorothioate linkage; and wherein L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol.
13. A method of treating a subject having a disease or disorder that would benefit from reduction in IGLAS expression, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby treating said subject.
14. A method of inhibiting IGFALS expression in a cell, the method comprising:
contacting the cell with the dsRNA agent of claim 1 or the pharmaceutical composition of claim 11 ; thereby inhibiting expression of the IGFALS gene in the cell.
15. The method of claim 14 , wherein the cell is within a subject.
16. The method of claim 15 , wherein the subject is a human.
17. The method of claim 14 , wherein IGF-1 expression is inhibited by at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or to below the level of detection.