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

Abstract

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 forming a double stranded region, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of any one of SEQ ID NO:1, 3, or 5, wherein said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of any one of SEQ ID NO:2, 4, or 6; and wherein the dsRNA agent comprises at least one modified nucleotide. 
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The dsRNA agent of  claim 1 , wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of any one of the nucleotide sequences in any one of Tables 3, 5, 6, 8, 12, or 14. 
     
     
         6 . (canceled) 
     
     
         7 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of an insulin-like growth factor 1 (IGF-1) gene, wherein said dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of any one of SEQ ID NO:11 or 13, wherein said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of any one of SEQ ID NO: 12 or 14; and wherein the dsRNA agent comprises at least one modified nucleotide. 
     
     
         8 .- 10 . (canceled) 
     
     
         11 . The dsRNA agent of  claim 7 , wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of any one of the nucleotide sequences in any one of Tables 9, 11, 15, 17, 18, or 20. 
     
     
         12 . (canceled) 
     
     
         13 . The dsRNA agent of  claim 1  or  7 , wherein substantially all of the nucleotides of said sense strand or substantially all of the nucleotides of said antisense strand comprise a nucleotide modification. 
     
     
         14 .- 21 . (canceled) 
     
     
         22 . The dsRNA agent of  claim 1  or  7 , 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. 
     
     
         23 .- 29 . (canceled) 
     
     
         30 . The dsRNA agent of  claim 1  or  7 , further comprising a ligand. 
     
     
         31 . (canceled) 
     
     
         32 . The dsRNA agent of  claim 30 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         33 . The dsRNA agent of  claim 32 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         34 .- 56 . (canceled) 
     
     
         57 . The dsRNA agent of  claim 1  or  7 , wherein each strand has 15-30 nucleotides. 
     
     
         58 .- 64 . (canceled) 
     
     
         65 . The dsRNA agent of  claim 1  or  7 , wherein said agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage. 
     
     
         66 .- 100 . (canceled) 
     
     
         101 . An isolated cell containing the dsRNA agent of  claim 1  or  7 . 
     
     
         102 . A pharmaceutical composition for inhibiting expression of an IGFALS gene comprising the dsRNA agent of  claim 1 . 
     
     
         103 . A pharmaceutical composition for inhibiting expression of an IGF-1 gene comprising the dsRNA agent of  claim 7 . 
     
     
         104 .- 106 . (canceled) 
     
     
         107 . A method of inhibiting IGFALS expression in a cell, the method comprising:
 contacting the cell with the dsRNA agent of  claim 1 ; thereby inhibiting expression of the IGFALS gene in the cell.   
     
     
         108 . A method of inhibiting IGF-1 expression in a cell, the method comprising:
 contacting the cell with the dsRNA agent of  claim 7 ; thereby inhibiting expression of the IGF-1 gene in the cell.   
     
     
         109 .- 111 . (canceled) 
     
     
         112 . A method of treating a subject having a disease or disorder that would benefit from reduction in IGLAS expression or IGF-1 expression, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of  claim 1  or  7 , thereby treating said subject. 
     
     
         113 - 127 . (canceled)