Angiopoietin-like 3 (angptl3) irna compositions and methods of use thereof

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ANGPTL3 gene, as well as methods of inhibiting expression of ANGPTL3 and methods of treating subjects having a disorder of lipid metabolism, such as hyperlipidemia or hypertriglyceridemia, using such dsRNA compositions.

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 any one of the antisense nucleotide sequences listed in any one of Tables 2A, 2B, 4A, 4B, 5, 7A, 7B, 7C, 8A, 8B, 10A, 10B, 13A, 13B, 14, 15A, and 15B. 
     
     
         2 . (canceled) 
     
     
         3 . The dsRNA of  claim 1 , wherein no more than four of the nucleotides of the sense strand are unmodified nucleotides; wherein no more than six of the nucleotides of the antisense strand are unmodified nucleotides; wherein all of the nucleotides of the sense strand are modified nucleotides; or wherein all of the nucleotides of the antisense strand are modified nucleotides. 
     
     
         4 . (canceled) 
     
     
         5 . The dsRNA of  claim 1 , wherein the region of complementarity is at least 17 nucleotides in length; 19-23 nucleotides in length; or 19 nucleotides in length. 
     
     
         6 . The dsRNA of  claim 1 , wherein each strand is no more than 30 nucleotides in length. 
     
     
         7 . The dsRNA of  claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or at least 2 nucleotides. 
     
     
         8 . The dsRNA of  claim 1 , further comprising a ligand. 
     
     
         9 . The dsRNA of  claim 8 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA. 
     
     
         10 . The dsRNA of  claim 9 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         11 . The dsRNA of  claim 10 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         12 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of angiopoietin-like 3 (ANGPTL3) in a cell, wherein said dsRNA comprises a sense strand complementary to an antisense strand, wherein said antisense strand comprises a region complementary to SEQ ID NO:2, wherein each strand is about 14 to about 30 nucleotides in length, and wherein said double-stranded RNAi agent is represented by formula (IIIe): 
       
         
           
                 
                 
               
                     
                   (IIIe) 
                 
                     
                   sense: 
                 
                     
                   5′-Na-Y Y Y-Nb-3′ 
                 
                     
                     
                 
                     
                   antisense: 
                 
                     
                   3′-np′-Na′-Y′Y′Y′-Nb′-5′ 
                 
             
                
                
                
                
                
                
               
            
           
         
         wherein: 
         np′ is a 2 nucleotide overhang and each nucleotide within np′ is linked to a neighboring nucleotide via a phosphorothioate linkage; 
         each Na, Nb, Na′ and Nb′ independently represents an oligonucleotide sequence comprising 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence comprising at least two differently modified nucleotides; 
         YYY and Y′Y′Y′ each independently represent one motif of three identical modifications on three consecutive nucleotides; 
         wherein the sense strand comprises no more than 4 2′-fluoro modifications; 
         wherein the antisense strand comprises no more than 6 2′-fluoro modifications; 
         wherein the sense strand and the antisense strand each independently comprise two phosphorothioate linkages at the 5′-terminus; and 
         wherein the sense strand is conjugated to at least one ligand. 
       
     
     
         13 . The dsRNA of  claim 12 , wherein the YYY motif occurs at or near the cleavage site of the sense strand. 
     
     
         14 . The dsRNA of  claim 12 , wherein the double-stranded region is 15-30 nucleotide pairs in length; 17-23 nucleotide pairs in length; 17-25 nucleotide pairs in length; 23-27 nucleotide pairs in length; 19-21 nucleotide pairs in length; or 21-23 nucleotide pairs in length. 
     
     
         15 . The dsRNA of  claim 12 , wherein each strand has 15-30 nucleotides; or 19-30 nucleotides. 
     
     
         16 . The dsRNA of  claim 12 , wherein the sense strand comprises no more than 3 2′-fluoro modifications; or no more than 2 2′-fluoro modifications; or wherein the antisense strand comprises no more than 5 2′-fluoro modifications; no more than 4 2′-fluoro modifications; no more than 3 2′-fluoro modifications; or no more than 2 2′-fluoro modifications. 
     
     
         17 . (canceled) 
     
     
         18 . The dsRNA of  claim 12 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, a bivalent, or a trivalent branched linker. 
     
     
         19 . The dsRNA of  claim 12 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         20 . The dsRNA of  claim 12 , wherein the ligand is attached to the 3′ end of the sense strand. 
     
     
         21 . (canceled) 
     
     
         22 . A cell containing the dsRNA of  claim 1 . 
     
     
         23 . A pharmaceutical composition for inhibiting expression of ion of an ANGPTL3 gene comprising the dsRNA of  claim 1 . 
     
     
         24 . 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.   
     
     
         25 .- 27 . (canceled) 
     
     
         28 . A method of treating a subject having a disorder that would benefit from a reduction in ANGPTL3 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA of  claim 1 , thereby treating said subject.