STEROL REGULATORY ELEMENT BINDING PROTEIN (SREBP) CHAPERONE (SCAP) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

Abstract

The invention relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting the SCAP gene, as well as methods of inhibiting expression of a SCAP gene and methods of treating subjects having a SCAP-associated disorder, such as nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), using such dsRNAi agents and compositions.

1 . A double stranded ribonucleic acid (RNAi) agent for inhibiting expression of a sterol regulatory element binding protein (SREBP) chaperone (SCAP) gene, wherein said 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 any one of the nucleotide sequences of SEQ ID NOs:1-13; and   wherein said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences of SEQ ID NOs:14-26.   
     
     
         2 . (canceled) 
     
     
         3 . The double stranded RNAi agent of  claim 1 , wherein the sense and antisense strands comprise sequences selected from the group consisting of any one of the sequences in any one of Tables 2, 3, 5 and 6. 
     
     
         4 . The double stranded RNAi agent of  claim 1 , wherein the double stranded RNAi agent comprises at least one modified nucleotide. 
     
     
         5 . The double stranded RNAi agent of  claim 4 , wherein at least one of the modified nucleotides is 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 5′-phosphorothioate group, a nucleotide comprising a 5′-methylphosphonate group, a nucleotide comprising a 5′ phosphate or 5′ phosphate mimic, a nucleotide comprising vinyl phosphate, a nucleotide comprising adenosine-glycol nucleic acid (GNA), a nucleotide comprising thymidine-glycol nucleic acid (GNA)S-Isomer, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate, a nucleotide comprising 2′-deoxythymidine-3′phosphate, a nucleotide comprising 2′-deoxyguanosine-3′-phosphate, and a terminal nucleotide linked to a cholesteryl derivative and a dodecanoic acid bisdecylamide group. 
     
     
         6 . The double stranded RNAi agent of  claim 4 , further comprising at least one phosphorothioate internucleotide linkage. 
     
     
         7 . (canceled) 
     
     
         8 . The double stranded RNAi agent of  claim 1 , wherein each strand is no more than 30 nucleotides in length. 
     
     
         9 . The double stranded RNAi agent of  claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or a 3′ overhang of at least 2 nucleotides. 
     
     
         10 . The double stranded RNAi agent of  claim 1 , wherein the double stranded RNAi agent further comprises an N-acetylgalactosamine (GalNAc) derivative conjugated to the 3′ end of the sense strand through a monovalent or branched bivalent or trivalent linker. 
     
     
         11 . The double stranded RNAi agent of  claim 10 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The double stranded RNAi agent of  claim 10 , wherein the double stranded RNAi agent is conjugated to the ligand as shown in the following schematic 
       
         
           
           
               
               
           
         
         and, wherein X is O or S. 
       
     
     
         13 . (canceled) 
     
     
         14 . The double stranded RNAi agent of  claim 10 , wherein the ligand is a cholesterol. 
     
     
         15 . A double stranded ribonucleic acid (RNAi) agent for inhibiting expression of a sterol regulatory element binding protein (SREBP) chaperone (SCAP) gene, wherein said double stranded RNAi agent comprises a sense strand complementary to an antisense strand, wherein said antisense strand comprises a region complementary to part of an mRNA encoding SCAP, wherein each strand is about 14 to about 30 nucleotides in length, wherein said double stranded RNAi agent is represented by formula (III): 
       
         
           
                 
                 
               
                     
                   (III) 
                 
                     
                   sense: 
                 
                     
                   5′ n p -N a -(X X X) i -N b -Y Y Y-N b - 
                 
                     
                     
                 
                     
                   (Z Z Z) j -Na-nq 3′ 
                 
                     
                     
                 
                     
                   antisense: 
                 
                     
                   3′ n p ′-N a ′-(X′X′X′) k -N b ′-Y′Y′Y′-N b ′- 
                 
                     
                     
                 
                     
                   (Z′Z′Z′) l -N a ′-n q ′ 5′ 
                 
             
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein: 
         j, k, and 1 are each independently 0 or 1; 
         p, p′, q, and q′ are each independently 0-6; 
         each N a  and N a ′ 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; 
         each N b  and N b ′ independently represents an oligonucleotide sequence comprising 0-10 nucleotides which are either modified or unmodified or combinations thereof; 
         each n p , n p ′, n q , and n q ′, each of which may or may not be present, independently represents an overhang nucleotide; 
         XXX, YYY, ZZZ, X′X′X′, Y′Y′Y′, and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides; 
         modifications on N b  differ from the modification on Y and modifications on N b ′ differ from the modification on Y′; and 
         wherein the sense strand is conjugated to at least one ligand. 
       
     
     
         16 . The double stranded RNAi agent of  claim 15 , wherein formula (III) is represented by formula (Ma): 
       
         
           
                 
                 
               
                     
                   (IIIa) 
                 
                     
                   sense: 
                 
                     
                   5′ n p -N a -Y Y Y-N a -n q  3′ 
                 
                     
                     
                 
                     
                   antisense: 
                 
                     
                   3′ n p′ -N a′ -Y Y Y-N a′ -n q′  5′; 
                 
             
                
                
                
                
                
                
               
            
           
         
         wherein formula (III) is represented by formula (IIIb): 
       
       
         
           
                 
                 
               
                     
                   (IIIb) 
                 
                     
                   sense: 
                 
                     
                   5′ n p -N a -Y Y Y-N b -Z Z Z-N a -n q  3′ 
                 
                     
                     
                 
                     
                   antisense: 
                 
                     
                   3′ n p′ -N a′ -Y′Y′Y′-N b ′-Z′Z′Z′-N a′ -n q′  5′ 
                 
             
                
                
                
                
                
                
               
            
           
         
         
           wherein each N b  and N b ′ independently represents an oligonucleotide sequence comprising 1-5 modified nucleotides; 
         
         wherein formula (III) is represented by formula (IIIc): 
       
       
         
           
                 
                 
               
                     
                   (IIIc) 
                 
                     
                   sense: 
                 
                     
                   5′ n p -N a -X X X-N b -Y Y Y-N a -n q  3′ 
                 
                     
                     
                 
                     
                   antisense: 
                 
                     
                   3′ n p′ -N a′ -X′X′X-N b -Y′Y′Y′ N a′ -n q′  5′ 
                 
             
                
                
                
                
                
                
               
            
           
         
         
           wherein each N b  and N b ′ independently represents an oligonucleotide sequence comprising 1-5 modified nucleotides; or 
         
         wherein formula (III) is represented by formula (IIId): 
       
       
         
           
                 
                 
               
                     
                   (IIId) 
                 
                     
                   sense: 
                 
                     
                   5′ n p -N a -X X X-N b -Y Y Y-N b -Z Z Z-N a -n q  3′ 
                 
                     
                     
                 
                     
                   antisense: 
                 
                     
                   3′ n p′ -N a′ -X′X′X′-N b -Y′Y′Y′-N b - 
                 
                     
                     
                 
                     
                   Z′Z′Z′ N a′ -n q′  5′ 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
         
           wherein each N b  and N b ′ independently represents an oligonucleotide sequence comprising 1-5 modified nucleotides and each N a  and N a ′ independently represents an oligonucleotide sequence comprising 2-10 modified nucleotides. 
         
       
     
     
         17 . (canceled) 
     
     
         18 . The double stranded RNAi agent of  claim 15 , 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. 
     
     
         19 . The double stranded RNAi agent of  claim 15 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; or a cholesterol. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . A cell containing the double stranded RNAi agent of  claim 1 . 
     
     
         23 . A pharmaceutical composition for inhibiting expression of a SCAP gene comprising the double stranded RNAi agent of  claim 1 . 
     
     
         24 . A method for inhibiting expression of a sterol regulatory element binding protein (SREBP) chaperone (SCAP) gene in a cell, the method comprising:
 (a) contacting the cell with the double stranded RNAi agent of  claim 1  or the pharmaceutical composition of  claim 23 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a SCAP gene, thereby inhibiting expression of the SCAP gene in the cell.   
     
     
         25 . The method of  claim 24 , wherein said cell is within a subject. 
     
     
         26 .- 29 . (canceled) 
     
     
         30 . A method of treating a subject having a disorder that would benefit from a reduction in SCAP expression, comprising administering to the subject a therapeutically effective amount of the double stranded RNAi agent of  claim 1  or the pharmaceutical composition of  claim 23 , thereby treating said subject. 
     
     
         31 . The method of  claim 30 , wherein the subject suffers from a SCAP-associated disorder. 
     
     
         32 . The method of  claim 30 , wherein the subject is a human. 
     
     
         33 . The method of  claim 31 , wherein the SCAP-associated disease is nonalcoholic fatty liver disease (NAFLD); fatty liver (steatosis); nonalcoholic steatohepatitis (NASH). 
     
     
         34 .- 40 . (canceled) 
     
     
         41 . A kit for performing the method of  claim 30 , comprising
 a) the double stranded RNAi agent, and   b) instructions for use, and   c) optionally, means for administering the double stranded RNAi agent to the subject.