HEPATITIS D VIRUS (HDV) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

Abstract

The present invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the hepatitis D virus (HDV) genome, and methods of using such RNAi agents to inhibit expression of one or more HBV genes and methods of treating subjects having an HDV infection and/or HDV-associated disorder.

1 . A double stranded RNAi agent for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region selected from the group consisting of
 (a) a sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:29, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:30;   (b) a sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:31, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:32;   (c) a sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:33, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:34;   (d) a sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:35, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:36;   (e) a sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:37, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:38;   (f) a sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:39, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:40;   (g) a sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:41, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:42;   (h) a sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:43, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:44; and   (i) a sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:2551, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:2552;
 wherein substantially all of the nucleotides of said sense strand and substantially all of the nucleotides of said antisense strand are modified nucleotides, 
 wherein said sense strand is conjugated to a ligand attached at the 3′-terminus, and 
 wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
   
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The double stranded RNAi agent of  claim 1 , wherein all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand are modified nucleotides. 
     
     
         5 . (canceled) 
     
     
         6 . The double stranded RNAi agent of  claim 1 , wherein said sense strand and said antisense strand comprise a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the sense and antisense strands of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, and AD-70275.1. 
     
     
         7 . (canceled) 
     
     
         8 . The double stranded RNAi agent of  claim 1 , wherein at least one of said modified nucleotides is selected from the group consisting of 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′-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. 
     
     
         9 . The double stranded RNAi agent of any  claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or at least 2 nucleotides. 
     
     
         10 . (canceled) 
     
     
         11 . The double stranded RNAi agent of  claim 1 , 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. 
     
     
         12 .- 16 . (canceled) 
     
     
         17 . The double stranded RNAi agent of  claim 1 , wherein each strand has 15-30 nucleotides; or 19-30 nucleotides. 
     
     
         18 . (canceled) 
     
     
         19 . The double stranded RNAi agent of  claim 1 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         20 . The double stranded RNAi agent of  claim 1 , wherein the RNAi agent is conjugated to the ligand as shown in the following schematic 
       
         
           
           
               
               
           
         
         wherein X is O or S. 
       
     
     
         21 . (canceled) 
     
     
         22 . The double stranded RNAi agent of  claim 1 , wherein said RNAi agent is selected from the consisting of any one of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1. 
     
     
         23 . A double stranded RNAi agent for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region,
 wherein said sense strand comprises any one of the sense sequences provided in any one of Table 11, 12, 31, and 32, and said antisense strand comprises any one of the antisense sequences provided in any one of Table 11, 12, 31, and 32,   wherein substantially all of the nucleotides of said sense strand and substantially all of the nucleotides of said antisense strand are modified nucleotides,   wherein said sense strand is conjugated to a ligand attached at the 3′-terminus, and   wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.   
     
     
         24 .- 38 . (canceled) 
     
     
         39 . A composition for inhibiting expression of hepatitis D virus (HDV) in a cell, said composition comprising:
 (a) a first double-stranded RNAi agent comprising a first sense strand and a first antisense strand forming a double-stranded region,   wherein substantially all of the nucleotides of said first sense strand and substantially all of the nucleotides of said first antisense strand are modified nucleotides,   wherein said first sense strand is conjugated to a ligand attached at the 3′-terminus, and   wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; and   (b) a second double-stranded RNAi agent comprising a second sense strand and a second antisense strand forming a double-stranded region,   wherein substantially all of the nucleotides of said second sense strand and substantially all of the nucleotides of said second antisense strand are modified nucleotides,   wherein said second sense strand is conjugated to a ligand attached at the 3′-terminus, and   wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker;   wherein the first and second sense strands each independently comprise a sequence selected from the group consisting of any one of the sense sequences of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1, and   wherein the first and second antisense strands each independently comprise a sequence selected from the group consisting of any one of the antisense sequences of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1.   
     
     
         40 .- 43 . (canceled) 
     
     
         44 . A double stranded RNAi agent comprising the sense strand nucleotide sequence and the antisense strand nucleotide sequence of any one of the RNAi agents provided in any one of Tables 11, 12, 31, and 32. 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . A pharmaceutical composition comprising the double stranded RNAi agent of  claim 1  or  23 , or the composition of claim  31  or  39 . 
     
     
         48 .- 52 . (canceled) 
     
     
         53 . A method of inhibiting Hepatitis D virus (HDV) gene expression in a cell, the method comprising:
 (a) contacting the cell with the double stranded RNAi agent of  claim 1  or  23 , or the composition of  claim 39 , or the pharmaceutical composition of  claim 47 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of an HDV gene, thereby inhibiting expression of the HDV gene in the cell.   
     
     
         54 .- 69 . (canceled) 
     
     
         70 . A method of treating a subject having a Hepatitis D virus (HDV) infection, comprising administering to the subject a therapeutically effective amount of the double stranded RNAi agent of  claim 1  or  23 , or the composition of  claim 39 , or the pharmaceutical composition of  claim 47 , thereby treating said subject. 
     
     
         71 .- 103 . (canceled) 
     
     
         104 . The method of  claim 70 , further comprising administering to the subject an additional therapeutic agent. 
     
     
         105 .- 111 . (canceled)