XANTHINE DEHYDROGENASE (XDH) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

Abstract

The present invention relates to RNAi agents, e.g., dsRNA agents, targeting the xanthine dehydrogenase (XDH) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of an XDH gene and to methods of treating or preventing an XDH-associated disease in a subject.

We claim: 
     
         1 . A method of treating a subject having a disorder that would benefit from reduction in xanthine dehydrogenase (XDH) expression, the method comprising administering to the subject a therapeutically effective amount of a double stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand forming a double stranded region,
 wherein the sense strand comprises at least 19 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of nucleotides 2701-2721 of SEQ ID NO: 1, and the antisense strand comprises at least 19 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO: 2,   wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides,   wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus, and   wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus.   thereby treating the subject having the disorder that would benefit from reduction in XDH expression.   
     
     
         2 . The method of  1 , wherein the disorder is an XDH-associated disease. 
     
     
         3 . The method of  claim 2 , wherein the XDH-associated disease is hyperuricemia. 
     
     
         4 . The method of  claim 2 , wherein the XDH-associated disease is gout. 
     
     
         5 . The method of  claim 1 , wherein the subject is human. 
     
     
         6 . The method of  claim 1 , wherein the dsRNA agent is administered to the subject at a dose of about 0.01 mg/kg to 50 mg/kg. 
     
     
         7 . The method of  claim 1 , wherein the dsRNA agent is administered to the subject subcutaneously. 
     
     
         8 . The method of  claim 1 , further comprising administering to the subject an additional therapeutic agent for the treatment of an XDH-associated disease. 
     
     
         9 . The method of  claim 1 , wherein at least one of the modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxythimidine (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, 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, a nucleotide comprising a 5′-phosphate mimic, a nucleotide comprising a 2′-phosphate, a thermally destabilizing nucleotide, a glycol modified nucleotide (GNA), and a 2-O—(N-methylacetamide) modified nucleotide; and combinations thereof. 
     
     
         10 . The method of  claim 1 , wherein the sense strand and the antisense strand are each independently 19-25 nucleotides in length. 
     
     
         11 . The method of  claim 1 , wherein the dsRNA agent further comprises a ligand. 
     
     
         12 . The method of  claim 11 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent. 
     
     
         13 . The method of  claim 12 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker. 
     
     
         14 . The method of  claim 13 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 14 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic 
       
         
           
           
               
               
           
         
       
       wherein X is O or S. 
     
     
         16 . The method of  claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-ACUCGUUCCAUAAUACUCUGAGA-3′ (SEQ ID NO:494). 
     
     
         17 . The method of  claim 16 , wherein the sense strand comprises the nucleotide sequence 5′-UCAGAGUAUUAUGGAACGAGU-3′(SEQ ID NO:135) and the antisense strand comprises the nucleotide sequence 5′-ACUCGUUCCAUAAUACUCUGAGA-3′(SEQ ID NO:494). 
     
     
         18 . The method of  claim 17 , wherein the sense strand comprises the nucleotide sequence 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and the antisense strand comprises the nucleotide sequence 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212), wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; and s is a phosphorothioate linkage. 
     
     
         19 . The method of  claim 18 , wherein the dsRNA agent further comprises a ligand. 
     
     
         20 . The method of  claim 19 , wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic 
       
         
           
           
               
               
           
         
       
       wherein X is O. 
     
     
         21 . A method of treating a subject having a disorder that would benefit from reduction in xanthine dehydrogenase (XDH) expression, the method comprising administering to the subject a therapeutically effective amount of a double stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand forming a double stranded region,
 wherein the sense strand comprises the nucleotide sequence 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and the antisense strand comprises the nucleotide sequence 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212),   wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; and s is a phosphorothioate linkage; and   wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic   
       
         
           
           
               
               
           
         
       
       wherein X is O,
 thereby treating the subject having the disorder that would benefit from reduction in XDH expression. 
 
     
     
         22 . The method of  claim 21 , wherein the disorder is an XDH-associated disease. 
     
     
         23 . The method of  claim 22 , wherein the XDH-associated disease is hyperuricemia. 
     
     
         24 . The method of  claim 22 , wherein the XDH-associated disease is gout. 
     
     
         25 . The method of  claim 21 , wherein the subject is human. 
     
     
         26 . The method of  claim 21 , wherein the dsRNA agent is administered to the subject at a dose of about 0.01 mg/kg to 50 mg/kg. 
     
     
         27 . The method of  claim 21 , wherein the dsRNA agent is administered to the subject subcutaneously. 
     
     
         28 . The method of  claim 21 , further comprising administering to the subject an additional therapeutic agent for the treatment of an XDH-associated disease. 
     
     
         29 . The method of  claim 28 , wherein the sense strand consists of the nucleotide sequence 5′-uscsagagUfaUfUfAfuggaacgagu-3′(SEQ ID NO:853) and the antisense strand consists of the nucleotide sequence 5′-asCfsucgUfuccauaaUfaCfucugasgsa-3′(SEQ ID NO:1212). 
     
     
         30 . The method of  claim 21 , wherein the dsRNA agent is present in a pharmaceutical composition.