COMPOSITIONS AND METHODS FOR INHIBITING EXPRESSION OF Nav1.8 GENE

Abstract

The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of the Nav1.8 gene (Nav1.8 gene), comprising an antisense strand having a nucleotide sequence which is less that 25 nucleotides in length and which is substantially complementary to at least a part of the Nav1.8 gene. The invention also relates to a pharmaceutical composition comprising the dsRNA together with a pharmaceutically acceptable carrier; methods for treating diseases caused by the expression of the Nav1.8 gene using the pharmaceutical composition; and methods for inhibiting the expression of the Nav1.8 gene in a cell.

1 . A double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a human Nav1.8 gene in a cell, wherein said dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding Nav1.8, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said Nav1.8, inhibits expression of said Nav1.8 gene by at least 20%. 
     
     
         2 . The dsRNA of  claim 1 , wherein said first sequence is selected from the group consisting of Tables 1, 4 and 6 and said second sequence is selected from the group consisting of Tables 1, 4 and 6. 
     
     
         3 . The dsRNA of  claim 1 , wherein said dsRNA comprises at least one modified nucleotide. 
     
     
         4 . The dsRNA of  claim 2 , wherein said dsRNA comprises at least one modified nucleotide. 
     
     
         5 . The dsRNA of  claim 3 , wherein said modified nucleotide is chosen from the group of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group. 
     
     
         6 . The dsRNA of  claim 3 , wherein said modified nucleotide is chosen from the group of: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-O-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. 
     
     
         7 . A cell comprising the dsRNA of  claim 1 . 
     
     
         8 . A pharmaceutical composition for inhibiting the expression of the Nav1.8 gene in an organism, comprising a dsRNA and a pharmaceutically acceptable carrier, wherein the dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding Nav1.8, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said Nav1.8, inhibits expression of said Nav1.8 gene by at least 20%. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein said first sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6 and said second sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said composition is formulated for administration selected from the group consisting of intrathecal infusion or injection, or intravenous infusion or injection. 
     
     
         11 . A method for inhibiting the expression of the Nav1.8 gene in a cell, the method comprising:
 (a) introducing into the cell a double-stranded ribonucleic acid (dsRNA), wherein the dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding Nav1.8, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said Nav1.8, inhibits expression of said Nav1.8 gene by at least 20%; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the Nav1.8 gene, thereby inhibiting expression of the Nav1.8 gene in the cell.   
     
     
         12 . The method of  claim 11 , wherein said first sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6 and said second sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6. 
     
     
         13 . A method of treating, preventing or managing pain comprising administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a dsRNA, wherein the dsRNA comprises at least two sequences that are complementary to each other and wherein a sense strand comprises a first sequence and an antisense strand comprises a second sequence comprising a region of complementarity which is substantially complementary to at least a part of a mRNA encoding Nav1.8, and wherein said region of complementarity is less than 30 nucleotides in length and wherein said dsRNA, upon contact with a cell expressing said Nav1.8, inhibits expression of said Nav1.8 gene by at least 20%. 
     
     
         14 . The method of  claim 13 , wherein said first sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6 and said second sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6. 
     
     
         15 . The method of  claim 14 , wherein said pain is selected from the group consisting of neuropathic pain and inflammatory pain. 
     
     
         16 . A vector for inhibiting the expression of the Nav1.8 gene in a cell, said vector comprising a regulatory sequence operably linked to a nucleotide sequence that encodes at least one strand of a dsRNA, wherein one of the strands of said dsRNA is substantially complementary to at least a part of a mRNA encoding Nav1.8 and wherein said dsRNA is less than 30 base pairs in length and wherein said dsRNA, upon contact with a cell expressing said Nav1.8, inhibits the expression of said Nav1.8 gene by at least 20%. 
     
     
         17 . The vector of  claim 16 , wherein said first sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6 and said second sequence of said dsRNA is selected from the group consisting of Tables 1, 4 and 6. 
     
     
         18 . A cell comprising the vector of  claim 16 . 
     
     
         19 . A cell comprising the vector of  claim 17 .