MicroRNA Compounds and Methods for Modulating MIR-122

Abstract

Described herein are compositions and methods for the inhibition of miR-122 activity. The compositions have certain nucleoside modifications that yield potent inhibitors of miR-122 activity. The compounds may comprise conjugates to facilitate delivery to the liver. The compositions may be administered to subjects infected with hepatitis C virus, as a treatment for hepatitis C virus and related conditions.

1 - 114 . (canceled) 
     
     
         115 . A conjugate having the structure: 
       
         
           
           
               
               
           
         
         wherein X is a phosphodiester linkage; m is 1; N in N m  is a β-D-deoxyriboadenosine; Y is a phosphodiester linkage; and MO is a modified oligonucleotide consisting of less than 16 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide comprises a nucleobase sequence that is complementary to nucleobases 2 to 9 of miR-122 (SEQ ID NO: 1), and wherein the modified oligonucleotide comprises at least 8 contiguous nucleosides of the following structure: 
       
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                 
                     
                   A E   Me C E A E   Me C E   Me C E A E T E TGU S C S AC S AC S TC S C S ,, 
                 
             
                
                
               
            
           
         
         wherein the superscript “Me” indicates 5-methylcytosine; nucleosides not followed by a subscript are β-D-deoxyribonucleosides; nucleosides followed by a subscript “E” are 2′-MOE nucleosides; nucleosides followed by a subscript “S” are S-cEt nucleosides; and each internucleoside linkage is a phosphorothioate internucleoside linkage; and wherein Y is linked to the 3′ terminus of the modified oligonucleotide. 
       
     
     
         116 . A pharmaceutical composition comprising the conjugate of  claim 115  and one or more pharmaceutically acceptable excipients. 
     
     
         117 . The pharmaceutical composition of  claim 116 , which is a sterile aqueous solution. 
     
     
         118 . A method of treating an HCV infection comprising administering to an HCV-infected human a therapeutically effective amount of the pharmaceutical composition of  claim 116 . 
     
     
         119 . The method of  claim 118 , wherein the administering reduces HCV RNA level. 
     
     
         120 . The method of  claim 118 , wherein the method achieves a sustained virological response. 
     
     
         121 . The method of  claim 118 , wherein the subject is infected with one or more HCV genotypes selected from genotype 1, genotype 2, genotype 3, genotype 4, genotype 5, and genotype 6. 
     
     
         122 . The method of  claim 121 , wherein the HCV genotype is selected from genotype 1a, genotype 1b, genotype 2a, genotype 2b, genotype 2c, genotype 2d, genotype 3a, genotype 3b, genotype 3c, genotype 3d, genotype 3e, genotype 3f, genotype 4a, genotype 4b, genotype 4c, genotype 4d, genotype 4e, genotype 4f, genotype 4g, genotype 4h, genotype 4i, genotype 4j, genotype 5a, and genotype 6a. 
     
     
         123 . The method of  claim 118 , comprising administering at least one additional therapeutic agent. 
     
     
         124 . The method of  claim 123 , wherein the at least one therapeutic agent is selected from a protease inhibitor, a polymerase inhibitor, a cofactor inhibitor, an RNA polymerase inhibitor, a structural protein inhibitor, a non-structural protein inhibitor, a cyclophilin inhibitor, an entry inhibitor, a TLR 7  agonist, and an interferon. 
     
     
         125 . The method of  claim 123 , wherein the at least one therapeutic agent is selected from a protease inhibitor, an NS5A inhibitor, an NS3/4A inhibitor, a nucleoside NS5B inhibitor, a nucleotide NS5B inhibitor, a non-nucleoside NS5B inhibitor, a cyclophilin inhibitor and an interferon. 
     
     
         126 . The method of  claim 123 , wherein the at least one therapeutic agent is selected from interferon alfa-2a, interferon alpha-2b, interferon alfacon-1, peginterferon alpha-2b, peginterferon alpha-2a, interferon-alpha-2b extended release, interferon lambda, sofosbuvir, ledipasvir, ribavirin, telapravir, boceprevir, vaniprevir, asunaprevir, ritonavir, setrobuvir, daclastavir, simeprevir, alisporivir, mericitabine, tegobuvir, danoprevir, sovaprevir, and neceprevir. 
     
     
         127 . The method of  claim 123 , wherein the at least one therapeutic agent is sofosbuvir. 
     
     
         128 . The method of  claim 123 , wherein the at least one therapeutic agent is sofosbuvir and ledipasvir. 
     
     
         129 . The method of  claim 123 , wherein the at least one therapeutic agent is daclatasvir. 
     
     
         130 . The method of  claim 123 , wherein the at least one therapeutic agent is simeprevir. 
     
     
         131 . The method of  claim 118 , wherein the subject is a direct-acting anti-viral non-responder. 
     
     
         132 . The method of  claim 118 , wherein the subject has an HCV-associated disease selected from cirrhosis, liver fibrosis, steatohepatitis, steatosis, and hepatocellular carcinoma. 
     
     
         133 . The method of  claim 118 , comprising administering the pharmaceutical composition once per week, once per two weeks, once per three weeks, once per month, once per two months, or once per three months. 
     
     
         134 . The method of  claim 118 , wherein the dose of the conjugate administered to the HCV-infected human is less than or equal to 10 mg/kg, less than or equal to 7.5 mg/kg, less than or equal to 5 mg/kg per week, less than or equal to 4.5 mg/kg, less than or equal to 4.0 mg/kg, less than or equal to 3.5 mg/kg, less than or equal to 3.0 mg/kg, less than or equal to 2.5 mg/kg, less than or equal to 2.0 mg/kg, less than or equal to 1.5 mg/kg, or less than or equal to 1.0 mg/kg.