Molecules and agents for treating hepatitis b virus

Abstract

This invention encompasses compounds and compositions useful in methods for medical therapy, in general, for inhibiting Hepatitis B virus in a subject. The compounds have a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers comprising UNA monomers and nucleic acid monomers, and the compounds are targeted to a sequence of an HBV genome.

What is claimed is: 
     
         1 . A compound comprising a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers comprising UNA monomers and nucleic acid monomers, wherein the compound has a duplex region of from 14 to 29 contiguous monomers in length, wherein the first strand is a sense strand for RNA interference and the second strand is an antisense strand for RNA interference, and wherein the compound comprises a sequence of bases targeted to inhibit expression of an HBV genome. 
     
     
         2 . The compound of  claim 1 , wherein the compound contains one to seven UNA monomers. 
     
     
         3 . The compound of  claim 1 , wherein the compound contains a UNA monomer at the 1-end (5′ end for non-UNA) of the first strand, a UNA monomer at the 3-end or second position from the 3-end (3′ end for non-UNA) of the sense strand, and a UNA monomer at the 3-end or second position from the 3-end (3′ end for non-UNA) of the antisense strand. 
     
     
         4 . The compound of  claim 1 , wherein the sense strand comprises SEQ ID NO:900 and the antisense strand comprises SEQ ID NO:941. 
     
     
         5 . The compound of  claim 1 , wherein the sense strand comprises SEQ ID NO:893 and the antisense strand comprises SEQ ID NO:934. 
     
     
         6 . The compound of  claim 1 , wherein the sense strand comprises SEQ ID NO:879 and the antisense strand comprises SEQ ID NO:920. 
     
     
         7 . The compound of  claim 1 , wherein the first and second strands are a sense-antisense pair selected from any of Tables 33 to 38. 
     
     
         8 . The compound of  claim 1 , wherein the compound has a 3′ overhang comprising one or more UNA monomers, natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically-modified nucleotides, and combinations thereof. 
     
     
         9 . The compound of  claim 1 , wherein the compound has a 3′ overhang comprising one or more deoxythymidine nucleotides, 2′-O-methyl nucleotides, inverted abasic monomers, inverted thymidine monomers, L-thymidine monomers, or glyceryl nucleotides. 
     
     
         10 . The compound of  claim 1 , wherein one or more of the nucleic acid monomers is a non-natural nucleotide, a modified nucleotide, or a chemically-modified nucleotide. 
     
     
         11 . The compound of  claim 1 , wherein one or more of three monomers at each end of each strand is connected by a phosphorothioate, a chiral phosphorothioate, or a phosphorodithioate linkage. 
     
     
         12 . The compound of  claim 1 , wherein the compound is conjugated to a delivery moiety. 
     
     
         13 . The compound of  claim 1 , wherein the compound is conjugated to a delivery moiety that binds to a glycoprotein receptor, wherein the delivery moiety comprises a galactose, a galactosamine, or a N-acetylgalactosamine. 
     
     
         14 . The compound of  claim 1 , wherein the compound is conjugated to a GalNAc delivery moiety or a cholesterol delivery moiety. 
     
     
         15 . A lipid nanoparticle-oligomer compound comprising one or more compounds of  claim 1  attached to the lipid nanoparticle. 
     
     
         16 . A composition comprising one or more compounds of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . The composition of  claim 16 , wherein the carrier comprises lipid nanoparticles or liposomes. 
     
     
         18 . A composition comprising a triad of compounds, wherein the triad is selected from the following:
 the first compound comprises SEQ ID NO:867 and 908, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:879 and 920, and substituted forms thereof;   the first compound comprises SEQ ID NO: 867 and 908, the second compound comprises SEQ ID NO:893 and 934, and the third compound comprises SEQ ID NO:875 and 916, and substituted forms thereof; and   the first compound comprises SEQ ID NO:900 and 941, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:875 and 916, and substituted forms thereof.   
     
     
         19 . An siRNA comprising nucleotides, wherein the siRNA is targeted to HBV and comprises SEQ ID NO:900 and 941, and substituted forms thereof. 
     
     
         20 . An siRNA comprising nucleotides, wherein the siRNA is targeted to HBV and comprises SEQ ID NO:893 and 934, and substituted forms thereof. 
     
     
         21 . An siRNA comprising nucleotides, wherein the siRNA is targeted to HBV and comprises SEQ ID NO:879 and 920, and substituted forms thereof. 
     
     
         22 . A method for preventing, ameliorating or treating a disease or condition associated with HBV infection in a subject in need, the method comprising administering to the subject an effective amount of a composition of  claim 16 . 
     
     
         23 . The method of  claim 22 , wherein the administration of the composition reduces HBV viral titer in the subject. 
     
     
         24 . The method of  claim 22 , wherein the subject has been diagnosed with a disease associated with Hepatitis B virus infection. 
     
     
         25 . The method of  claim 22 , wherein the subject has been diagnosed with liver disease. 
     
     
         26 . A method for inhibiting the replication, maturation, growth, or transmission of a Hepatitis B virus in a subject in need, the method comprising administering to the subject an effective amount of a composition of  claim 16 . 
     
     
         27 . The method of  claim 26 , wherein the administration of the composition reduces serum concentration of HBsAg in the subject by 2-log 10 -fold for at least 7 days. 
     
     
         28 . The method of  claim 26 , wherein the administration of the composition reduces HBeAg in the subject. 
     
     
         29 . The method of  claim 26 , wherein the administration of the composition reduces HBV DNA in the subject. 
     
     
         30 . A method for inhibiting expression of a Hepatitis B virus polynucleotide in a subject in need, the method comprising administering to the subject a composition of  claim 16 .