Nucleic acid molecules for reduction of papd5 or papd7 mrna for treating hepatitis b infection

Abstract

The present invention relates to a method for identifying a compound that prevents, ameliorates and/or inhibits a hepatitis virus (HBV) infection, wherein a compound that reduces the expression and/or activity of PAP associated domain containing 5 (PAPD5) and/or PAP associated domain containing 7 (PAPD7) is identified as a compound that prevents, ameliorates and/or inhibits a BV infection. The invention also provides for inhibitors of PAPD5 or PAPD7 for use in treating and/or preventing a HBV infection; as well as a combined preparation comprising an inhibitor of PAPD5 and an inhibitor of PAPD7 for simultaneous or sequential use in the treatment or prevention of a HBV infection. Also comprised in the present invention is a pharmaceutical composition for use in the treatment and/or prevention of a HBV infection, and a method for monitoring the therapeutic success during the treatment of a HBV infection.

1 . A composition comprising a nucleic acid molecule for use in the treatment and/or prevention of Hepatitis B virus infection, wherein said nucleic acid molecule inhibits expression and/or activity of PAP associated domain containing 5 (PAPD5). 
     
     
         2 . The composition of  claim 1 , wherein said composition is a combined preparation comprising:
 a. a nucleic acid molecule which inhibits expression and/or activity PAPD5; and   b. a nucleic acid molecule which inhibits expression and/or activity of PAP associated domain containing 7 (PAPD7).   
     
     
         3 . The composition of  claim 1 , wherein the nucleic acid molecules are independently selected from the group consisting of:
 a. a single stranded antisense oligonucleotide;   b. a siRNA molecule;   c. a shRNA molecule; and   d. a genome editing machinery, comprising:
 i. a site-specific DNA nuclease or a polynucleotide encoding a site-specific DNA 
 nuclease; and 
 ii. a guide RNA or a polynucleotide encoding a guide RNA. 
   
     
     
         4 . The composition of  claim 2 , wherein the nucleic acid molecules are selected from:
 a. a single stranded antisense oligonucleotide comprising a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 80% complementarity to PAPD5 target nucleic acid and which capable of reducing expression of PAPD5; and   b. a single stranded antisense oligonucleotide comprising a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 80% complementarity to a PAPD7 target nucleic acid and which is capable of reducing expression of PAPD7.   
     
     
         5 . The composition of  claim 1 , wherein the composition reduces secretion of HBsAg, HBeAg and/or inhibits production of intracellular HBV mRNA or HBV DNA. 
     
     
         6 . The composition of  claim 1 , wherein the composition inhibits development of chronic HBV infection and/or reduces the infectiousness of a HBV infected person. 
     
     
         7 . A method for identifying a compound or composition that prevents, ameliorates and/or inhibits a hepatitis B virus (HBV) infection, comprising:
 a. contacting a test compound or composition with a cell expressing PAPD5 and/or PAPD7;   b. measuring the expression and/or activity of PAPD5 and/or PAPD7 in the presence and absence of said test compound or composition; and   c. identifying a compound or composition that reduces the expression and/or activity of PAPD5 and/or PAPD7 as a compound that prevents, ameliorates and/or inhibits a HBV infection.   
     
     
         8 . The method of  claim 7 , wherein the test compound is a library of nucleic acid molecules and step c) identifies nucleic acid molecules that reduce PAPD5 or PAPD7 mRNA expression by at least 60%. 
     
     
         9 . The method of  claim 7 , wherein the test composition is a combined preparation of a nucleic add molecule capable of reducing PAPD5 and a nucleic add molecule capable of reducing PAPD7. 
     
     
         10 . The method of  claim 7 , wherein the compound that inhibits propagation of HBV inhibits secretion of HBV surface antigen (HBsAg), and/or inhibits secretion of HBV envelope antigen (HBeAg), and/or inhibits production of intracellular HBV mRNA. 
     
     
         11 . A single stranded antisense oligonucleotide which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length wherein the contiguous nucleotide sequence is at least 80% complementarity to a PAPD5 target nucleic add and the antisense oligonucleotide is capable of reducing expression of PAPD5. 
     
     
         12 . A nucleic add molecule which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length wherein the contiguous nucleotide sequence is at least 80% complementarity to a PAPD7 target nucleic add and the nucleic add molecule is capable of reducing expression of PAPD7. 
     
     
         13 . The nucleic add molecule of  claim 12 , wherein the nucleic add molecule is a single stranded antisense oligonucleotide. 
     
     
         14 . The antisense oligonucleotide or nucleic add molecule of  claim 11 , comprising one or more 2′ sugar modified nucleoside(s). 
     
     
         15 . The antisense oligonucleotide or nucleic add molecule of  claim 14 , wherein the one or more 2′ sugar modified nucleoside is independently selected from the group consisting of 2′-0-alkyl-RNA, 2′-0-methyl-RNA, 2′-alkoxy-RNA, 2′-0-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic add (ANA), 2′-fluoro-ANA and LNA nucleosides. 
     
     
         16 . The antisense oligonucleotide or nucleic add molecule of  claim 14 , wherein the one or more 2′ sugar modified nucleoside is a LNA nucleoside. 
     
     
         17 . The antisense oligonucleotide or nucleic acid molecule of  claim 11 , wherein the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate internucleoside linkages. 
     
     
         18 . The antisense oligonucleotide of  claim 11 , wherein the oligonucleotide is a gapmer of formula 5′-F-G-F′-3′, where region F and F′ independently comprise 1-7 2′ sugar modified nucleosides and G is a region between 6 and 16 nucleosides which are capable of recruiting RNaseH. 
     
     
         19 . A conjugate comprising the antisense oligonucleotide according to  claim 11 , and at least one conjugate moiety covalently attached to said oligonucleotide. 
     
     
         20 . A combined preparation comprising
 a. a nucleic acid molecule which inhibits expression and/or activity of PAPD5; and   b. a nucleic acid molecule which inhibits expression and/or activity of PAPD7.   
     
     
         21 . The combined preparation of  claim 20 , wherein the nucleic acid molecule is a single stranded antisense oligonucleotide which comprises or consists of a contiguous nucleotide sequence of 10 to 30 nucleotides in length wherein the contiguous nucleotide sequence is at least 80% complementarity to a PAPD5 target nucleic acid and the antisense oligonucleotide is capable of reducing expression of PAPD5. 
     
     
         22 . A pharmaceutical composition comprising the antisense oligonucleotide or nucleic acid molecule according to  claim 11 .