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

Patent metadata

Field	Value
Publication number	US-2019216846-A1
Application number	US-201716310789-A
Country	US
Kind code	A1
Filing date	Jun 19, 2017
Priority date	Jun 17, 2016
Publication date	Jul 18, 2019
Grant date	—

Abstract

The present invention relates to a method for identifying a compound that prevents, ameliorates and/or inhibits a hepatitis B 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 HBV 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.

First claim

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 6 , 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 6 , wherein the test composition is a combined preparation of a nucleic acid molecule capable of reducing PAPD5 and a nucleic acid molecule capable of reducing PAPD7.

10 . The method of claim 6 , 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 100% complementarity to a PAPD5 target nucleic acid and the antisense oligonucleotide is capable of reducing expression of PAPD5.

12 . A nucleic acid molecule which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length wherein the contiguous nucleotide sequence is 100% complementarity to a PAPD7 target nucleic acid and the nucleic acid molecule is capable of reducing expression of PAPD7.

13 . The nucleic acid molecule of claim 11 , wherein the nucleic acid molecule is a single stranded antisense oligonucleotide.

14 . The antisense oligonucleotide or nucleic acid molecule of claim 10 , comprising one or more 2′ sugar modified nucleoside(s).

15 . The antisense oligonucleotide of claim 13 , wherein the one or more 2′ sugar modified nucleoside is independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA and LNA nucleosides.

16 . The antisense oligonucleotide of claim 13 , wherein the one or more 2′ sugar modified nucleoside is a LNA nucleoside.

17 . The antisense oligonucleotide of claim 10 , wherein the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate internucleoside linkages.

18 . The antisense oligonucleotide of claim 10 , 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 10 , 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 - 22 . (canceled)

Assignees

• Hoffmann La Roche

Inventors

• Javanbakht Hassan
• Ottosen Søren
• Pedersen Lykke
• Mueller Henrik

Classifications

• A61K31/4745 Primary

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• C12N15/1137

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title

• A61K31/7125 Primary

  Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters · CPC title

• C12Q1/706

  for hepatitis · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title