Nucleic acid molecules for reduction of PAPD5 or PAPD7 mRNA for treating hepatitis B infection

Patent metadata

Field	Value
Publication number	US-11534452-B2
Application number	US-201716310789-A
Country	US
Kind code	B2
Filing date	Jun 19, 2017
Priority date	Jun 17, 2016
Publication date	Dec 27, 2022
Grant date	Dec 27, 2022

Abstract

A method for identifying a compound that prevents, ameliorates and/or inhibits a hepatitis B virus (HBV) infection is provided, 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. Inhibitors of PAPD5 or PAPD7 are provided 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.

First claim

The invention claimed is:

1. A method for the treatment of Hepatitis B virus infection in a subject, said method comprising administering an effective amount of a composition comprising a nucleic acid molecule which directly inhibits expression and/or activity of PAP associated domain containing 5 (PAPD5) to the subject; wherein the nucleic acid molecule is independently selected from the group consisting of:
a. single stranded antisense oligonucleotide;
b. siRNA molecule; and
c. shRNA molecule.

2. The method of claim 1 , wherein said composition is a combined preparation further comprising:
a. nucleic acid molecule which directly inhibits expression and/or activity of PAP associated domain containing 7 (PAPD7).

3. The method of claim 2 , wherein the nucleic acid molecule is selected from:
a. single stranded antisense oligonucleotide comprising a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 80% complementarity to a PAPD5 target nucleic acid and which is capable of reducing expression of PAPD5; and
b. 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.

4. The method of claim 2 wherein the nucleic acid molecule comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length wherein the contiguous nucleotide sequence is 100% complementary to a PAPD7 target nucleic acid and the nucleic acid molecule is capable of reducing expression of PAPD7.

5. The nucleic method of claim 4 , wherein the nucleic acid molecule is a single stranded antisense oligonucleotide.

6. The method of claim 5 , 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.

7. The method according to claim 5 wherein the antisense oligonucleotide is a conjugate comprising at least one conjugate moiety covalently attached to said oligonucleotide.

8. The method of claim 4 , wherein the contiguous nucleotide sequence comprises phosphorothioate internucleoside linkages.

9. The method of claim 1 , wherein the composition reduces secretion of HBsAg, HBeAg and/or inhibits production of intracellular HBV mRNA or HBV DNA.

10. The method of claim 1 , wherein the composition inhibits development of chronic HBV infection and/or reduces the infectiousness of a HBV infected person.

11. The method of claim 10 , wherein the composition 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.

12. The method of claim 1 wherein the nucleic acid molecule is 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% complementary to a PAPD5 target nucleic acid and the antisense oligonucleotide is capable of reducing expression of PAPD5.

13. The method of claim 12 , wherein the antisense oligonucleotide comprises one or more 2′ sugar modified nucleoside(s).

14. The method of claim 13 , wherein the one or more 2′ sugar modified nucleoside(s) 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.

15. The method of claim 13 , wherein the one or more 2′ sugar modified nucleoside(s) is a LNA nucleoside.

16. The method of claim 12 , wherein the contiguous nucleotide sequence comprises phosphorothioate internucleoside linkages.

17. The method of claim 12 , 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.

18. The method according to claim 12 wherein the antisense oligonucleotide is a conjugate comprising at least one conjugate moiety covalently attached to said oligonucleotide.

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• C12N2320/31

  Combination therapy · CPC title

• C12Q2600/136

  Screening for pharmacological compounds · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• 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

• A61K31/7125 Primary

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