Nucleic acid molecule for reduction of PAPD5 and PAPD7 mRNA for treating hepatitis B infection

Patent metadata

Field	Value
Publication number	US-10953034-B2
Application number	US-201816162279-A
Country	US
Kind code	B2
Filing date	Oct 16, 2018
Priority date	Oct 16, 2017
Publication date	Mar 23, 2021
Grant date	Mar 23, 2021

Abstract

The present invention relates to nucleic acid molecules that are complementary to both PAP associated domain containing 5 (PAPD5) and PAP associated domain containing 7 (PAPD7), leading to inhibition of the expression of both PAPD5 and PAPD7 when using a single nucleic acid molecule. The invention also provides for PAPD5 and PAPD7 specific nucleic acid molecules for use in treating and/or preventing a HBV infection, in particular a chronic HBV infection. Also comprised in the present invention is a pharmaceutical composition for use in the treatment and/or prevention of a HBV infection.

First claim

The invention claimed is:

1. An antisense oligonucleotide conjugate of the formula GN2-C6 ocoao TCAactttcacttCAG (SEQ ID NO: 20) or pharmaceutically acceptable salt thereof; wherein capital letters represent beta-D-oxy LNA nucleosides; all cytosine LNA nucleosides are 5-methyl cytosine; lowercase letters represent DNA nucleosides; subscript o represents a phosphodiester nucleoside linkage; and all other internucleoside linkages are phosphorothioate internucleoside linkages;
wherein C6 represents an amino alkyl group with 6 carbons; and
wherein GN2 represents a trivalent GalNAc cluster shown in FIG. 2 ;
wherein the wavy bond line in FIG. 2 indicates the site of conjugation of the trivalent GalNAc cluster to the C6 amino alkyl group.

2. A pharmaceutically acceptable sodium salt of the antisense oligonucleotide conjugate of claim 1 .

3. A pharmaceutical composition comprising the oligonucleotide conjugate or pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

4. A method for modulating PAPD 5 and PAPD7 expression in a target cell which is expressing PAPD5 and PAPD7, the method comprising administering the oligonucleotide conjugate according to claim 1 or a pharmaceutically acceptable salt thereof to said cell in an effective amount.

5. A method for treating HBV infection in a subject suffering from HBV infection, the method comprising administering a therapeutically effective amount of the oligonucleotide conjugate of claim 1 or a pharmaceutically acceptable salt thereof to the subject suffering from HBV infection.

6. A method for treating chronic HBV infection in a subject suffering from chronic HBV infection, the method comprising administering a therapeutically effective amount of the oligonucleotide conjugate of claim 1 or a pharmaceutically acceptable salt thereof to the subject suffering from chronic HBV infection.

7. A method for reduction of the infectiousness of a HBV-infected subject, the method comprising administering a therapeutically effective amount of the oligonucleotide conjugate of claim 1 or a pharmaceutically acceptable salt thereof to the HBV-infected subject.

8. An antisense oligonucleotide with a design and motif sequence of TCAactttcacttCAG (SEQ ID NO: 18) or a pharmaceutically acceptable salt thereof; wherein capital letters represent beta-D-oxy LNA nucleosides; lowercase letters represent DNA nucleosides; all cytosine LNA nucleosides are 5-methyl cytosine; and all internucleoside linkages are phosphorothioate internucleoside linkages.

9. A pharmaceutically acceptable sodium salt of the antisense oligonucleotide of claim 8 .

10. A pharmaceutical composition comprising the antisense oligonucleotide of claim 8 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

11. A method for modulating PAPD5 and PAPD7 expression in a target cell which is expressing PAPD5 and PAPD7, the method comprising administering the antisense oligonucleotide according to claim 8 or a pharmaceutically acceptable salt thereof to said cell in an effective amount.

12. A method for treating HBV infection in a subject suffering from HBV infection, the method comprising administering a therapeutically effective amount of the antisense oligonucleotide of claim 8 or a pharmaceutically acceptable salt thereof to the subject suffering from HBV infection.

13. A method for treating chronic HBV infection in a subject suffering from chronic HBV infection, the method comprising administering a therapeutically effective amount of the antisense oligonucleotide of claim 8 or a pharmaceutically acceptable salt thereof to the subject suffering from chronic HBV infection.

14. A method for reduction of the infectiousness of a HBV-infected subject, the method comprising administering a therapeutically effective amount of the antisense oligonucleotide of claim 8 or a pharmaceutically acceptable salt thereof to the HBV-infected subject.

15. A conjugate compound comprising the antisense oligonucleotide of claim 8 or a pharmaceutically acceptable salt thereof and a conjugate moiety attached to said antisense oligonucleotide or pharmaceutically acceptable salt thereof.

16. The conjugate compound of claim 15 , wherein the conjugate moiety is a trivalent N-acetyl-galactosamine (GalNAc) moiety capable of binding to an asialoglycoprotein receptor.

17. The conjugate compound of claim 15 , wherein the conjugate moiety is covalently attached to said antisense oligonucleotide or pharmaceutically acceptable salt thereof.

18. The conjugate compound of claim 15 , wherein the conjugate moiety is covalently attached to said antisense oligonucleotide or pharmaceutically acceptable salt thereof; and
wherein a linker is positioned between the antisense oligonucleotide or pharmaceutically acceptable salt thereof and the conjugate moiety.

19. The conjugate compound of claim 18 , wherein the linker is a physiologically labile linker.

20. The conjugate of claim 19 , wherein the physiologically labile linker is a nuclease susceptible linker.

21. The pharmaceutical composition of claim 10 wherein the pharmaceutically acceptable diluent is sterile phosphate buffered saline.

22. A pharmaceutically acceptable potassium salt of the antisense oligonucleotide conjugate of claim 1 .

23. A pharmaceutically acceptable potassium salt of the antisense oligonucleotide of claim 8 .

24. The pharmaceutical composition of claim 3 wherein the pharmaceutically acceptable diluent is sterile phosphate buffered saline.

Assignees

• Hoffmann La Roche

Inventors

• Kammler Susanne
• Lopez Anaïs
• Mueller Henrik
• Ottosen Søren
• Pedersen Lykke

Classifications

• A61K31/7115 Primary

  Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N2310/351

  Conjugate · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title