Enhanced oligonucleotides for inhibiting RTEL1 expression

Patent metadata

Field	Value
Publication number	US-11898145-B2
Application number	US-202217590754-A
Country	US
Kind code	B2
Filing date	Feb 1, 2022
Priority date	Feb 2, 2021
Publication date	Feb 13, 2024
Grant date	Feb 13, 2024

Abstract

The present disclosure provides antisense oligonucleotides targeting Regulator of telomere elongation helicase 1 (RTEL1). The disclosure also provides, enhanced antisense oligonucleotides targeting RTEL1 for use in treating and/or preventing a hepatitis B virus (HBV) infection. Also disclosed are pharmaceutical compositions and their use.

First claim

The invention claimed is:

1. An antisense oligonucleotide consisting of CTttattataactTgaAtCTC (SEQ ID NO 6), wherein capital letters are beta-D-oxy LNA nucleosides, lowercase letters are DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages.

2. The antisense oligonucleotide of claim 1 , wherein at least one conjugate moiety is covalently attached to said antisense oligonucleotide.

3. The antisense oligonucleotide of claim 2 , wherein the at least one conjugate moiety binds to the asialoglycoprotein receptor.

4. The antisense oligonucleotide of claim 2 , wherein the conjugate moiety is:

5. The antisense oligonucleotide of claim 4 , wherein the conjugate moiety is the trivalent GalNAc moiety:

or a mixture of both trivalent GalNAc moieties.

6. The antisense oligonucleotide of claim 2 , comprising a linker positioned between the antisense oligonucleotide and the conjugate moiety.

7. The antisense oligonucleotide of claim 6 , wherein the linker comprises 2 to 5 consecutive phosphodiester-linked nucleosides.

8. The conjugate that is:

9. A pharmaceutically acceptable salt of the antisense oligonucleotide of claim 1 .

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

11. An in vitro method for modulating RTEL1 expression in a target cell which is expressing RTEL1, said method comprising administering the antisense oligonucleotide of claim 1 , in an effective amount to said cell.

12. A method for treating a hepatitis B virus (HBV) infection in a subject in need thereof, comprising administering a therapeutically effective amount of the antisense oligonucleotide of claim 1 to the subject, wherein said administration results in inhibition of the HBV infection.

13. A pharmaceutically acceptable salt of the antisense oligonucleotide of claim 2 .

14. A pharmaceutical composition comprising the antisense oligonucleotide of claim 2 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

15. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 9 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

16. A pharmaceutical composition comprising the pharmaceutically acceptable salt of the conjugate of claim 13 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

17. The method of claim 12 , wherein the hepatitis B virus (HBV) infection is chronic HBV infection.

Assignees

• Hoffmann La Roche

Inventors

• Funder Erik
• Hruschka Natascha
• Kammler Susanne
• Koller Erich
• Leonard Brian
• Luangsay Souphalone
• Mohr Susanne
• Nilsson Tobias
• Ottosen Søren
• Pedersen Lykke
• Rasmussen Søren V
• Schmidt Steffen
• Sewing Sabine
• Turley Daniel
• Walther Johanna Marie

Classifications

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61P31/20

  for DNA viruses · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N2310/315

  Phosphorothioates · CPC title