Compounds and methods for reducing ATXN2 expression

Patent metadata

Field	Value
Publication number	US-11926825-B2
Application number	US-202117238814-A
Country	US
Kind code	B2
Filing date	Apr 23, 2021
Priority date	Jul 25, 2018
Publication date	Mar 12, 2024
Grant date	Mar 12, 2024

Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN2 RNA in a cell or animal, and in certain instances reducing the amount of Ataxin-2 protein in a cell or animal Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. Such neurodegenerative diseases include spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and parkinsonism.

First claim

The invention claimed is:

1. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

2. The modified oligonucleotide of claim 1 , which is a sodium salt or a potassium salt.

3. A population of modified oligonucleotides of claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

4. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 , and a pharmaceutically acceptable diluent.

5. The pharmaceutical composition of claim 4 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

6. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

7. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 3 and a pharmaceutically acceptable diluent.

8. The pharmaceutical composition of claim 7 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

9. A pharmaceutical composition comprising the modified oligonucleotide of claim 2 and a pharmaceutically acceptable diluent.

10. The pharmaceutical composition of claim 9 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

11. A population of modified oligonucleotides of claim 2 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

12. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 11 , and a pharmaceutically acceptable diluent.

13. The pharmaceutical composition of claim 12 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

14. A modified oligonucleotide according to the following chemical structure:

15. A pharmaceutical composition comprising the modified oligonucleotide of claim 14 , and a pharmaceutically acceptable diluent.

16. The pharmaceutical composition of claim 15 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

17. A population of modified oligonucleotides of claim 14 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

18. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 17 , and a pharmaceutically acceptable diluent.

19. The pharmaceutical composition of claim 18 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

20. An oligomeric compound comprising a modified oligonucleotide according to the following formula:
Ges Teo Aeo mCeo Teo Tds Tds Tds mCds Tds mCds Ads Tds Gds Tds Geo mCeo Ges Ges mCe (SEQ ID NO: 1714); wherein,
A=an adenine nucleobase,
mC=a 5 methylcytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-O(CH 2 ) 2 OCH 3 ribosyl sugar moiety,
d=a 2′-deoxyribosyl sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.

21. A pharmaceutical composition comprising the oligomeric compound of claim 20 and a pharmaceutically acceptable diluent.

22. The pharmaceutical composition of claim 21 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

23. The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

24. A population of oligomeric compounds of claim 20 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

25. A pharmaceutical composition comprising the population of oligomeric compounds of claim 24 , and a pharmaceutically acceptable diluent.

26. The pharmaceutical composition of claim 25 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Freier Susan M
• Rigo Frank

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

• A61K47/02

  Inorganic compounds · CPC title

• A61K47/46

  Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N2310/315

  Phosphorothioates · CPC title