Compounds and methods for reducing ATXN2 expression
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.
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).