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 formula:
or a salt thereof.
2. The modified oligonucleotide of claim 1 , which is a sodium salt or a potassium salt of the formula.
3. A modified oligonucleotide according to the following formula:
4. A chirally enriched population of modified oligonucleotides of claim 1 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration.
5. The chirally enriched population of claim 4 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) configuration.
6. The chirally enriched population of claim 4 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Rp) configuration.
7. The chirally enriched population of claim 4 , wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage.
8. The chirally enriched population of claim 7 , wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each phosphorothioate internucleoside linkage.
9. The chirally enriched population of claim 7 , wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at each phosphorothioate internucleoside linkage.
10. The chirally enriched population of claim 4 , wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp-Sp-Rp configuration, in the 5′ to 3′ direction.
11. A population of modified oligonucleotides of claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
12. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 , and a pharmaceutically acceptable diluent or carrier.
13. The pharmaceutical composition of claim 12 , comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).
14. The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).
15. An oligomeric compound comprising a modified oligonucleotide according to the following formula:
T es G eo G eo A eo T eo T eo m C ds T ds G ds T ds A ds m C ds T ds T ds T ds T ds m C eo T es m C es A e (SEQ ID NO: 3235);
wherein,
A=an adenine nucleobase,
m C=a 5′-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-MOE modified sugar,
d=a 2′-deoxyribose sugar,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.
16. A pharmaceutical composition comprising the chirally enriched population of modified oligonucleotides of claim 4 , and a pharmaceutically acceptable diluent or carrier.
17. The oligomeric compound of claim 15 , wherein the modified oligonucleotide is covalently linked to a conjugate group.
18. An oligomeric duplex comprising the modified oligonucleotide of claim 1 .
19. An oligomeric duplex comprising the oligomeric compound of claim 15 .
20. A pharmaceutical composition comprising the oligomeric compound of claim 15 and a pharmaceutically acceptable carrier or diluent.
21. The pharmaceutical composition of claim 20 , comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).
22. The pharmaceutical composition of claim 20 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).
23. A pharmaceutical composition comprising the oligomeric compound of claim 17 and a pharmaceutically acceptable carrier or diluent.
24. The pharmaceutical composition of claim 23 , comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).
25. The pharmaceutical composition of claim 23 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).
26. The chirally enriched population of claim 7 , wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages.
27. The modified oligonucleotide of claim 1 , which is a potassium salt of the formula.
28. A pharmaceutical composition comprising the modified oligonucleotide of claim 3 and a pharmaceutically acceptable carrier or diluent.
29. The pharmaceutical composition of claim 28 , comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).
30. The pharmaceutical composition of claim 28 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBC) or artificial cerebrospinal fluid (aCSF).
31. A pharmaceutical composition comprising the modified oligonucleotide of claim 27 and a pharmaceutically acceptable carrier or diluent.
32. The pharmaceutical composition of claim 31 , comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).
33. The pharmaceutical composition of claim 31 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).
34. A pharmaceutical composition comprising the oligomeric duplex of claim 18 and a pharmaceutically acceptable carrier or diluent.
35. The pharmaceutical composition of claim 34 , comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).
36. The pharmaceutical composition of claim 34 , wherein the pharmaceutical composition consists essentially of the oligomeric duplex and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).