Compounds and methods for reducing ATXN3 expression
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN3 RNA in a cell or animal, and in certain embodiments reducing the amount of ATXN3 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 motor dysfunction, aggregation formation, and neuron death. Such neurodegenerative diseases include spinocerebellar ataxia type 3(SCA3).
1. A modified oligonucleotide according to the following chemical structure:
or a salt thereof.
2. The modified oligonucleotide of claim 1 , which is the sodium salt or the potassium salt.
3. A modified oligonucleotide according to the following chemical structure:
4. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
Ges m Ceo Teo m Ceo Aes Tds Tds Tds Ads Tds Tds m Cds Tds m Cds Ads Aeo Geo Tes Aes m Ce (SEQ ID NO: 423); wherein,
A=an adenine nucleobase,
m C=a 5-methylcytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-MOE sugar moiety,
d=a 2′-β-D deoxyribosyl sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.
5. A population of modified oligonucleotides of claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
6. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable diluent.
7. The pharmaceutical composition of claim 6 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
8. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
9. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
10. A population of modified oligonucleotides of claim 3 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
11. A pharmaceutical composition comprising the modified oligonucleotide of claim 3 and a pharmaceutically acceptable diluent.
12. The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
13. The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
14. The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
15. A population of oligomeric compounds of claim 4 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
16. A pharmaceutical composition comprising the oligomeric compound of claim 4 and a pharmaceutically acceptable diluent.
17. The pharmaceutical composition of claim 16 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
18. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and artificial cerebrospinal fluid.
19. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and PBS.
20. A method comprising administering to a subject a pharmaceutical composition of claim 6 .
21. A method of treating a disease associated with ATXN3, comprising administering to a subject having or at risk for developing a disease associated with ATXN3 a therapeutically effective amount of a pharmaceutical composition according to claim 6 and thereby treating the disease associated with ATXN3.
22. The method of claim 21 , wherein the disease associated with ATXN3 is a neurodegenerative disease.
23. The method of claim 22 , wherein the neurodegenerative disease is SCA3.
24. The method of claim 22 , wherein at least one symptom or hallmark of the neurodegenerative disease is ameliorated.
25. The method of claim 24 , wherein the symptom or hallmark is any of ataxia, neuropathy, and aggregate formation.
26. The method of claim 21 , wherein the subject is human.
27. A method of reducing expression of ATXN3 in a cell comprising contacting the cell with a modified oligonucleotide of claim 1 .
28. The method of claim 27 , wherein the cell is a human cell.
29. The method of claim 20 , wherein the subject has or is at risk for developing a disease associated with ATXN3.
30. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 5 and a pharmaceutically acceptable diluent.
31. The pharmaceutical composition of claim 30 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
32. The pharmaceutical composition of claim 31 , wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and artificial cerebrospinal fluid.
33. The pharmaceutical composition of claim 31 , wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and PBS.
34. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 10 and a pharmaceutically acceptable diluent.
35. The pharmaceutical composition of claim 34 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
36. The pharmaceutical composition of claim 35 , wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and artificial cerebrospinal fluid.
37. The pharmaceutical composition of claim 35 , wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and PBS.
38. A pharmaceutical composition comprising the population of oligomeric compounds of claim 15 and a pharmaceutically acceptable diluent.
39. The pharmaceutical composition of claim 38 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
40. The pharmaceutical composition of claim 39 , wherein the pharmaceutical composition consists essentially of the population of oligomeric compounds and artificial cerebrospinal fluid.
41. The pharmaceutical composition of claim 39 , wherein the pharmaceutical composition consists essentially of the population of oligomeric compounds and PBS.
42. A population of modified oligonucleotides of claim 2 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
43. A pharmaceutical composition comprising the modified oligonucleotide of claim 2 and a pharmaceutically acceptable diluent.
44. The pharmaceutical composition of claim 43 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artficial cerebrospinal fluid.
45. The pharmaceutical composition of claim 44 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
46. The pharmaceutical composition of claim 44 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
47. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 42 and a pharmaceutically acceptable diluent.
48. The pharmaceutical composition of claim 47 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artficial cerebrospinal fluid.
49. The pharmaceutical composition of claim 48 , wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and artificial cerebrospinal fluid.
50. The pharmaceutical composition of claim 48 , wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and PBS.