Compounds and methods for reducing LRRK2 expression
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of LRRK2 RNA in a cell or animal, and in certain instances reducing the amount of LRRK2 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 Parkinson's disease.
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 modified oligonucleotide according to the following chemical structure:
4. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation (5′ to 3′):
(SEQ ID NO: 852)
mCes Geo mCes Aes mCes Tds Tds Ads Ads mCds Ads
Ads Tds Ads Tds mCes Aeo Tes Aes Te;
wherein,
A=an adenine nucleobase,
mC=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.
5. A population of modified oligonucleotides of claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.
6. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable diluent or carrier.
7. The pharmaceutical composition of claim 6 , wherein the pharmaceutically acceptable diluent or carrier is phosphate-buffered saline or artificial cerebrospinal fluid.
8. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline or artificial cerebrospinal fluid.
9. A method comprising administering to a subject the pharmaceutical composition of claim 6 .
10. A population of modified oligonucleotides of claim 3 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.
11. A pharmaceutical composition comprising the modified oligonucleotide of claim 3 and a pharmaceutically acceptable diluent or carrier.
12. The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable diluent or carrier is phosphate-buffered saline or artificial cerebrospinal fluid.
13. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline or artificial cerebrospinal fluid.
14. A method comprising administering to a subject the pharmaceutical composition of claim 11 .
15. A population of oligomeric compounds of claim 4 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.
16. A pharmaceutical composition comprising the oligomeric compound of claim 4 and a pharmaceutically acceptable diluent or carrier.
17. The pharmaceutical composition of claim 16 , wherein the pharmaceutically acceptable diluent or carrier is phosphate-buffered saline or artificial cerebrospinal fluid.
18. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and phosphate-buffered saline or artificial cerebrospinal fluid.
19. A method comprising administering to a subject the pharmaceutical composition of claim 16 .
20. A method of treating Parkinson's disease comprising administering to a subject having or at risk for developing Parkinson's disease a therapeutically effective amount of the pharmaceutical composition according to claim 6 , thereby treating the Parkinson's disease.
21. The method of claim 20 , wherein at least one symptom or hallmark of Parkinson's disease is ameliorated.
22. The method of claim 21 , wherein the symptom or hallmark is any of ataxia, neuropathy, and aggregate formation.
23. The method of claim 20 , wherein the subject is human.
24. A method of reducing expression of LRRK2 in a cell comprising contacting the cell with the modified oligonucleotide of claim 1 .
25. The method of claim 24 , wherein the cell is a human cell.
26. A method of treating Parkinson's disease comprising administering to a subject having or at risk for developing Parkinson's disease a therapeutically effective amount of a pharmaceutical composition according to claim 11 , thereby treating the Parkinson's disease.
27. The method of claim 26 , wherein at least one symptom or hallmark of Parkinson's disease is ameliorated.
28. The method of claim 27 , wherein the symptom or hallmark is any of ataxia, neuropathy, and aggregate formation.
29. The method of claim 26 , wherein the subject is human.
30. A method of reducing expression of LRRK2 in a cell comprising contacting the cell with the modified oligonucleotide of claim 3 .
31. The method of claim 30 , wherein the cell is a human cell.
32. A method of treating Parkinson's disease comprising administering to a subject having or at risk for developing Parkinson's disease a therapeutically effective amount of a pharmaceutical composition according to claim 16 , and thereby treating the Parkinson's disease.
33. The method of claim 32 , wherein at least one symptom or hallmark of Parkinson's disease is ameliorated.
34. The method of claim 33 , wherein the symptom or hallmark is any of ataxia, neuropathy, and aggregate formation.
35. The method of claim 32 , wherein the subject is human.
36. A method of reducing expression of LRRK2 in a cell comprising contacting the cell with the oligomeric compound of claim 4 .
37. The method of claim 36 , wherein the cell is a human cell.