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 5 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:
(SEQ ID NO: 3590)
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:
(SEQ ID NO: 3590).
4. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
Aes mCeo Geo mCeo Aes mCds Tds Tds Ads Ads mCds Ads Ads Tds Ads Teo mCeo Aes Tes Ae (SEQ ID NO: 3590); wherein,
A=an adenine nucleobase,
mC=a 5-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-OCH 2 CH 2 OCH 3 ribosyl sugar moiety,
d=a 2′-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 oligonucleotides are stereorandom.
6. A pharmaceutical composition comprising a 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 oligonucleotides are stereorandom.
11. A pharmaceutical composition comprising a 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 compund and artificial cerebrospinal fluid.
19. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition consists essentially of the oligomeric compund and PBS.
20. A method comprising administering to a subject a pharmaceutical composition of claim 6 .
21. 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 6 and thereby treating Parkinson's disease.
22. The method of claim 21 , wherein at least one symptom or hallmark of Parkinson's disease is ameliorated.
23. The method of claim 22 , wherein the symptom or hallmark is any of ataxia, neuropathy, and aggregate formation.
24. A method of reducing expression of LRRK2 in a cell comprising contacting the cell with a modified oligonucleotide of claim 1 .
25. The method of claim 21 , wherein the subject is human.
26. The method of claim 24 , wherein the cell is a human cell.