Compositions for modulating SOD-1 expression
Disclosed herein are antisense compounds and methods for decreasing SOD-1 mRNA and protein expression. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate SOD-1 associated diseases, disorders, and conditions. Such SOD-1 associated diseases include amyotrophic sclerosis (ALS).
1. A method for treating a superoxide dismutase 1 (SOD1) associated neurodegenerative disorder in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent; and an antisense oligonucleotide having the following formula:
5′-mCes Aeo Ges Geo Aes Tds Ads mCds Ads Tds Tds Tds mCds Tds Ads mCeo Aes Geo mCes Te -3′ (nucleobase sequence of SEQ ID NO: 725); wherein,
A=an adenine,
mC=a 5-methylcytosine,
G=a guanine,
T=a thymine,
e=a 2′-O-methoxyethylribose modified sugar,
d=a 2′-deoxyribose sugar,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage; or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the pharmaceutically acceptable carrier or diluent is a sterile aqueous solution.
3. The method of claim 1 , wherein the pharmaceutically acceptable carrier or diluent is phosphate buffered saline (PBS).
4. The method of claim 1 , wherein the pharmaceutical composition is administered intrathecally.
5. The method of claim 1 , wherein the SOD1 associated neurodegenerative disorder is amyotrophic lateral sclerosis (ALS) associated with a mutation in the SOD1 gene.
6. The method of claim 5 , wherein the mutation is a missense mutation.
7. The method of claim 5 , wherein the mutation is a gain of function mutation.
8. The method of claim 5 , wherein the ALS is familial SOD1 associated ALS.
9. The method of claim 5 , wherein the ALS is sporadic SOD1 associated ALS.
10. The method of claim 5 , wherein the pharmaceutical composition is administered intrathecally.
11. The method of claim 8 , wherein the pharmaceutical composition is administered intrathecally.
12. The method of claim 9 , wherein the pharmaceutical composition is administered intrathecally.
13. A method for treating a superoxide dismutase 1 (SOD1) associated neurodegenerative disorder in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent; and an antisense oligonucleotide according to the following formula:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the pharmaceutically acceptable carrier or diluent is a sterile aqueous solution.
15. The method of claim 13 , wherein the pharmaceutically acceptable carrier or diluent is PBS.
16. The method of claim 13 , wherein the pharmaceutical composition is administered intrathecally.
17. The method of claim 13 , wherein the SOD1 associated neurodegenerative disorder is amyotrophic lateral sclerosis (ALS) associated with a mutation in the SOD1 gene.
18. The method of claim 17 , wherein the mutation is a missense mutation.
19. The method of claim 17 , wherein the mutation is a gain of function mutation.
20. The method of claim 17 , wherein the ALS is familial SOD1 associated ALS.
21. The method of claim 17 , wherein the ALS is sporadic SOD1 associated ALS.
22. The method of claim 17 , wherein the pharmaceutical composition is administered intrathecally.
23. The method of claim 20 , wherein the pharmaceutical composition is administered intrathecally.
24. The method of claim 21 , wherein the pharmaceutical composition is administered intrathecally.