Methods for treating Alzheimer's disease
Disclosed herein are methods for reducing expression of Tau mRNA and protein in an animal with Tau antisense compounds. Also disclosed are methods for modulating splicing of Tau mRNA in an animal with Tau antisense compounds. Such methods are useful to treat, prevent, or ameliorate neurodegenerative diseases in an individual in need thereof. Examples of neurodegenerative diseases that can be treated, prevented, and ameliorated with the administration Tau antisense oligonucleotides include Alzheimer's Disease, Fronto-temporal Dementia (FTD), FTDP-17, Progressive Supranuclear Palsy, Chronic Traumatic Encephalopathy, Epilepsy, and Dravet's Syndrome.
1. A method of treating Alzheimer's disease in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a modified single-stranded antisense oligonucleotide consisting of (i) 20 to 30 linked nucleosides and having a nucleobase sequence that is selected from the group consisting of SEQ ID NOs.: 12, 13, and 14; or (ii) 18 to 30 linked nucleosides and having a nucleobase sequence that is selected from the group consisting of SEQ ID NOs.: 15, 16, 17, and 18.
2. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide has a nucleobase sequence that is set forth in SEQ ID NO: 12.
3. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide has a nucleobase sequence that is set forth in SEQ ID NO: 13.
4. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide comprises at least one modified nucleoside.
5. The method of claim 4 , wherein the modified single-stranded antisense oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.
6. The method of claim 5 , wherein the modified single-stranded antisense oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.
7. The method of claim 6 , wherein the modified single-stranded antisense oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety having a 2′-4′ bridge, wherein the 2′-4′ bridge is selected from —O—CH 2 —; —O—CH 2 —CH 2 ; and —O—CH(CH 3 )—.
8. The method of claim 4 , wherein the modified single-stranded antisense oligonucleotide comprises at least one modified nucleoside comprising a modified non-bicyclic sugar moiety.
9. The method of claim 8 , wherein the modified single-stranded antisense oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic sugar moiety comprising a 2′-O-methoxyethyl (2′-MOE) or 2′-OMe.
10. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides; wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar moiety.
11. The method of claim 5 , wherein each nucleoside of the modified single-stranded antisense oligonucleotide comprises a modified sugar moiety.
12. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide comprises at least one modified internucleoside linkage.
13. The method of claim 12 , wherein each internucleoside linkage of the modified single-stranded antisense oligonucleotide is a modified internucleoside linkage.
14. The method of claim 12 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.
15. The method of claim 14 , wherein the modified single-stranded antisense oligonucleotide comprises at least one phosphodiester internucleoside linkage.
16. The method of claim 13 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
17. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide comprises at least one modified nucleobase.
18. The method of claim 17 , wherein the modified nucleobase is a 5-methylcytosine.
19. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide comprises at least one modified internucleoside linkage, at least one modified nucleobase, and at least one modified sugar moiety.
20. The method of claim 19 , wherein the at least one modified internucleoside linkage comprises a phosphorothioate internucleoside linkage.
21. The method of claim 20 , wherein each cytosine of the modified single-stranded antisense oligonucleotide is 5-methylcytosine.
22. The method of claim 21 , wherein each sugar moiety of the modified single-stranded antisense oligonucleotide is 2′-MOE.
23. The method of claim 19 , wherein the modified single-stranded antisense oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides; wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar moiety.
24. The method of claim 23 , wherein each nucleoside of each wing segment comprises 2′-MOE.
25. The method of claim 24 , wherein the at least one modified internucleoside linkage comprises a phosphorothioate internucleoside linkage.
26. The method of claim 25 , wherein each cytosine of the modified single-stranded antisense oligonucleotide is 5-methylcytosine.
27. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide has a nucleobase sequence that is set forth in SEQ ID NO:14.
28. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide has a nucleobase sequence that is set forth in SEQ ID NO:15.
29. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide has a nucleobase sequence that is set forth in SEQ ID NO:16.
30. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide has a nucleobase sequence that is set forth in SEQ ID NO: 17.
31. The method of claim 1 , wherein the modified single-stranded antisense oligonucleotide has a nucleobase sequence that is set forth in SEQ ID NO:18.
32. The method of claim 2 , wherein each cytosine of the modified single-stranded antisense oligonucleotide is 5-methylcytosine, each sugar moiety of the modified single-stranded antisense oligonucleotide is 2′-MOE, and wherein each internucleoside linkage of the modified single-stranded antisense oligonucleotide is a phosphorothioate internucleoside linkage.
33. The method of claim 3 , wherein each cytosine of the modified single-stranded antisense oligonucleotide is 5-methylcytosine, each sugar moiety of the modified single-stranded antisense oligonucleotide is 2′-MOE, and wherein each internucleoside linkage of the modified single-stranded antisense oligonucleotide is a phosphorothioate internucleoside linkage.
34. The method of claim 27 , wherein each cytosine of the modified single-stranded antisense oligonucleotide is 5-methylcytosine, each sugar moiety of the modified single-stranded antisense oligonucleotide is 2′-MOE, and wherein each internucleoside linkage of the modified single-stranded antisense oligonucleotide is a phosphorothioate internucleoside linkage.
35. The method of claim 28 , wherein each cytosine of the modified single-stranded antisense oligonucleotide is 5-methylcytosine, each sugar moiety of the modified single-stranded antisense oligonucleotide is 2′-MOE, and wherein each internucleoside linkage of the modified single-stranded antisense oligonucleotide is a phosphorothioate internucleoside linkage.
36. The method of claim 29 , wherein each cytosine of the modified single-stranded antisense oligonucleotide is 5-methylcytosine, each sugar moiety of the modified single-stranded antisense oligonucleotide is 2′-MOE, and wherein each internucleoside linkage of the modified single-stranded antisense oligonucleotide is a phosphorothioate internucleoside linkage.
37. The method of claim 30 , wherein each cytosine of the modified single-stranded antisense oligonucleotide is 5-methylcytosine, each sugar moiety of the modified single-stranded antisense oligonucleotide is 2′-MOE, and wherein each internucleoside linkage of the modified single-stranded antisense oligonucleotide is a phosphorothioate internucleoside linkage.
38. The method of claim 31 , wherein each cytosine of the modified single-stranded antisense oligonucleotide is 5-methylcytosine, each sugar moiety of the modified single-stranded antisense oligonucleotide is 2′-MOE, and wherein each internucleoside linkage of the modified single-stranded antisense oligonucleotide is a phosphorothioate internucleoside linkage.