Compositions for modulating Tau expression
Disclosed herein are antisense compounds and methods for decreasing Tau mRNA and protein expression. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate Tau-associated diseases, disorders, and conditions.
1. A compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of a sequence selected from among SEQ ID Nos:1699, 1700, 1701, 1702, and 1703, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1.
2. The compound of claim 1 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.
3. The compound of claim 2 , wherein the modified oligonucleotide is a single-stranded oligonucleotide.
4. The compound of claim 2 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
5. The compound of claim 4 , wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphodiester internucleoside linkage.
6. The compound of claim 2 , wherein at least one nucleobase of the modified oligonucleotide is a modified nucleobase.
7. The compound of claim 6 , wherein the modified nucleobase is a 5-methylcytosine.
8. The compound of claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.
9. The compound of claim 8 , wherein at least one modified sugar is a bicyclic sugar.
10. The compound of claim 9 , wherein each bicyclic sugar comprises a chemical bridge between the 4′ and 2′ positions of the sugar, wherein each chemical bridge is independently selected from: 4′-CH(R)—O-2′ and 4′-(CH 2 ) 2 —O-2′, wherein each R is independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
11. The compound of claim 10 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is methyl.
12. The compound of claim 10 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is H.
13. The compound of claim 10 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is —CH 2 —O—CH 3 .
14. The compound of claim 7 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group or a 2′-O-methyl group.
15. The compound of claim 1 , wherein the at least one nucleoside of the modified oligonucleotide comprises a sugar surrogate.
16. The compound of claim 15 , wherein the at least one sugar surrogate is a morpholino or a peptide nucleic acid.
17. The compound of claim 1 , wherein the modified oligonucleotide comprises:
a 5′ wing segment having from 1 to 6 nucleosides and wherein each nucleoside of the 5′ wing segment comprises a modified sugar;
a 3′ wing segment having from 1 to 6 nucleosides and wherein each nucleoside of the 3′ wing segment comprises a modified sugar; and
a gap segment having from 8 to 15 nucleosides and wherein each nucleoside of the gap segment is a deoxynucleoside.
18. The compound of claim 1 , wherein the compound comprises a conjugate group.
19. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
20. A compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and comprising a nucleobase sequence having at least 8 consecutive nucleobases complementary to an equal length portion of nucleobases 139811 to 139836 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1.
21. The compound of claim 20 , wherein the nucleobase sequence has at least 12 consecutive nucleobases selected from among SEQ ID Nos: 1699 -1703.
22. The compound of claim 20 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.
23. The compound of claim 22 , wherein the modified oligonucleotide is a single-stranded oligonucleotide.
24. The compound of claim 22 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
25. The compound of claim 24 , wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphodiester internucleoside linkage.
26. The compound of claim 22 , wherein at least one nucleobase of the modified oligonucleotide is a modified nucleobase.
27. The compound of claim 26 , wherein the modified nucleobase is a 5-methylcytosine.
28. The compound of claim 20 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.
29. The compound of claim 28 , wherein at least one modified sugar is a bicyclic sugar.
30. The compound of claim 29 , wherein each bicyclic sugar comprises a chemical bridge between the 4′ and 2′ positions of the sugar, wherein each chemical bridge is independently selected from: 4′-CH(R)—O-2′ and 4′-(CH 2 ) 2 —O-2′, wherein each R is independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
31. The compound of claim 30 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is methyl.
32. The compound of claim 30 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is H.
33. The compound of claim 30 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is —CH 2 —O—CH 3 .
34. The compound of claim 28 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group or a 2′-O-methyl group.
35. The compound of claim 20 , wherein the at least one nucleoside of the modified oligonucleotide comprises a sugar surrogate.
36. The compound of claim 35 , wherein the at least one sugar surrogate is a morpholino or a peptide nucleic acid.
37. The compound of claim 20 , wherein the modified oligonucleotide comprises:
a 5′ wing segment having from 1 to 6 nucleosides and wherein each nucleoside of the 5′ wing segment comprises a modified sugar;
a 3′ wing segment having from 1 to 6 nucleosides and wherein each nucleoside of the 3′ wing segment comprises a modified sugar; and
a gap segment having from 8 to 15 nucleosides and wherein each nucleoside of the gap segment is a deoxynucleoside.
38. The compound of claim 20 , wherein the compound comprises a conjugate group.
39. A composition comprising a compound according to claim 20 and a pharmaceutically acceptable carrier or diluent.
40. The compound of claim 1 , wherein the modified oligonucleotide comprises:
a 5′ wing segment having from 1 to 6 nucleosides and wherein at least 4 nucleosides of the 5′ wing segment comprises a modified sugar;
a 3′ wing segment having from 1 to 6 nucleosides and wherein at least 4 nucleosides of the 3′ wing segment comprises a modified sugar; and
a gap segment having from 8 to 15 nucleosides and wherein each nucleoside of the gap segment is a deoxynucleoside.
41. The compound of claim 40 , wherein 1 or 2 nucleosides of the 5′ wing segment is a deoxynucleoside and 1 or 2 nucleosides of the 3′ wing segment is a deoxynucleoside.
42. The compound of claim 41 , wherein at least one modified sugar is a bicyclic sugar.
43. The compound of claim 42 , wherein each bicyclic sugar comprises a chemical bridge between the 4′ and 2′ positions of the sugar, wherein each chemical bridge is independently selected from: 4′-CH(R)—O-2′ and 4′-(CH 2 ) 2 —O-2′, wherein each R is independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
44. The compound of claim 20 , wherein the modified oligonucleotide comprises:
a 5′ wing segment having from 1 to 6 nucleosides and wherein at least 4 nucleosides of the 5′ wing segment comprises a modified sugar;
a 3′ wing segment having from 1 to 6 nucleosides and wherein at least 4 nucleosides of the 3′ wing segment comprises a modified sugar; and
a gap segment having from 8 to 15 nucleosides and wherein each nucleoside of the gap segment is a deoxynucleoside.
45. The compound of claim 44 , wherein 1 or 2 nucleosides of the 5′ wing segment is a deoxynucleoside and 1 or 2 nucleosides of the 3′ wing segment is a deoxynucleoside.
46. The compound of claim 45 , wherein at least one modified sugar is a bicyclic sugar.
47. The compound of claim 46 , wherein each bicyclic sugar comprises a chemical bridge between the 4′ and 2′ positions of the sugar, wherein each chemical bridge is independently selected from: 4′-CH(R)—O-2′ and 4′-(CH 2 ) 2 —O-2′, wherein each R is independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.