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: 56, 57, 248, 462-467, 1668-1698, 2025-2048, 2301-2309, 2331-2443, 2478-2483, and 2532-2565, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1, and wherein the modified oligonucleotide comprises at least one modified internucleoside linkage and/or at least one modified sugar.
2. The compound of claim 1 , wherein the modified oligonucleotide is a single-stranded oligonucleotide.
3. The compound of claim 1 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.
4. The compound of claim 3 , 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 1 , 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 the 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 8 , wherein the at least one modified sugar comprises a 2′-O-methoxyethyl group or a 2′-O-methyl group.
13. The compound of claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a sugar surrogate.
14. The compound of claim 13 , wherein the sugar surrogate is a morpholino or a peptide nucleic acid.
15. 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;
a gap segment having from 8 to 15 nucleosides and wherein each nucleoside of the gap segment is a deoxynucleoside.
16. 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;
a gap segment having from 8 to 15 nucleosides and wherein each nucleoside of the gap segment is a deoxynucleoside.
17. The compound of claim 16 , 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.
18. The compound of claim 17 , wherein the at least one modified sugar is a bicyclic sugar.
19. The compound of claim 18 , 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.
20. The compound of claim 19 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is methyl.
21. The compound of claim 1 , wherein the compound comprises a conjugate group.
22. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
23. A method of treating a tau associated disease comprising administering the composition of claim 22 .
24. The method of claim 23 , wherein the tau associated disease is a neurodegenerative disorder.
25. The method of claim 24 , wherein the neurodegenerative disorder is selected from among a Tauopathy, Alzheimer's Disease, Fronto-temporal Dementia (FTD), FTDP-17, Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Epilepsy, and Dravet's Syndrome.
26. The compound of claim 10 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is H.
27. 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 .
28. The compound of claim 19 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is H.
29. The compound of claim 19 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is —CH 2 —O—CH 3 .
30. A compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 135867 to 135887 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1, and wherein the modified oligonucleotide comprises at least one modified internucleoside linkage and/or at least one modified sugar.
31. The compound of claim 30 , wherein the modified oligonucleotide is a single-stranded oligonucleotide.
32. The compound of claim 30 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.
33. The compound of claim 32 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
34. The compound of claim 33 , wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphodiester internucleoside linkage.
35. The compound of claim 30 , wherein at least one nucleobase of the modified oligonucleotide is a modified nucleobase.
36. The compound of claim 35 , wherein the modified nucleobase is a 5-methylcytosine.
37. The compound of claim 30 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar.
38. The compound of claim 37 , wherein the at least one modified sugar is a bicyclic sugar.
39. The compound of claim 38 , 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.
40. The compound of claim 39 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is methyl.
41. The compound of claim 39 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is H.
42. The compound of claim 39 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is —CH 2 —O—CH 3 .
43. The compound of claim 37 , wherein the at least one modified sugar comprises a 2′-O-methoxyethyl group or a 2′-O-methyl group.
44. The compound of claim 30 , wherein at least one nucleoside of the modified oligonucleotide comprises a sugar surrogate.
45. The compound of claim 44 , wherein the sugar surrogate is a morpholino or a peptide nucleic acid.
46. The compound of claim 30 , 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;
a gap segment having from 8 to 15 nucleosides and wherein each nucleoside of the gap segment is a deoxynucleoside.
47. The compound of claim 30 , 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;
a gap segment having from 8 to 15 nucleosides and wherein each nucleoside of the gap segment is a deoxynucleoside.
48. The compound of claim 47 , 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.
49. The compound of claim 48 , wherein the at least one modified sugar is a bicyclic sugar.
50. The compound of claim 49 , 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.
51. The compound of claim 50 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is methyl.
52. The compound of claim 50 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is H.
53. The compound of claim 50 , wherein at least one chemical bridge is 4′-CH(R)—O-2′ and wherein R is —CH 2 —O—CH 3 .
54. The compound of claim 30 , wherein the compound comprises a conjugate group.
55. A composition comprising a compound according to claim 30 and a pharmaceutically acceptable carrier or diluent.
56. A method of treating a tau associated disease comprising administering the composition of claim 55 .
57. The method of claim 56 , wherein the tau associated disease is a neurodegenerative disorder.
58. The method of claim 57 , wherein the neurodegenerative disorder is selected from among a Tauopathy, Alzheimer's Disease, Fronto-temporal Dementia (FTD), FTDP-17, Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Epilepsy, and Dravet's Syndrome.