Compounds and methods for reducing Tau expression
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of Tau mRNA in a cell or animal, and in certain instances reducing the amount of Tau protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a neurodegenerative disease. Such symptoms include loss of memory, loss of motor function, and increase in the number and/or volume of neurofibrillary inclusions. Such neurodegenerative diseases include tauopathies, 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.
1. A method of reducing tau messenger ribonucleic acid (mRNA) expression in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a modified oligonucleotide according to the following formula:
or a salt thereof.
2. The method of claim 1 , wherein the salt is a sodium salt.
3. The method of claim 1 , wherein the modified oligonucleotide or salt thereof is administered intrathecally.
4. The method of claim 2 , wherein the modified oligonucleotide or salt thereof is administered intrathecally.
5. A method of reducing tau messenger ribonucleic acid (mRNA) expression in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a compound comprising a modified oligonucleotide, wherein the modified oligonucleotide is a gapmer consisting of a 5′ wing segment, a central gap segment, and a 3′ wing segment, wherein:
the 5′ wing segment consists of five 2′-MOE nucleosides,
the central gap segment consists of eight 2′-deoxynucleosides, and
the 3′ wing segment consists of five 2′-MOE nucleosides;
wherein the modified oligonucleotide has the nucleobase sequence 5′-CCGTTTTCTTACCACCCT-3′ (SEQ ID NO: 8), wherein each cytosine is a 5-methylcytosine; and wherein the internucleoside linkages of the modified oligonucleotide are, from 5′ to 3′, sossssssssssssoss, wherein each s is a phosphorothioate linkage and each o is a phosphodiester linkage.
6. The method of claim 5 , wherein the compound is administered intrathecally.
7. A method of reducing tau messenger ribonucleic acid (mRNA) expression in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a modified oligonucleotide, wherein the modified oligonucleotide is a gapmer consisting of a 5′ wing segment, a central gap segment, and a 3′ wing segment, wherein:
the 5′ wing segment consists of five 2′-MOE nucleosides,
the central gap segment consists of eight 2′-deoxynucleosides, and
the 3′ wing segment consists of five 2′-MOE nucleosides;
wherein the modified oligonucleotide has the nucleobase sequence 5′-CCGTTTTCTTACCACCCT-3′ (SEQ ID NO: 8), wherein each cytosine is a 5-methylcytosine; and wherein the internucleoside linkages of the modified oligonucleotide are, from 5′ to 3′, sossssssssssssoss, wherein each s is a phosphorothioate linkage and each o is a phosphodiester linkage.
8. The method of claim 7 , wherein the modified oligonucleotide is administered intrathecally.
9. A method of treating a neurodegenerative disease associated with tau in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a modified oligonucleotide according to the following formula:
or a salt thereof.
10. The method of claim 9 , wherein the salt is a sodium salt.
11. The method of claim 9 , wherein the neurodegenerative disease is a tauopathy.
12. The method of claim 9 , wherein the neurodegenerative disease is Alzheimer's disease, Fronto-temporal Dementia (FTD), FTDP-17, Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Epilepsy, or Dravet's Syndrome.
13. The method of claim 9 , wherein the neurodegenerative disease is Alzheimer's disease.
14. The method of claim 9 , wherein the modified oligonucleotide or salt thereof is administered intrathecally.
15. The method of claim 10 , wherein the modified oligonucleotide or salt thereof is administered intrathecally.
16. The method of claim 11 , wherein the modified oligonucleotide or salt thereof is administered intrathecally.
17. The method of claim 12 , wherein the modified oligonucleotide or salt thereof is administered intrathecally.
18. The method of claim 13 , wherein the modified oligonucleotide or salt thereof is administered intrathecally.
19. A method of treating a neurodegenerative disease associated with tau in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a compound comprising a modified oligonucleotide, wherein the modified oligonucleotide is a gapmer consisting of a 5′ wing segment, a central gap segment, and a 3′ wing segment, wherein:
the 5′ wing segment consists of five 2′-MOE nucleosides,
the central gap segment consists of eight 2′-deoxynucleosides, and
the 3′ wing segment consists of five 2′-MOE nucleosides;
wherein the modified oligonucleotide has the nucleobase sequence 5′-CCGTTTTCTTACCACCCT-3′ (SEQ ID NO: 8), wherein each cytosine is a 5-methylcytosine; and wherein the internucleoside linkages of the modified oligonucleotide are, from 5′ to 3′, sossssssssssssoss, wherein each s is a phosphorothioate linkage and each o is a phosphodiester linkage.
20. The method of claim 19 , wherein the neurodegenerative disease is a tauopathy.
21. The method of claim 19 , wherein the neurodegenerative disease is Alzheimer's disease, Fronto-temporal Dementia (FTD), FTDP-17, Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Epilepsy, or Dravet's Syndrome.
22. The method of claim 19 , wherein the neurodegenerative disease is Alzheimer's disease.
23. The method of claim 19 , wherein the compound is administered intrathecally.
24. The method of claim 20 , wherein the compound is administered intrathecally.
25. The method of claim 21 , wherein the compound is administered intrathecally.
26. The method of claim 22 , wherein the compound is administered intrathecally.
27. A method of treating a neurodegenerative disease associated with tau in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a modified oligonucleotide, wherein the modified oligonucleotide is a gapmer consisting of a 5′ wing segment, a central gap segment, and a 3′ wing segment, wherein:
the 5′ wing segment consists of five 2′-MOE nucleosides,
the central gap segment consists of eight 2′-deoxynucleosides, and
the 3′ wing segment consists of five 2′-MOE nucleosides;
wherein the modified oligonucleotide has the nucleobase sequence 5′-CCGTTTTCTTACCACCCT-3′ (SEQ ID NO: 8), wherein each cytosine is a 5-methylcytosine; and wherein the internucleoside linkages of the modified oligonucleotide are, from 5′ to 3′, sossssssssssssoss, wherein each s is a phosphorothioate linkage and each o is a phosphodiester linkage.
28. The method of claim 27 , wherein the neurodegenerative disease is a tauopathy.
29. The method of claim 27 , wherein the neurodegenerative disease is Alzheimer's disease, Fronto-temporal Dementia (FTD), FTDP-17, Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Epilepsy, or Dravet's Syndrome.
30. The method of claim 27 , wherein the neurodegenerative disease is Alzheimer's disease.
31. The method of claim 27 , wherein the modified oligonucleotide is administered intrathecally.
32. The method of claim 28 , wherein the modified oligonucleotide is administered intrathecally.
33. The method of claim 29 , wherein the modified oligonucleotide is administered intrathecally.
34. The method of claim 30 , wherein the modified oligonucleotide is administered intrathecally.
35. The method of claim 1 , wherein the salt is a potassium salt.
36. The method of claim 35 , wherein the modified oligonucleotide or salt thereof is administered intrathecally.
37. The method of claim 9 , wherein the salt is a potassium salt.
38. The method of claim 37 , wherein the modified oligonucleotide or salt thereof is administered intrathecally.