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 modified oligonucleotide according to the following formula:
or a salt thereof.
2. The modified oligonucleotide of claim 1 , which is a sodium salt of the formula.
3. 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.
4. 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.
5. A chirally enriched population of modified oligonucleotides of claim 1 wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration.
6. The chirally enriched population of claim 5 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) configuration.
7. The chirally enriched population of claim 5 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Rp) configuration.
8. The chirally enriched population of claim 5 , wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage.
9. The chirally enriched population of claim 8 , wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each phosphorothioate internucleoside linkage.
10. The chirally enriched population of claim 8 , wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at each phosphorothioate internucleoside linkage.
11. The chirally enriched population of claim 8 , wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages.
12. The chirally enriched population of claim 5 , wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5′ to 3′ direction.
13. A chirally enriched population of modified oligonucleotides of claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
14. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable diluent or carrier.
15. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 5 and a pharmaceutically acceptable diluent or carrier.
16. The pharmaceutical composition of claim 14 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial CSF (aCSF).
17. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS) or artificial CSF (aCSF).
18. The chirally enriched population of claim 8 wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5′ to 3′ direction.
19. The compound of claim 3 , wherein the modified oligonucleotide is linked to a conjugate group.
20. An oligomeric duplex comprising the modified oligonucleotide of claim 1 .
21. An oligomeric duplex comprising the compound of claim 3 .
22. An oligomeric duplex comprising the modified oligonucleotide of claim 4 .
23. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier or diluent.
24. The pharmaceutical composition of claim 23 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial CSF (aCSF).
25. The pharmaceutical composition of claim 23 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS) or artificial CSF (aCSF).
26. A pharmaceutical composition comprising the modified oligonucleotide of claim 4 and a pharmaceutically acceptable carrier or diluent.
27. The pharmaceutical composition of claim 26 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial CSF (aCSF).
28. The pharmaceutical composition of claim 26 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS) or artificial CSF (aCSF).
29. A pharmaceutical composition comprising the compound of claim 19 and a pharmaceutically acceptable carrier or diluent.
30. The pharmaceutical composition of claim 29 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial CSF (aCSF).
31. The pharmaceutical composition of claim 29 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS) or artificial CSF (aCSF).