Modulation of frataxin expression
View Patent ↗Certain embodiments are directed to methods and compounds for increasing FXN. Such methods and compounds are useful for increasing expression of FXN in cells and animals.
1. A method of treating, preventing, or ameliorating a disease associated with frataxin in an individual comprising administering to the individual a compound targeted to the repeat of frataxin thereby treating, preventing, or ameliorating the disease, wherein the compound comprises a modified oligonucleotide 16 to 80 linked nucleosides in length having a nucleobase sequence comprising at least 16 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 and wherein the compound comprises a sugar motif selected from the group consisting of e16, (edd)5-e, (kdd)5-k, (kee)5k, e18, e-(edd)5ee, k-(kdd)5kk, k-(kee)5-kk, and e-(fm)9-ee, where e represents a 2′-methoxyethyl modified nucleoside, d represents a 2′-deoxy nucleoside, k represents a 2′-cEt modified nucleoside, f represents a 2′F modified nucleoside and m represents a 2′OMe modified nucleoside.
2. The method of claim 1 , wherein the disease is Friedreich's Ataxia.
3. The method of claim 1 , wherein administering the compound inhibits, reduces, or improves the symptoms of Friedreich's Ataxia.
4. A method of increasing expression of frataxin in a cell comprising contacting the cell with a compound targeted to the GAA repeat of frataxin, thereby increasing expression of frataxin in the cell, wherein the compound comprises a modified oligonucleotide 16 to 80 linked nucleosides in length having a nucleobase sequence comprising at least 16 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 and wherein the compound comprises a sugar motif selected from the group consisting of e16, (edd)5-e, (kdd)5-k, (kee)5k, e18, e-(edd)5ee, k-(kdd)5kk, k-(kee)5-kk, and e-(fm)9-ee, where e represents a 2′-methoxyethyl modified nucleoside, d represents a 2′-deoxy nucleoside, k represents a 2′-cEt modified nucleoside, f represents a 2′F modified nucleoside and m represents a 2′OMe modified nucleoside.
5. The method of claim 4 , wherein the cell is in the CNS of an individual.
6. The method of claim 5 , wherein the individual has, or is at risk of having, Friedreich's ataxia.
7. The method of claim 1 , wherein the compound is administered to the CNS of the individual.
8. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage or at least one modified nucleobase.
9. The method of claim 8 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
10. The method of claim 1 , wherein the compound is single-stranded.
11. The method of claim 1 , wherein the compound is double-stranded.
12. The method of claim 1 , wherein the sugar motif is (edd)5-e, where e represents a 2′-methoxyethyl modified nucleoside and d represents a 2′-deoxy nucleoside.
13. The method of claim 1 , wherein the sugar motif is (kdd)5-k, where k represents a 2′-cEt modified nucleoside and d represents a 2′-deoxy nucleoside.
14. The method of claim 1 , wherein the sugar motif is (kee)5-k, where k represents a 2′-cEt modified nucleoside and e represents a 2′-methoxyethyl modified nucleoside.
15. The method of claim 1 , wherein each internucleoside linkage is selected from phosphorothioate internucleoside linkage and phosphodiester internucleoside linkage.
16. The method of claim 1 , wherein each internucleoside linkage is phosphorothioate.
17. The method of claim 8 , wherein each sugar is a modified sugar.
18. The method of claim 17 , wherein each modified sugar is a 2′-methoxyethyl sugar.
19. The method of claim 10 , wherein the single-stranded oligonucleotide consists of 16 to 30 linked nucleosides having a nucleobase sequence complementary to a repeat region of an expanded repeat-containing target RNA, wherein the 5′-terminal nucleoside of the single-stranded oligonucleotide comprises a stabilized phosphate moiety and an internucleoside linking group linking the 5′-terminal nucleoside to the remainder of the single-stranded oligonucleotide.
20. The method of claim 19 , wherein the single-stranded oligonucleotide has a nucleobase sequence comprising at least 16 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 14, 15, or 16.
21. The method of claim 1 , wherein the sugar motif is e-(edd)5-ee, where e represents a 2′-methoxyethyl modified nucleoside and d represents a 2′-deoxy nucleoside.
22. The method of claim 1 , wherein the sugar motif is k-(kdd)5-kk, where k represents a 2′-cEt modified nucleoside and d represents a 2′-deoxy nucleoside.
23. The method of claim 1 , wherein the sugar motif is k-(kee)5-kk, where k represents a 2′-cEt modified nucleoside and e represents a 2′-methoxyethyl modified nucleoside.