METHODS FOR MODULATING EXPRESSION OF C9ORF72 ANTISENSE TRANSCRIPT

• US 20160237432A1
• Filed: 10/14/2014
• Published: 08/18/2016
• Est. Priority Date: 10/14/2013
• Status: Abandoned Application

• Current Assignee: Ionis Pharmaceuticals, Inc., Ludwig Institute for Cancer Research, Ltd., Regents of the University of California (University of California)
• Original Assignee: Ionis Pharmaceuticals, Inc., Ludwig Institute for Cancer Research, Ltd., Regents of the University of California (University of California)
• Inventors: Bennett, C. Frank, Lagier-Tourenne, Clotilde, Rigo, Frank, Cleveland, Don W., Ravits, John M., Baughn, Michael W.
• Application Number:
  US15/029,210
• Publication Number:
  US 20160237432A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/113 targeting other non-coding nucleic acids, e.g. antagomirs
• CPC Class Codes: C12N 2310/20 involving clustered regularly interspaced short palindromic repeats [CRISPRs]
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy

Abstract

Disclosed herein are methods for reducing expression of C90RF72 antisense transcript in an animal with C90RF72 antisense transcript specific inhibitors. Such methods are useful to treat, prevent, or ameliorate neurodegenerative diseases in an individual in need thereof. Such C90RF72 antisense transcript specific inhibitors include antisense compounds.

Claims

1. A method, comprising contacting a cell with a C9ORF72 antisense transcript specific inhibitor.

5. The method of any of claim 1-4, wherein the C9ORF72 antisense specific inhibitor is an antisense compound.

7. The method of any of claims 1-6, wherein the cell is in vitro.

8. The method of any of claims 1-6, wherein the cell is in an animal.

21. The method of any preceding claim, wherein the C9ORF72 antisense transcript specific antisense compound is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to a C9ORF72 antisense transcript.

22. The method of any preceding claim, wherein the C9ORF72 sense transcript specific antisense compound is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to a C9ORF72 sense transcript.

23. The method of any preceding claim, wherein the C9ORF72 antisense transcript is SEQ ID NO:

11.

24. The method of any preceding claim, wherein the C9ORF72 sense transcript is any of SEQ ID NO:

1-10.

28. The method of any preceding claim, wherein the contacting or administering reduces C9ORF72 foci.

29. The method of claim 28, wherein the C9ORF72 foci are C9ORF72 sense foci.

30. The method of claim 28, wherein the C9ORF72 foci are C9ORF72antisense foci.

31. The method of claim 28, wherein the C9ORF72 foci are both C9ORF72 sense foci and C9ORF72 antisense foci.

32. The method of any preceding claim, wherein the contacting or administering reduces C9ORF72 antisense transcript associated RAN translation products.

39. The method of any preceding claim, wherein the C9ORF72 antisense transcript specific antisense compound is an antisense oligonucleotide.

40. The method of any preceding claim, wherein the C9ORF72 sense transcript specific antisense compound is an antisense oligonucleotide.

41. The method of claim 39 or 40, wherein the antisense oligonucleotide is a modified antisense oligonucleotide.

42. The method of claim 41, wherein at least one internucleoside linkage of the antisense oligonucleotide is a modified internucleoside linkage.

43. The method of claim 42, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

44. The method of claim 43, wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.

45. The method of claims 39-44, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified nucleobase.

46. The method of claim 45, wherein the modified nucleobase is a 5-methylcytosine.

47. The method of claims 39-46, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified sugar.

48. The method of claim 47, wherein the at least one modified sugar is a bicyclic sugar.

49. The method of claim 48, wherein the bicyclic sugar comprises a chemical bridge between the 2′

and 4′

position of the sugar, wherein the chemical bridge is selected from;

4′

-CH₂—

O-2′

;

4′

-CH(CH₃)—

O-2′

;

4′

-(CH₂)₂—

O-2′

; and

4′

-CH₂—

N(R)—

O-2′

wherein R is, independently, H, C₁-C₁₂ alkyl, or a protecting group.

50. The method of claim 47, wherein at least one modified sugar comprises a 2′

-O-methoxyethyl group.

51. The method of any preceding claim, wherein the antisense oligonucleotide is a gapmer.

2. A method, comprising contacting a cell with a C9ORF72 antisense transcript specific inhibitor and a C9ORF72 sense transcript specific inhibitor.

3. A method, comprising contacting a cell with a C9ORF72 antisense transcript specific inhibitor;

and thereby reducing the level or expression of C9ORF72 antisense transcript in the cell.

4. A method, comprising contacting a cell with a C9ORF72 antisense transcript specific inhibitor and a C9ORF72 sense transcript specific inhibitor;

and thereby reducing the level or expression of both C9ORF72 antisense transcript and C9ORF72 sense transcript in the cell.

6. The method of any of claim 4 or 5, wherein the C9ORF72 antisense transcript specific inhibitor is an antisense compound.

9. A method, comprising administering to an animal in need thereof a therapeutically effective amount of a C9ORF72 antisense transcript specific inhibitor.

10. The method of claim 9, wherein said amount is effective to reduce the level or expression of the C9ORF72 antisense transcript.

13. The method of claim 9-12, wherein the C9ORF72 antisense transcript inhibitor is a C9ORF72 antisense transcript specific antisense compound.

11. A method, comprising coadministering to an animal in need thereof a therapeutically effective amount of a C9ORF72 antisense transcript inhibitor and a therapeutically effective amount of a C9ORF72 sense transcript inhibitor.

12. The method of claim 11, wherein said amount is effective to reduce the level or expression of the C9ORF72 antisense transcript and the C9ORF72 sense transcript.

14. The method of claims 11-13, wherein the C9ORF72 sense transcript inhibitor is a C9ORF72 sense transcript specific antisense compound.

15. A method, comprising:

identifying an animal having a C9ORF72 associated disease; and

administering to the animal a therapeutically effective amount of a C9ORF72 antisense transcript specific inhibitor.

16. The method of claim 15, wherein the amount is effective to reduce the level or expression of the C9OR72 antisense transcript.

19. The method of claims 15-18, wherein the C9ORF72 antisense transcript specific inhibitor is a C9ORF72 antisense transcript specific antisense compound.

25. The method of claims 15-24, wherein the C9ORF72 associated disease is a C9ORF72 hexanucleotide repeat expansion associated disease.

26. The method of claims 19-25, wherein the C9ORF72 associated disease or C9ORF72 hexanucleotide repeat expansion associated disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), corticalbasal degeneration syndrome (CBD), atypical Parkinsonian syndrome, or olivopontocerellar degeneration (OPCD).

27. The method of claim 26, wherein the amyotrophic lateral sclerosis (ALS) is familial ALS or sporadic ALS.

34. The method of claims 15-33, wherein the administering and coadministering is parenteral administration.

36. The method of claims 34 and 35, wherein the parenteral administration is any of intrathecal administration or intracerebroventricular administration.

37. The method of claims 19-24, wherein at least one symptom of a C9ORF72 associated disease or a C9ORF72 hexanucleotide repeat expansion associated disease is slowed, ameliorated, or prevented.

38. The method of claim 37, wherein at least one symptom is any of motor function, respiration, muscle weakness, fasciculation and cramping of muscles, difficulty in projecting the voice, shortness of breath, difficulty in breathing and swallowing, inappropriate social behavior, lack of empathy, distractibility, changes in food preferences, agitation, blunted emotions, neglect of personal hygiene, repetitive or compulsive behavior, and decreased energy and motivation.

17. A method, comprising:

identifying an animal having a C9ORF72 associated disease; and

coadministering to the animal a therapeutically effective amount of a C9ORF72 antisense transcript specific inhibitor and a therapeutically effective amount of a C9ORF72 sense transcript inhibitor.

18. The method of claim 17, wherein said amount is effective to reduce the level or expression of the C9ORF72 antisense transcript and the C9ORF72 sense transcript.

20. The method of claims 17-19, wherein the C9ORF72 sense transcript inhibitor is a C9ORF72 sense transcript specific antisense compound.

33. The method of claim 33, wherein the C9ORF72 antisense transcript associated RAN translation products are any of poly-(proline-alanine), poly-(proline-arginine), and poly-(proline-glycine).

35. The method of claim 35, wherein the parental administration is any of injection or infusion.