COMPOSITIONS FOR MODULATING EXPRESSION OF C9ORF72 ANTISENSE TRANSCRIPT

• US 20160230172A1
• Filed: 10/14/2014
• Published: 08/11/2016
• Est. Priority Date: 10/14/2013
• Status: Abandoned Application

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Rigo, Frank
• Application Number:
  US15/029,039
• Publication Number:
  US 20160230172A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• 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 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• 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 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3521 Methyl

Abstract

Disclosed herein are compositions and 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 compound comprising a C9ORF72 antisense transcript specific inhibitor.

2. The compound of claim 1 wherein the C9ORF72 antisense transcript specific inhibitor is a C9ORF72 antisense transcript specific antisense compound.

3. The compound of claim 2, wherein the C9ORF72 antisense transcript specific antisense compound comprises an antisense oligonucleotide.

4. The compound of claim 3, wherein the antisense oligonucleotide consists of 12-30 linked nucleosides.

5. The compound of claim 3, wherein the antisense oligonucleotide consists of 16-25 linked nucleosides.

6. The compound of claim 3, wherein the antisense oligonucleotide consists of 18-22 linked nucleosides

7. The compound of any of claims 3-6, wherein the antisense oligonucleotide has a nucleobase sequence that 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.

8. The compound of any of claims 3-6, wherein the antisense oligonucleotide has a nucleobase sequence that is at least 90% complementary to a C9ORF72 antisense transcript.

9. The compound of any of claims 3-6, wherein the antisense oligonucleotide has a nucleobase sequence that is at least 95% complementary to a C9ORF72 antisense transcript.

10. The compound of any of claims 3-6, wherein the antisense oligonucleotide has a nucleobase sequence that is 100% complementary to a C9ORF72 antisense transcript.

11. The compound of any of claims 10-13, wherein the C9ORF72 antisense transcript is SEQ ID NO:

11.

12. The compound of any of claims 3-10, wherein the antisense oligonucleotide has a nucleobase sequence comprising least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of a sequence selected from among SEQ ID NO:

19-20, 22-26, 28-32, 34-42, 44, 46-55, 58-59, and 61.

13. The compound of claim 3-11, wherein the antisense oligonucleotide is a modified antisense oligonucleotide.

14. The compound of claim 12, wherein the modified antisense oligonucleotide comprises at least one modified internucleoside linkage.

15. The compound of claim 13, wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

16. The compound of claim 14, wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.

17. The compound of any of claims 12-15 wherein the modified antisense oligonucleotide comprises at least one phosphodiester internucleoside linkage.

18. The compound of claims 12-15, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified nucleobase.

19. The compound of claim 16, wherein the modified nucleobase is a 5-methylcytosine.

20. The compound of claims 12-17, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified sugar.

21. The compound of claim 18, wherein the at least one modified sugar is a bicyclic sugar.

22. The compound of claim 19, 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.

23. The compound of claim 18, wherein at least one modified sugar comprises a 2′

-O-methoxyethyl group.

24. The compound of any of claims 12-22, wherein the antisense oligonucleotide is a gapmer.

25. The compound of any of claims 12-23, wherein the antisense oligonucleotide is single-stranded.

26. The compound of any of claims 2-24, wherein the C9ORF72 antisense transcript specific antisense compound comprises at least one conjugate.

27. The compound of any of claims 2-24, wherein the C9ORF72 antisense transcript specific antisense compound consists of an antisense oligonucleotide.

28. A pharmaceutical composition comprising the compound of any of claims 1-26 and a pharmaceutically acceptable diluent or carrier.

29. A pharmaceutical composition of claim 27 further comprising a C9ORF72 sense transcript specific inhibitior.

30. The pharmaceutical composition of claim 28, wherein the C9ORF72 sense transcript specific inhibitor is a C9ORF72 sense transcript specific antisense compound.

31. The pharmaceutical composition of claim 29, wherein the C9ORF72 sense transcript specific antisense compound is an antisense oligonucleotide.

37. The pharmaceutical composition of claims 29-36, wherein the antisense transcript is SEQ ID NO:

11.

38. The pharmaceutical composition of claims 29-36, wherein the antisense transcript is any of SEQ ID NOs:

1-10.

39. Use of the compound of any preceding claim for the manufacture of a medicament for treating a neurodegenerative disease.

32. A pharmaceutical composition comprising a C9ORF72 antisense transcript specific inhibitor and a C9ORF sense transcript specific inhibitior.

33. The pharmaceutical composition of claim 32, wherein the C9ORF72 sense transcript specific inhibitor is a C9ORF72 sense transcript specific antisense compound.

34. The pharmaceutical composition of claim 32, wherein the C9ORF72 antisense transcript specific inhibitor is a C9ORF72 antisense transcript specific antisense compound.

35. The pharmaceutical composition of claim 33, wherein the C9ORF72 sense transcript specific antisense compound is an antisense oligonucleotide

36. The pharmaceutical composition of claim 34, wherein the C9ORF72 antisense transcript specific antisense compound is an antisense oligonucleotide.