Compositions for modulating C9ORF72 expression

• US 9,605,263 B2
• Filed: 04/15/2016
• Issued: 03/28/2017
• Est. Priority Date: 04/16/2015
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Rigo, Frank
• Primary Examiner(s): SCHNIZER, RICHARD A
• Application Number:
  US15/130,818
• Publication Number:
  US 20160304871A1
• Time in Patent Office: 347 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-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
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

Disclosed herein are compositions and methods for reducing expression of C9ORF72 mRNA and protein in an animal. Such methods are useful to treat, prevent, ameliorate, or slow progression of neurodegenerative diseases in an individual in need thereof.

Claims

1. A modified oligonucleotide according to the following formula:

3. The modified oligonucleotide of claim 1, which is a sodium salt of the formula.

4. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable diluent or carrier.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).

6. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS).

7. A pharmaceutical composition comprising the modified oligonucleotide of claim 3 and a pharmaceutically acceptable diluent or carrier.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).

9. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS).

2. A modified oligonucleotide according to the following formula:

10. A pharmaceutical composition comprising the modified oligonucleotide of claim 2 and a pharmaceutically acceptable diluent or carrier.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).

12. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS).

13. 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 four 2′

-O-methoxyethyl nucleosides,

the central gap segment consists of eight β

-D-deoxyribonucleosides, and

the 3′

wing segment consists of six 2′

-O-methoxyethyl nucleosides;

wherein the modified oligonucleotide has the nucleobase sequence 5′

-GCCCCTAGCGCGCGACTC-3′

(SEQ ID NO;

     33), wherein each cytosine is a 5-methylcytosine; and

wherein the internucleoside linkages of the modified oligonucleotide are, from 5′

to 3′

, soosssssssssoooss, wherein each s is a phosphorothioate linkage and each o is a phosphodiester linkage.

14. The compound of claim 13, comprising the modified oligonucleotide covalently linked to a conjugate group.

15. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable diluent or carrier.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).

17. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition consists essentially of the compound and phosphate-buffered saline (PBS).

18. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable diluent or carrier.

19. The pharmaceutical composition of claim 18, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).

20. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition consists essentially of the compound and phosphate-buffered saline (PBS).