Compositions and methods for modulation of SMN2 splicing

Patent metadata

Field	Value
Publication number	US-8946183-B2
Application number	US-201213720474-A
Country	US
Kind code	B2
Filing date	Dec 19, 2012
Priority date	Jun 23, 2005
Publication date	Feb 3, 2015
Grant date	Feb 3, 2015

Abstract

Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2 mRNA in a cell, tissue or animal. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders, including spinal muscular atrophy.

First claim

What is claimed is:

1. An antisense oligonucleotide targeted to intron 6 of a nucleic acid molecule encoding SMN2, wherein said oligonucleotide is 12 to 20 nucleotides in length and comprises a 2′-O-methoxyethyl sugar modification at each position, and wherein said oligonucleotide is targeted to an intronic splicing silencer element.

2. The oligonucleotide of claim 1 which is 12 nucleotides in length.

3. The oligonucleotide of claim 1 which is 15 nucleotides in length.

4. The oligonucleotide of claim 1 which is 16 nucleotides in length.

5. The oligonucleotide of claim 1 which is 18 nucleotides in length.

6. The oligonucleotide of claim 1 , wherein a 5′-most nucleotide of a target site of said oligonucleotide is nucleotide 5, 6, 7 or 8 of SEQ ID NO: 1.

7. The oligonucleotide of claim 1 , wherein the nucleotide sequence of said oligonucleotide comprises at least an 8-nucleobase portion of SEQ ID NO: 6, 7, 8, 9, 10, 11, 12 or 13.

8. The oligonucleotide of claim 1 , wherein the nucleotide sequence of said oligonucleotide consists of the nucleotide sequence of SEQ ID NO: 8.

9. A pharmaceutical composition comprising the antisense oligonucleotide of claim 1 .

10. A pharmaceutical composition comprising the antisense oligonucleotide of claim 8 .

11. A method of promoting inclusion of exon 7 in SMN2 transcripts in a cell, tissue or organ, comprising contacting said cell, tissue or organ with the antisense oligonucleotide of claim 1 .

12. The method of claim 11 , wherein the nucleotide sequence of the oligonucleotide comprises at least an 8-nucleobase portion of SEQ ID NO: 6, 7, 8, 9, 10, 11, 12 or 13.

13. The method of claim 11 , wherein the nucleotide sequence of said oligonucleotide consists of the nucleotide sequence of SEQ ID NO: 8.

14. The method of claim 11 , wherein a 5′-most nucleotide of a target site of said oligonucleotide is nucleotide 5, 6, 7 or 8 of SEQ ID NO: 1.

Assignees

• Isis Pharmaceuticals Inc
• Cold Spring Harbor Lab

Inventors

• Baker Brenda F
• Krainer Adrian R
• Hua Yimin

Classifications

• C12N2310/11

  Antisense · CPC title

• C12N2310/3341

  5-Methylcytosine · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N15/113 Primary

  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 title

• C12N2320/33

  Alteration of splicing · CPC title