Compositions and methods for modulation of SMN2 splicing in a subject

Patent metadata

Field	Value
Publication number	US-9926559-B2
Application number	US-201414760171-A
Country	US
Kind code	B2
Filing date	Jan 9, 2014
Priority date	Jan 9, 2013
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

Abstract

Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2 mRNA in a subject. 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. A method of treating a human subject having spinal muscular atrophy (SMA), the method comprising administering to the human subject an antisense oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence SEQ ID NO:1, wherein each internucleoside linkage of the oligonucleotide is a phosphorothioate linkage, wherein each nucleoside of the oligonucleotide is a 2′-MOE nucleoside, and wherein each cytosine of the oligonucleotide is a 5-methyl cytosine, wherein the antisense oligonucleotide is administered into the cerebrospinal fluid by bolus injection into the intrathecal space at a dose of 9.6, 10.3, 10.8, 11.3, or 12.0 milligrams of the antisense oligonucleotide.

2. The method of claim 1 , wherein the administration is through a 21, 22, 23, 24, or 25 gauge needle.

3. The method of claim 1 , wherein the administration is through a 22 gauge needle.

4. The method of claim 1 , wherein the administration is between the L3 and L4 vertebrae.

5. The method of claim 1 , wherein a 9.6 mg dose of the antisense oligonucleotide is administered in a volume of 4 mL, and wherein the dose is administered to the subject within 3 months of birth of the subject.

6. The method of claim 1 , wherein a 10.3 mg dose of the antisense oligonucleotide is administered in a volume of 4.3 mL, and wherein the dose is administered to the subject between 3 and 6 months of birth of the subject.

7. The method of claim 1 , wherein a 10.8 mg dose of the antisense oligonucleotide is administered in a volume of 4.5 mL, and wherein the dose is administered to the subject between 6 months and 12 months of birth of the subject.

8. The method of claim 1 , wherein a 11.3 mg dose of the antisense oligonucleotide is administered in a volume of 4.7 mL, and wherein the dose is administered to the subject between 12 months and 24 months of birth of the subject.

9. The method of claim 1 , wherein a 12.0 mg dose of the antisense oligonucleotide is administered in a volume of 5 mL, and wherein the dose is administered to the subject after 24 months of birth of the subject.

10. The method of claim 1 , comprising administering to the human subject at least two doses wherein the second dose is administered 12-18 days after the first dose.

Assignees

• Biogen Ma Inc

Inventors

• Bennett C Frank
• Hung Gene
• Rigo Frank

Classifications

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61K9/0085

  Brain, e.g. brain implants; Spinal cord · CPC title

• A61K38/30

  Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 {(insulin-like growth factor binding protein A61K38/1754)} · CPC title

• C12N2310/322

  2'-R Modification · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title