Compositions and methods for modulation of SMN2 splicing in a subject

• US 9,926,559 B2
• Filed: 01/09/2014
• Issued: 03/27/2018
• Est. Priority Date: 01/09/2013
• Status: Active Grant

• Current Assignee: Biogen MA Inc. (Biogen, Inc.)
• Original Assignee: Biogen MA Inc. (Biogen, Inc.)
• Inventors: Bennett, C. Frank, Hung, Gene, Rigo, Frank
• Primary Examiner(s): Poliakova-Georgantas, Kate
• Application Number:
  US14/760,171
• Publication Number:
  US 20160002627A1
• Time in Patent Office: 1,538 Days
• Field of Search: None
• CPC Class Codes: A61B 5/316 Modalities, i.e. specific diagnostic methods
• CPC Class Codes: A61B 5/389 Electromyography [EMG]
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 35/545 Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
• CPC Class Codes: A61K 38/30 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 insulin-like growth factor binding protein A61K38/1754
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/46 Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 9/0019 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 Class Codes: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: G01N 33/5091 for testing the pathological state of an organism

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.

Claims

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.