COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT

• US 20120190728A1
• Filed: 06/17/2010
• Published: 07/26/2012
• Est. Priority Date: 06/17/2009
• Status: Active Grant

• Current Assignee: Biogen MA Inc. (Biogen, Inc.), Cold Spring Harbor Laboratory
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Bennett, C. Frank, Hung, Gene, Hua, Yimin, Passini, Marco A., Shihabuddin, Lamya, Cheng, Seng H., Klinger, Katherine W., Rigo, Frank, Krainer, Adrian R.
• Granted Patent: US 8,980,853 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/712 Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 25/28 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: 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 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12N 2320/33 Alteration of splicing

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

1-107. -107. (canceled)

108. A method comprising administering to a subject having at least one symptom associated with SMA an antisense compound comprising an antisense oligonucleotide consisting of 15-25 linked nucleosides and complementary to intron 7 of a nucleic acid encoding human SMN2 pre-mRNA.

109. The method of claim 108, wherein the administration is into the central nervous system.

110. The method of claim 108, wherein the administration is into the cerebrospinal fluid.

111. The method of claim 108, wherein the administration is into the intrathecal space.

112. The method of claim 108, wherein the administration comprises a bolus injection.

113. The method claim 108, wherein the administration comprises infusion with a delivery pump.

114. The method of claim 108, wherein the antisense compound is administered at a dose from 0.01 to 10 milligrams of antisense compound per kilogram of body weight of the subject.

115. The method of claim 108, wherein inclusion of exon 7 of SMN2 mRNA in a motoneuron in the subject is increased.

116. The method of claim 108, wherein the subject has SMA.

117. The method of claim 108, wherein the subject has type I SMA

118. The method of claim 108, wherein the subject has type II SMA.

119. The method of claim 108, wherein the subject has type III SMA.

120. The method of claim 108, wherein the administering of the antisense compound ameliorates at least one symptom of SMA in the subject.

121. The method of claim 108, wherein the antisense oligonucleotide is at least 90% complementary to the nucleic acid encoding human SMN2.

122. The method of claim 108, wherein the oligonucleotide has a nucleobase sequence comprising at least 10 contiguous nucleobases of the nucleobase sequence SEQ ID NO:

1.

123. The method of claim 108, wherein the oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence SEQ ID NO:

1.

124. The method of claim 108, wherein the antisense oligonucleotide consists of 18 linked nucleosides.

125. The method of claim 108, wherein at least one nucleoside is a modified nucleoside.

126. The method of claim 108, wherein each nucleoside is a modified nucleoside.

127. The method of claim 108, wherein each nucleoside is a 2′

-MOE nucleoside.