Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model
- Yimin Hua1,
- Kentaro Sahashi1,
- Gene Hung2,
- Frank Rigo2,
- Marco A. Passini3,
- C. Frank Bennett2 and
- Adrian R. Krainer1,4
- 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
- 2Isis Pharmaceuticals, Carlsbad, California 92008, USA;
- 3Genzyme Corporation, Framingham, Massachusetts 01701, USA
Abstract
Increasing survival of motor neuron 2, centromeric (SMN2) exon 7 inclusion to express more full-length SMN protein in motor neurons is a promising approach to treat spinal muscular atrophy (SMA), a genetic neurodegenerative disease. Previously, we identified a potent 2′-O-(2-methoxyethyl) (MOE) phosphorothioate-modified antisense oligonucleotide (ASO) that blocks an SMN2 intronic splicing silencer element and efficiently promotes exon 7 inclusion in transgenic mouse peripheral tissues after systemic administration. Here we address its efficacy in the spinal cord—a prerequisite for disease treatment—and its ability to rescue a mild SMA mouse model that develops tail and ear necrosis, resembling the distal tissue necrosis reported in some SMA infants. Using a micro-osmotic pump, we directly infused the ASO into a lateral cerebral ventricle in adult mice expressing a human SMN2 transgene; the ASO gave a robust and long-lasting increase in SMN2 exon 7 inclusion measured at both the mRNA and protein levels in spinal cord motor neurons. A single embryonic or neonatal intracerebroventricular ASO injection strikingly rescued the tail and ear necrosis in SMA mice. We conclude that this MOE ASO is a promising drug candidate for SMA therapy, and, more generally, that ASOs can be used to efficiently redirect alternative splicing of target genes in the CNS.
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Footnotes
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↵4 Corresponding author.
E-MAIL krainer{at}cshl.edu; FAX (516) 367-8453.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1941310.
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Supplemental material is available at http://www.genesdev.org.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press