Journal article
Oligonucleotide-Mediated Survival of Motor Neuron Protein Expression in CNS Improves Phenotype in a Mouse Model of Spinal Muscular Atrophy
The Journal of neuroscience, v 29(24), pp 7633-7638
17 Jun 2009
PMID: 19535574
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Spinal muscular atrophy (SMA) is caused by homozygous mutation or deletion of the
SMN1
gene encoding survival of motor neuron (SMN) protein, resulting in the selective loss of α-motor neurons. Humans typically have one or more copies of the
SMN2
gene, the coding region of which is nearly identical to
SMN1
, except that a point mutation causes splicing out of exon 7 and production of a largely nonfunctional SMNΔ7 protein. The development of drugs that mitigate aberrant
SMN2
splicing is an attractive therapeutic approach for SMA. A steric block antisense oligonucleotide (AO) has recently been developed that blocked an intronic splice suppressor element, and enhanced
SMN2
exon 7 inclusion in SMA patient fibroblasts. Here, we show that periodic intracerebroventricular (ICV) delivery of this AO resulted in increased SMN expression in brain and spinal cord to as much as 50% of the level of healthy littermates. Real-time PCR of
SMN2
transcripts confirmed the AO-mediated increase in full-length SMN. The AO-derived increase in SMN expression led to a concomitant improvement in bodyweight throughout the lifespan of the SMA animals. Treatment of SMA mice with AO also provided partial correction of motor deficits, manifest as improved righting response. Injections of a scrambled oligonucleotide had no effect on SMN expression or phenotype in the SMA mice. Our results validate that AOs that abrogate aberrant splicing of
SMN2
are promising compounds for treating SMA.
Metrics
Details
- Title
- Oligonucleotide-Mediated Survival of Motor Neuron Protein Expression in CNS Improves Phenotype in a Mouse Model of Spinal Muscular Atrophy
- Creators
- Jason H. Williams - Drexel UniversityRebecca C. Schray - Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Carlyn A. Patterson - Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Semira O. Ayitey - Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Melanie K. Tallent - Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102Gordon J. Lutz - Drexel University
- Publication Details
- The Journal of neuroscience, v 29(24), pp 7633-7638
- Publisher
- Society for Neuroscience
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000267131000002
- Scopus ID
- 2-s2.0-67449135902
- Other Identifier
- 991019169626604721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Neurosciences