Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7

Staropoli, John F., Li, Huo, Chun, Seung J., Allaire, Norm, Cullen, Patrick, Thai, Alice, Fleet, Christina M., Hua, Yimin, Bennett, C. Frank, Krainer, Adrian R., Kerr, Doug, McCampbell, Alexander, Rigo, Frank, Carulli, John P. (January 2015) Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7. Genomics, 105 (4). pp. 220-228. ISSN 0888-7543

URL: http://www.ncbi.nlm.nih.gov/pubmed/25645699
DOI: 10.1016/j.ygeno.2015.01.007

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by disruption of the survival motor neuron 1 (SMN1) gene, partly compensated for by the paralogous gene SMN2. Exon 7 inclusion is critical for full-length SMN protein production and occurs at a much lower frequency for SMN2 than for SMN1. Antisense oligonucleotide (ASO)-mediated blockade of intron 7 was previously shown to promote inclusion of SMN2 exon 7 in SMA mouse models and mediate phenotypic rescue. However, downstream molecular consequences of this ASO therapy have not been defined. Here we characterize the gene-expression changes that occur in an induced model of SMA and show substantial rescue of those changes in central nervous system tissue upon intracerebroventricular administration of an ASO that promotes inclusion of exon 7, with earlier administration promoting greater rescue. This study offers a robust reference set of preclinical pharmacodynamic gene expression effects for comparison of other investigational therapies for SMA.

Item Type: Paper
Uncontrolled Keywords: Spinal muscular atrophy Gene expression Mouse model SMN2 Antisense Oligonucleotide
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > antisense
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > oligonucleotide
diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy
CSHL Authors:
Communities: CSHL labs > Krainer lab
Depositing User: Matt Covey
Date: 31 January 2015
Date Deposited: 06 Feb 2015 19:32
Last Modified: 25 Mar 2015 14:32
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31182

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