Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2011-10

AUTHORS

Yimin Hua, Kentaro Sahashi, Frank Rigo, Gene Hung, Guy Horev, C. Frank Bennett, Adrian R. Krainer

ABSTRACT

Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality; it results from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. Humans have a paralogue, SMN2, whose exon 7 is predominantly skipped, but the limited amount of functional, full-length SMN protein expressed from SMN2 cannot fully compensate for a lack of SMN1. SMN is important for the biogenesis of spliceosomal small nuclear ribonucleoprotein particles, but downstream splicing targets involved in pathogenesis remain elusive. There is no effective SMA treatment, but SMN restoration in spinal cord motor neurons is thought to be necessary and sufficient. Non-central nervous system (CNS) pathologies, including cardiovascular defects, were recently reported in severe SMA mouse models and patients, reflecting autonomic dysfunction or direct effects in cardiac tissues. Here we compared systemic versus CNS restoration of SMN in a severe mouse model. We used an antisense oligonucleotide (ASO), ASO-10-27, that effectively corrects SMN2 splicing and restores SMN expression in motor neurons after intracerebroventricular injection. Systemic administration of ASO-10-27 to neonates robustly rescued severe SMA mice, much more effectively than intracerebroventricular administration; subcutaneous injections extended the median lifespan by 25 fold. Furthermore, neonatal SMA mice had decreased hepatic Igfals expression, leading to a pronounced reduction in circulating insulin-like growth factor 1 (IGF1), and ASO-10-27 treatment restored IGF1 to normal levels. These results suggest that the liver is important in SMA pathogenesis, underscoring the importance of SMN in peripheral tissues, and demonstrate the efficacy of a promising drug candidate. More... »

PAGES

123

Journal

TITLE

Nature

ISSUE

7367

VOLUME

478

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature10485

DOI

http://dx.doi.org/10.1038/nature10485

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1007630795

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21979052


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Turtle is a human-readable linked data format.

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RDF/XML is a standard XML format for linked data.

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