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

Oct 8, 2011Nature

Restoring the body's movement nerve system is crucial for long-term recovery in severe spinal muscular atrophy mice

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Regenerative Health on OpenScience ↗PubMed ↗DOI ↗

Abstract

Subcutaneous injections of ASO-10-27 extended the median lifespan of severe SMA mice by 25 fold.

Systemic administration of ASO-10-27 was more effective than intracerebroventricular administration in rescuing severe SMA mice.
ASO-10-27 treatment corrected SMN2 splicing and restored SMN expression in motor neurons.
Neonatal SMA mice exhibited decreased expression of a liver gene associated with insulin-like growth factor 1 (IGF1), leading to lower circulating IGF1 levels.
Treatment with ASO-10-27 normalized IGF1 levels, suggesting a role for the liver in SMA pathogenesis.
Findings indicate that SMN restoration in peripheral tissues may play a critical role in SMA.

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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.

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

Abstract

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