[The role of RNA splicing in the pathogenesis of spinal muscular atrophy and development of its therapeutics].

Abstract

Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Degeneration of alpha-motor neurons that results in progressive paralysis is a pathological hallmark of SMA. Recently, peripheral-tissue involvement has also been reported in SMA. Patients have low levels of functional SMN which is attributed to alternative splicing in SMN2, a gene closely-related to SMN1. This decrease in the expression of SMN, a ubiquitously expressed protein involved in promoting snRNP assembly required for splicing, is responsible for SMA. However, the mechanism through which decrease in SMN levels causes SMA remains unclear. Currently, no curative treatment is available for SMA, but SMN restoration is thought to be necessary and sufficient for cure. Antisense oligonucleotides (ASOs) can be designed to specifically alter splicing patterns of target pre-mRNAs. We identified an ASO that redirects SMN2 splicing and is currently in clinical trials for use as RNA-targeting therapeutics. Further, we have also reported a novel application of splicing-modulating ASOs--creation of animal phenocopy models of diseases by inducing mis-splicing. Exploring the relationship between the spatial and temporal effects of therapeutic and pathogenic ASOs yields relevant insights into the roles of SMN in SMA pathogenesis and into its normal physiological functions. This knowledge, in turn, contributes to the ongoing development of targeted therapeutics.

• Authors: Kentaro Sahashi, Gen Sobue
• Journal: Brain and nerve = Shinkei kenkyu no shinpo (Brain Nerve) Vol. 66 Issue 12 Pg. 1471-80 (Dec 2014) ISSN: 1881-6096 [Print] Japan
• PMID: 25475034 (Publication Type: English Abstract, Journal Article, Review)

Chemical References

• Nerve Tissue Proteins
• RNA

Topics

• Animals
• Disease Models, Animal
• Humans
• Motor Neurons (pathology)
• Muscular Atrophy, Spinal (genetics, physiopathology, therapy)
• Nerve Tissue Proteins (metabolism)
• RNA (genetics)
• RNA Splicing