Therapeutic strategies for spinal muscular atrophy: SMN and beyond

Melissa Bowerman, Catherina G Becker, Rafael J Yáñez-Muñoz, Ke Ning, Matthew J. Wood, Thomas Gillingwater, Kevin Talbot

Research output: Contribution to journalArticlepeer-review

Abstract

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood, and is caused by low levels of the survival motor neuron (SMN) protein due to inactivating mutations in the encoding gene SMN1. A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trial, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that requirement for SMN is highest as the structural connections of the neuromuscular system are being established from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe Types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery.
Original languageEnglish
JournalDisease Models and Mechanisms
Volume10
Issue number8
Early online date2 Aug 2017
DOIs
Publication statusE-pub ahead of print - 2 Aug 2017

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