Abstract
ABSTRACTSpinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) 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 trials, 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 the requirement for SMN protein is highest when 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.
Highlights
The SMN2 gene always generates a small amount of functional protein, which maintains viability, as homozygous deletion of survival motor neuron 1 (SMN1) is uniformly lethal (Gennarelli et al, 1995; Lefebvre et al, 1995)
As the first successful survival motor neuron protein (SMN)-targeted therapeutic approaches are emerging into the clinical arena (Finkel et al, 2016; Gillingwater, 2016), we review here how to best move forward in the development of combinatorial therapeutic approaches for Spinal muscular atrophy (SMA) that, ideally, would target the CNS and the periphery, operating via SMNdependent and SMN-independent processes
Translational research should address the development of non-CNS and SMN-independent therapeutic approaches to complement and enhance the benefits of CNSdirected and SMN-dependent therapies, taking into account the need to maintain the neuromuscular system of an SMA patient through childhood and puberty, when there is maximal growth of the axial skeleton, and into adult life when the process of age-related attrition of motor units is likely to contribute to progressive loss of motor function (Fig. 4)
Summary
Spinal muscular atrophy (SMA) is the most common genetic disease resulting in death in infancy, affecting approximately 1 in 6000 to 1. The most advanced therapies currently in clinical trials for SMA are aimed at increasing FL SMN either by exogenously expressing SMN1 or upregulating FL SMN2 production (d’Ydewalle and Sumner, 2015). Unless these current SMN-dependent approaches can be given pre-symptomatically, when motor neuron dysfunction may still be reversible, and delivered with a very high level of efficiency to drastically induce SMN levels in spinal cord motor neurons, it is likely that the progressive neurodegenerative process will not be completely abrogated but slowed down. There are a large number of older children and adults living with SMA who do not fulfill the present criteria for inclusion (on the grounds of age and various clinical parameters) in the ongoing clinical trials and for whom it is not currently clear that SMN-inducing treatments will be beneficial
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
