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Developmental regulation of SMN expression: pathophysiological implications and perspectives for therapy development in spinal muscular atrophy

Gene Therapy volume 24, pages 506–513 (2017)Cite this article

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Abstract

Spinal muscular atrophy (SMA), the predominant form of motoneuron disease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction. This review summarizes current knowledge about the pathophysiological alterations in Smn-deficient motoneurons, which lead to defective neuromuscular transmission and altered spinal circuit formation. Both pathological mechanisms are important targets for therapeutic intervention. However, the developmental time window when therapeutic interventions ideally should start is not known. Endogenous SMN expression both from SMN1 and SMN2 genes is high at early developmental stages and declines progressively in humans and mice. Thus, therapeutic SMN upregulation should start just before SMN declines below a critical threshold, and before irreversible defects occur at neuromuscular junctions and in spinal circuits. Previous results indicate that loss of Smn function leads to synaptic dysfunction during a stage of neuromuscular development when synaptic strength determines which synapses are maintained or not. This time window appears as an important target for therapy, which possibly could be supported by additional strategies that strengthen synaptic transmission.

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Acknowledgements

This Work in the author's lab is supported by the Deutsche Forschungsgemeinschaft, Grants JA 1823/3-1 und SE 697/6-1, and by the German Bundesministerium für Bildung und Forschung, Grant Dystract, TP6 to MS. We thank Oxford University Press for permission to reproduce Figure 1 from reference 36, and Rockefeller University Press for permission to reproduce Figure 2 from reference 57.

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  1. Institute of Clinical Neurobiology, University Hospital, University of Würzburg, Würzburg, Germany

    S Jablonka & M Sendtner

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  1. S Jablonka
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Jablonka, S., Sendtner, M. Developmental regulation of SMN expression: pathophysiological implications and perspectives for therapy development in spinal muscular atrophy. Gene Ther 24, 506–513 (2017). https://doi.org/10.1038/gt.2017.46

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