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  • Review Article
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Spinal muscular atrophy — insights and challenges in the treatment era

Nature Reviews Neurology volume 16, pages 706–715 (2020)Cite this article

Subjects

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by deletion or mutation of SMN1. Four subtypes exist, characterized by different clinical severities. New therapeutic approaches have become available in the past few years, dramatically changing the natural history of all SMA subtypes, including substantial clinical improvement with the severe and advanced SMA type 1 variant. Trials have now demonstrated that phenotypic rescue is even more dramatic when pre-symptomatic patients are treated, and emerging real-world data are demonstrating the benefits of intervention even in the chronic phase of the condition. Here, we critically review how the field is rapidly evolving in response to the new therapies and questions that the new treatments have posed, including the effects of treatment at different ages and stages of disease, new phenotypes and long-term outcomes in patients who would not have survived without treatment, and decisions of who to treat and when. We also discuss how the outcomes associated with different timing of therapeutic intervention are contributing to our understanding of the biology and pathogenesis of SMA.

Key points

  • Drugs that increase levels of survival motor neuron (SMN) protein are revolutionizing the disease course and treatment of spinal muscular atrophy (SMA) across the spectrum of the disease.

  • Clinical responses in patients with symptomatic SMA can reach levels that were unanticipated, but the longer the disease duration and the greater the severity, the more modest the response.

  • Clinical trials and biomarker studies are providing new information about disease processes, highlighting prenatal onset in children with severe SMA and in pre-symptomatic patients with two copies of SMN2.

  • Some of the drugs that have been developed address SMN deficiency only in the CNS, whereas others address deficiency in the CNS and periphery, which could increase the benefit.

  • The phenotypes of treated patients with SMA are evolving before our eyes; from their observation, we could learn more about disease processes and treatment effects.

  • Which of the available drugs works best in the long term for particular subgroups of patients remains unclear, as does whether combination treatments will be superior to monotherapy.

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Fig. 1: Possible therapeutic targets, strategies and treatments for spinal muscular atrophy.

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Author information

Authors and Affiliations

  1. Department of Paediatric Neurology, Catholic University, Rome, Italy

    Eugenio Mercuri & Maria Carmela Pera

  2. Centro Clinico Nemo, Fondazione Policlinico Gemelli IRCCS, Rome, Italy

    Eugenio Mercuri & Maria Carmela Pera

  3. Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK

    Mariacristina Scoto & Francesco Muntoni

  4. National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London, UK

    Mariacristina Scoto & Francesco Muntoni

  5. Center for Experimental Neurotherapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Richard Finkel

Authors
  1. Eugenio Mercuri
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  2. Maria Carmela Pera
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  3. Mariacristina Scoto
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  4. Richard Finkel
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  5. Francesco Muntoni
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Contributions

All authors contributed to all aspects of manuscript preparation.

Corresponding author

Correspondence to Francesco Muntoni.

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Competing interests

E.M. is involved as an investigator in clinical trials for AveXis, Biogen, Roche and Scholar Rock. He has received honoraria for participating in symposia and advisory boards for AveXis, Biogen, Roche and Scholar Rock. His institution receives funding from Biogen for the coordination of an Italian registry for SMA, iSMAC. M.C.P. is involved as an investigator in clinical trials for AveXis, Biogen, Roche and Scholar Rock. She has received honoraria for participating in symposia and advisory boards for Biogen and Roche. Her institution receives funding from Biogen for the coordination of an Italian registry for SMA, iSMAC. M.S. is involved as an investigator in clinical trials for AveXis, Biogen and Roche. She has received honoraria for participating in symposia and advisory boards for AveXis, Biogen and Roche. Her institution receives funding from Biogen for the coordination of a UK-wide registry for SMA, SMA REACH UK. R.F. is involved as an investigator in clinical trials for AveXis, Biogen, Cytokinetics, Ionis, Roche and Scholar Rock. He has received honoraria for participating in symposia and advisory boards for AveXis, Biogen, Cytokinetics, Ionis, Roche and Scholar Rock. His institution receives funding from Biogen for the coordination of a US registry for SMA, iSMAC. F.M. is involved as an investigator in clinical trials for AveXis, Biogen and Roche. He has received honoraria for participating in symposia and advisory boards for AveXis, Biogen and Roche. His institution receives funding from Biogen for the coordination of a UK-wide registry for SMA, SMA REACH UK.

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Nature Reviews Neurology thanks J. Melki, H. Nishio, B. Wirth and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Mercuri, E., Pera, M.C., Scoto, M. et al. Spinal muscular atrophy — insights and challenges in the treatment era. Nat Rev Neurol 16, 706–715 (2020). https://doi.org/10.1038/s41582-020-00413-4

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