Advances in therapy for spinal muscular atrophy: promises and challenges

Key Points

  • The approval of nusinersen represents an important milestone for spinal muscular atrophy (SMA) research and treatment

  • Promising results from clinical trials indicate that several additional treatment options, such as gene therapy, could be available for patients with SMA in the near future

  • Preclinical research has highlighted the powerful potential of combinatorial targeting of both survival motor neuron protein (SMN)-dependent and SMN-independent pathways ('SMN-plus' therapy) to deliver maximal therapeutic benefits

  • The rapid emergence of many new therapeutic options for SMA raises major issues concerning the coordination of future clinical trials in this small population of patients

  • The development of therapies for SMA has the potential to offer important insights and tools that are applicable to patients with other neuromuscular and neurodegenerative conditions

Abstract

Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease-modifying therapy for SMA by US and European authorities — the antisense oligonucleotide nusinersen. At the same time, promising data from early-stage clinical trials of SMN1 gene therapy have indicated that additional therapeutic options are likely to emerge for patients with SMA in the near future. However, the approval of nusinersen has generated a number of immediate and substantial medical, ethical and financial implications that have the potential to resonate beyond the specific treatment of SMA. Here, we provide an overview of the rapidly evolving therapeutic landscape for SMA, highlighting current achievements and future opportunities. We also discuss how these developments are providing important lessons for the emerging second generation of combinatorial ('SMN-plus') therapies that are likely to be required to generate robust treatments that are effective across a patient's lifespan.

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Figure 1: Genetics of SMA.
Figure 2: Cellular pathways and therapeutic targets in SMA.

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All authors contributed to the research, discussion, writing and revision of the manuscript.

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Correspondence to Thomas H. Gillingwater.

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T.H.G. and K.T. serve as Chair of the Scientific and Clinical Advisory Board and Trustee of the SMA Trust, respectively.

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Groen, E., Talbot, K. & Gillingwater, T. Advances in therapy for spinal muscular atrophy: promises and challenges. Nat Rev Neurol 14, 214–224 (2018). https://doi.org/10.1038/nrneurol.2018.4

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