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Curing SMA: Are we there yet?

Gene Therapy volume 30, pages 8–17 (2023)Cite this article

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Abstract

Loss or deletion of survival motor neuron 1 gene (SMN1) is causative for a severe and devastating neuromuscular disease, Spinal Muscular Atrophy (SMA). SMN1 produces SMN, a ubiquitously expressed protein, that is essential for the development and survival of motor neurons. Major advances and developments in SMA therapeutics are shifting the natural history of the disease. With three relatively new available therapies, nusinersen (Spinraza), onasemnogene abeparvovec (Zolgensma), and risdiplam (Evrysdi), patients survive longer and have improved outcomes. However, patients and families continue to face many challenges associated with use of these therapies, including poor treatment response and a variability in the benefits to those that do respond, suggesting that the quest for the SMA cure is not over. In this review, we discuss the current therapies, their limitations, and highlight necessary gaps that need to be addressed to guarantee the best outcomes for SMA patients.

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Fig. 1: Summary of SMA types, and the observed and projected change in the natural history of SMA due to now available treatments.
Fig. 2: Summary of the three SMN-targeted therapies approved for the treatment of SMA by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) and corresponding clinic trials.
Fig. 3: Timeline of Spinraza (nusinersen) clinical trials.
Fig. 4: Timeline of Zolgensma (onasemnogene abeparvovec) clinical trials.

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Acknowledgements

We are thankful for our laboratory members and the colleagues who work in this field for their important contributions.

Funding

This work was supported by Cure SMA/Families of SMA Canada (Grant number KOT-1819 and KOT-2021); Muscular Dystrophy Association Inc. (USA) (Grant number 575466); and Canadian Institutes of Health Research (CIHR) (Grant number PJT-156379). A.R is supported by a uOttawa Eric Poulin Centre for Neuromuscular Disease (CNMD) Scholarship in Translational Research Award. LC is supported by a CIHR Vanier Canada Graduate Scholarship.

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  1. These authors contributed equally: Aoife Reilly, Lucia Chehade.

Authors and Affiliations

  1. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Aoife Reilly, Lucia Chehade & Rashmi Kothary

  2. Centre for Neuromuscular Disease, University of Ottawa, Ottawa, ON, Canada

    Aoife Reilly, Lucia Chehade & Rashmi Kothary

  3. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada

    Aoife Reilly, Lucia Chehade & Rashmi Kothary

  4. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada

    Rashmi Kothary

  5. Department of Medicine, University of Ottawa, Ottawa, ON, Canada

    Rashmi Kothary

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AR, LC, and RK wrote the paper. All authors have read and agreed to the published version of the paper.

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Correspondence to Rashmi Kothary.

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RK and the Ottawa Hospital Research Institute have a licensing agreement with Biogen for the Smn2B/− mouse model. This COI is outside the scope of this study. All other authors declare no competing interests.

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Reilly, A., Chehade, L. & Kothary, R. Curing SMA: Are we there yet?. Gene Ther 30, 8–17 (2023). https://doi.org/10.1038/s41434-022-00349-y

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