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Restoring Protein Expression in Neuromuscular Conditions: A Review Assessing the Current State of Exon Skipping/Inclusion and Gene Therapies for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy

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Abstract

The debilitating neuromuscular disorders Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), which harm 1 in 5000 newborn males and 1 in 11,000 newborns, respectively, are marked by progressive muscle wasting among other complications. While DMD causes generalized muscle weakness due to the absence of the dystrophin protein, SMA patients generally face motor neuron degeneration because of the lack of the survival motor neuron (SMN) protein. Many of the most promising therapies for both conditions restore the absent proteins dystrophin and SMN. Antisense oligonucleotide-mediated exon skipping and inclusion therapies are advancing clinically with the approved DMD therapies casimersen, eteplirsen, golodirsen, and viltolarsen, and the SMA therapy nusinersen. Existing antisense therapies focus on skeletal muscle for DMD and motor neurons for SMA, respectively. Through innovative techniques, such as peptide conjugation and multi-exon skipping, these therapies could be optimized for efficacy and applicability. By contrast, gene replacement therapy is administered only once to patients during treatment. Currently, only onasemnogene abeparvovec for SMA has been approved. Safety shortcomings remain a major challenge for gene therapy. Nevertheless, gene therapy for DMD has strong potential to restore dystrophin expression in patients. In light of promising functional improvements, antisense and gene therapies stand poised to elevate the lives of patients with DMD and SMA.

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  1. Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Edmonton, T6G 2R3, Canada

    Omar Sheikh & Toshifumi Yokota

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  1. Omar Sheikh
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Correspondence to Toshifumi Yokota.

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TY is a founder and shareholder of OligomicsTx, which aims to commercialize antisense oligonucleotide technology. OS has no conflicts of interest to report.

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Literature review draft preparation by Omar Sheikh. Supervision and funding acquisition by Toshifumi Yokota. Review and editing performed jointly. All authors have read and agreed to the published version of the manuscript.

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This work was supported by Muscular Dystrophy Canada, the Friends of Garrett Cumming Research Fund, the HM Toupin Neurological Science Research Fund, Fulbright Scholarship Program, and the Women and Children’s Health Research Institute (WCHRI).

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The authors wish to thank Mary Claire De Villa for writing feedback.

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Sheikh, O., Yokota, T. Restoring Protein Expression in Neuromuscular Conditions: A Review Assessing the Current State of Exon Skipping/Inclusion and Gene Therapies for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy. BioDrugs 35, 389–399 (2021). https://doi.org/10.1007/s40259-021-00486-7

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