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CRISPR editing as a therapeutic strategy for Duchenne muscular dystrophy—anti-Cas9 immune response casts its shadow over safety and efficacy

Gene Therapy volume 29, pages 575–577 (2022)Cite this article

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Duchenne muscular dystrophy is a progressive disorder that affects primarily boys, impacts mainly cardiac and skeletal muscle, and is caused by variants in the X-linked Dystrophin (DMD) gene [1]. DMD encodes a membrane associated protein that serves as a bridge between the extracellular matrix and the cytoskeletal network within the sarcoplasm, and its loss is associated with impaired membrane integrity and abnormalities in multiple signaling pathways [2]. The disease course is largely consistent across affected individuals, with onset around age 2 years, progressive proximal muscle dysfunction leading to loss of ambulation between ages 12–14, and continued muscle weakness and wasting associated with increasing respiratory and cardiac impairments. The implementation of glucocorticoid therapy, along with changes in respiratory and cardiac management, have led to improvements in quality of life and extension of life expectancy into the 30s [3]. However, DMD remains a severe, fatal disorder with a very high unmet need for disease modifying therapies.

DMD is a disorder well suited for genetic therapies [4, 5]. Pathogenic variants largely come in two flavors, nonsense mutations that promote nonsense mediated decay, and full exon (or multi exon) deletions that shift reading frame and result in frameshift and stop gain. The consequence at the molecular level is loss of Dystrophin protein. Previous therapeutic programs have concentrated on drugs that promote read-through of premature stop codons or ones that promote exon skipping to restore gene reading frame. These approaches have been only marginally successful, largely due to failure to restore meaningful levels of Dystrophin protein [6]. More recently, gene replacement therapy has emerged as an excited potential strategy [7]. Since DMD is too large for conventional AAV-based packaging, miniaturized versions of DMD are being tested. Currently there are 4 ongoing clinical trials evaluating different micro dystrophins, with results likely in the near future.

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Fig. 1: Anti-Cas9 immunity and its impact on CRISPR editing in a DMD dog model.

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Acknowledgements

The author thanks Zachary Coulson for generating the figure, and for helpful review of the manuscript.

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Authors and Affiliations

  1. Division of Neurology, Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada

    James J. Dowling

  2. Departments of Paediatrics and Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A1, Canada

    James J. Dowling

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JJD conceived, wrote, edited, and finalized all aspects of this manuscript. Zachary Coulson helped generated the figure (see acknowledgements).

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Correspondence to James J. Dowling.

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Dowling, J.J. CRISPR editing as a therapeutic strategy for Duchenne muscular dystrophy—anti-Cas9 immune response casts its shadow over safety and efficacy. Gene Ther 29, 575–577 (2022). https://doi.org/10.1038/s41434-022-00323-8

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