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Gene therapies that restore dystrophin expression for the treatment of Duchenne muscular dystrophy

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Abstract

Duchenne muscular dystrophy is one of the most common inherited genetic diseases and is caused by mutations to the DMD gene that encodes the dystrophin protein. Recent advances in genome editing and gene therapy offer hope for the development of potential therapeutics. Truncated versions of the DMD gene can be delivered to the affected tissues with viral vectors and show promising results in a variety of animal models. Genome editing with the CRISPR/Cas9 system has recently been used to restore dystrophin expression by deleting one or more exons of the DMD gene in patient cells and in a mouse model that led to functional improvement of muscle strength. Exon skipping with oligonucleotides has been successful in several animal models and evaluated in multiple clinical trials. Next-generation oligonucleotide formulations offer significant promise to build on these results. All these approaches to restoring dystrophin expression are encouraging, but many hurdles remain. This review summarizes the current state of these technologies and summarizes considerations for their future development.

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Acknowledgments

This work has been supported by the Muscular Dystrophy Association (MDA277360), a Duke-Coulter Translational Partnership Grant, a Duke/UNC-Chapel Hill CTSA Consortium Collaborative Translational Research Award, a Hartwell Foundation Individual Biomedical Research Award, a March of Dimes Foundation Basil O’Connor Starter Scholar Award, National Institutes of Health (NIH) grant R01AR069085, an NIH Director’s New Innovator Award (DP2-OD008586), and the Office of the Assistant Secretary of Defense for Health Affairs, through the Duchenne Muscular Dystrophy Research Program under Award No. W81XWH-15-1-0469. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the NIH or Department of Defense. J.R.H. is supported by a National Science Foundation Graduate Research Fellowship.

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  1. Department of Biomedical Engineering, Duke University, Room 1427, Fitzpatrick CIEMAS, 101 Science Drive, Box 90281, Durham, NC, 27708-0281, USA

    Jacqueline N. Robinson-Hamm & Charles A. Gersbach

  2. Center for Genomic and Computational Biology, Duke University, Durham, NC, 27708, USA

    Jacqueline N. Robinson-Hamm & Charles A. Gersbach

  3. Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, 27710, USA

    Charles A. Gersbach

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  1. Jacqueline N. Robinson-Hamm
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Correspondence to Charles A. Gersbach.

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CA.G. and J.R.H. have filed patent applications related to genome editing for Duchenne muscular dystrophy. C.A.G. is an advisor to Editas Medicine, a company engaged in development of therapeutic genome editing.

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Robinson-Hamm, J.N., Gersbach, C.A. Gene therapies that restore dystrophin expression for the treatment of Duchenne muscular dystrophy. Hum Genet 135, 1029–1040 (2016). https://doi.org/10.1007/s00439-016-1725-z

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