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Gene Therapy for X-Linked Myotubular Myopathy

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Muscle Gene Therapy

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Abstract

X-linked myotubular myopathy (XLMTM) emerges from mutations in the MTM1 gene and affects around 1 in 50,000 live-born male infants. This congenital myopathy has currently no treatment and leads to a severe impairment of motor skills and ventilation and premature death. In this chapter, we synthetize the results of gene therapy studies using recombinant adeno-associated vectors in preclinical models of X-linked myotubular myopathy. Over the past few years, the field has rapidly moved from myotubularin-deficient mice to dogs and has now begun the first clinical gene therapy trial for XLMTM. In both mice and dogs, a single intravenous injection of adeno-associated vector leads to a complete rescue of key pathological phenotypes, including motor and respiratory functions, and life expectancy. Despite the treatment being well tolerated in both animal models, we also interrogated some of the issues commonly encountered in gene therapy studies, notably immune responses against the vector capsid or the transgene product, genotoxicity, and off-target effects.

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Author information

Authors and Affiliations

  1. Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA

    Jean-Baptiste Dupont & Martin K. Childers

  2. Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    Michael W. Lawlor

Authors
  1. Jean-Baptiste Dupont
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  2. Michael W. Lawlor
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  3. Martin K. Childers
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Corresponding author

Correspondence to Jean-Baptiste Dupont .

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Editors and Affiliations

  1. Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA, Department of Biomedical Sciences College of Veterinary Medicine, University of Missouri, Columbia, MO, USA; Department of Bioengineering, University of Missouri, Columbia, MO, USA

    Dongsheng Duan

  2. Department of Pediatrics Nationwide Children’s Hospital and Research Institute, Department of Neurology Nationwide Children’s Hospital and Research Institute, The Ohio State University, Columbus, OH, USA

    Jerry R. Mendell

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Dupont, JB., Lawlor, M.W., Childers, M.K. (2019). Gene Therapy for X-Linked Myotubular Myopathy. In: Duan, D., Mendell, J. (eds) Muscle Gene Therapy. Springer, Cham. https://doi.org/10.1007/978-3-030-03095-7_32

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