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Dystroglycanopathy Gene Therapy: Unlocking the Potential of Genetic Engineering

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Muscle Gene Therapy

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Abstract

Muscular dystrophy-dystroglycanopathies (MDDGs) are neuromuscular disorders associated with aberrant O-glycosylation of α-dystroglycan—an extracellular peripheral membrane glycoprotein central to the dystrophin-glycoprotein complex. The majority of these disorders are caused by loss-of-function mutations in a multitude of genes that disrupt the posttranslational modification of α-dystroglycan, affecting its ability to function as a receptor for extracellular matrix proteins containing laminin globular domains. As a result, clinical manifestations of MDDGs are highly variable, exhibiting a wide spectrum of clinical phenotypes including mild to severe defects in the development of the muscles, brain, and/or eyes. Over the last couple of decades, significant progress has been made in the elucidation of O-mannosyl glycan structures on α-dystroglycan and characterization of the underlying mechanisms of MDDGs, which has prompted concerted efforts toward the development and evaluation of potential clinical treatment options. Current genetic engineering efforts designed to treat MDDGs employ adeno-associated virus (AAV)-mediated delivery of expression vectors for gene replacement/supplementation and antisense oligonucleotide (AON) splice-modulation therapy to suppress exon trapping. Future therapeutic strategies are focused on the optimization of these current technologies and exploration of newer technologies such as genome editing. In this chapter, we address the disruption of functional α-dystroglycan as it relates to various clinical manifestations and highlight the potential genetic engineering strategies for treating MDDGs with an emphasis on preclinical data. We also discuss the problems that must be solved before effective treatment options are readily available.

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Acknowledgments

This work was supported by the Carolinas Muscular Dystrophy Research Endowment at the Atrium Health Foundation and Carolinas Medical Center, Charlotte, NC.

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Authors and Affiliations

  1. McColl-Lockwood Laboratory for Muscular Dystrophy Research, Carolinas Medical Center, Atrium Health, Charlotte, NC, USA

    Charles H. Vannoy, Anthony Blaeser & Qi L. Lu

Authors
  1. Charles H. Vannoy
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  2. Anthony Blaeser
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  3. Qi L. Lu
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Corresponding author

Correspondence to Qi L. Lu .

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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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Vannoy, C.H., Blaeser, A., Lu, Q.L. (2019). Dystroglycanopathy Gene Therapy: Unlocking the Potential of Genetic Engineering. In: Duan, D., Mendell, J. (eds) Muscle Gene Therapy. Springer, Cham. https://doi.org/10.1007/978-3-030-03095-7_27

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