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Elimination of Mutant Mitochondrial DNA in Mitochondrial Myopathies Using Gene-Editing Enzymes

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Muscle Gene Therapy

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Abstract

Mitochondrial diseases form a genetically and clinically heterogeneous group of disorders that result in the dysfunction of the mitochondria oxidative phosphorylation (OXPHOS). This system is responsible for the generation of the cellular energy required for the function of cells, tissues, and organs. Skeletal and cardiac muscle dysfunction is also a common feature of mitochondrial diseases. Effective treatments have not been developed and are mostly related to supportive management and palliative therapies. Most pathogenic mitochondrial DNA (mtDNA) mutations are in a heteroplasmic state, and high levels of mutated mtDNA within a cell are required to exceed a critical threshold to cause a phenotype. Therefore, the goal of a therapeutic intervention would be to eliminate or decrease the amount of mutated mtDNA below a certain threshold to avoid clinical and biochemical manifestations of the disease. Our group and others have made several advances over the last 15 years inducing heteroplasmy shift as a potential strategy to treat mtDNA disorders. Although mitochondrial-targeted restriction endonucleases can efficiently change mtDNA heteroplasmy both ex vivo and in vivo, this approach can be used therapeutically only if a unique restriction site is created by a mtDNA mutation. To overcome this, non-specific endonucleases targeted to mitochondrial mutations have been developed using gene-editing nucleases such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). These are being used to reduce mutant mtDNA in the muscle and heart of mouse models. Although some limitations and concerns exist, future experiments should make this approach safe to treat patients.

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Acknowledgments

This work was supported by the US National Institutes of Health grants 5R01EY010804, 1R01AG036871, and 1R01NS079965. The following grants also helped support this work: the Muscular Dystrophy Association and the NEI center grant P30-EY014801 from the National Institutes of Health (NIH).

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  1. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA

    Sandra R. Bacman & Carlos T. Moraes

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Correspondence to Carlos T. Moraes .

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  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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Bacman, S.R., Moraes, C.T. (2019). Elimination of Mutant Mitochondrial DNA in Mitochondrial Myopathies Using Gene-Editing Enzymes. In: Duan, D., Mendell, J. (eds) Muscle Gene Therapy. Springer, Cham. https://doi.org/10.1007/978-3-030-03095-7_34

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