DNA‐editing enzymes as potential treatments for heteroplasmic mtDNA diseases

• Published in: Journal of internal medicine Vol. 287; no. 6; pp. 685 - 697
• Main Authors: Zekonyte, U., Bacman, S. R., Moraes, C. T.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2020
• Subjects: Animals; Cell culture; Deoxyribonucleic acid; Dietary supplements; DNA; DNA Repair - genetics; DNA Repair Enzymes - genetics; DNA Repair Enzymes - therapeutic use; DNA, Mitochondrial - genetics; DNA-editing enzyme; Editing; Enzymes; Gene therapy; Genetic Therapy - methods; Genomes; Health services; Heteroplasmy; Heteroplasmy - genetics; Humans; I-TevI; Mammalian cells; Medical treatment; mitochondria; Mitochondrial Diseases; Mitochondrial DNA; Mutants; Mutation; Neuromuscular diseases; Symptom management; Vitamins; gene therapy; mitochondrial diseases; I-TevI; DNA-editing enzyme; mitochondria; mitochondrial DNA
• ISSN: 0954-6820; 1365-2796
• DOI: 10.1111/joim.13055

Mutations in the mitochondrial genome are the cause of many debilitating neuromuscular disorders. Currently, there is no cure or treatment for these diseases, and symptom management is the only relief doctors can provide. Although supplements and vitamins are commonly used in treatment, they provide little benefit to the patient and are only palliative. This is why gene therapy is a promising research topic to potentially treat and, in theory, even cure diseases caused by mutations in the mitochondrial DNA (mtDNA). Mammalian cells contain approximately a thousand copies of mtDNA, which can lead to a phenomenon called heteroplasmy, where both wild‐type and mutant mtDNA molecules co‐exist within the cell. Disease only manifests once the per cent of mutant mtDNA reaches a high threshold (usually >80%), which causes mitochondrial dysfunction and reduced ATP production. This is a useful feature to take advantage of for gene therapy applications, as not every mutant copy of mtDNA needs to be eliminated, but only enough to shift the heteroplasmic ratio below the disease threshold. Several DNA‐editing enzymes have been used to shift heteroplasmy in cell culture and mice. This review provides an overview of these enzymes and discusses roadblocks of applying these to gene therapy in humans. Content List ‐ Read more articles from the symposium: “Mitochondria in human disease”.