Setting the Stage for Replacement of Mitochondrial Genes The goal of this project is to perform required pre-clinical investigations in a novel approach to reduce the levels of disease-causing mutant mtDNA in cells from patients with mitochondrial diseases. We will use mitochondrial-targeted TAL-effector nucleases (mitoTALENs) as novel gene therapy tools to specifically eliminate selected mtDNA haplotypes. This approach was successful in cultured cells and now we to use mitoTALENs in novel ways to alter mtDNA heteroplasmy in mouse tissues, focusing on expression from rAAV2/9 in limb muscles, extra-ocular muscles and the retina. In addition, we will optimize a mitoTALEN that we hope can be used in human patients in the near future.

Public Health Relevance

Setting the Stage for Replacement of Mitochondrial Genes There are no treatments for patients with heteroplasmic mtDNA mutations. We have developed an approach to eliminate the mutant mtDNA population through the expression of specific mitochondrial- targeted nucleases. The newest versions, mitoTALENs appear to be a general tool to efficiently select for specific mtDNA haplotypes. We propose to test this approach in vivo, using a novel mouse model.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Araj, Houmam H
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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