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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010804-23
Application #
9551605
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Araj, Houmam H
Project Start
1994-12-01
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
23
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Madsen, Pernille M; Pinto, Milena; Patel, Shreyans et al. (2017) Mitochondrial DNA Double-Strand Breaks in Oligodendrocytes Cause Demyelination, Axonal Injury, and CNS Inflammation. J Neurosci 37:10185-10199
Tengan, Celia H; Moraes, Carlos T (2017) NO control of mitochondrial function in normal and transformed cells. Biochim Biophys Acta 1858:573-581
Pinto, Milena; Pickrell, Alicia M; Wang, Xiao et al. (2017) Transient mitochondrial DNA double strand breaks in mice cause accelerated aging phenotypes in a ROS-dependent but p53/p21-independent manner. Cell Death Differ 24:288-299
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Pinto, Milena; Nissanka, Nadee; Peralta, Susana et al. (2016) Pioglitazone ameliorates the phenotype of a novel Parkinson's disease mouse model by reducing neuroinflammation. Mol Neurodegener 11:25
Peralta, Susana; Garcia, Sofia; Yin, Han Yang et al. (2016) Sustained AMPK activation improves muscle function in a mitochondrial myopathy mouse model by promoting muscle fiber regeneration. Hum Mol Genet 25:3178-3191
Pinto, Milena; Moraes, Carlos T (2015) Mechanisms linking mtDNA damage and aging. Free Radic Biol Med 85:250-8
Reddy, Pradeep; Ocampo, Alejandro; Suzuki, Keiichiro et al. (2015) Selective elimination of mitochondrial mutations in the germline by genome editing. Cell 161:459-469
(2015) Retraction Notice to: mTERF2 Regulates Oxidative Phosphorylation by Modulating mtDNA Transcription. Cell Metab 22:751
Hashimoto, Masami; Bacman, Sandra R; Peralta, Susana et al. (2015) MitoTALEN: A General Approach to Reduce Mutant mtDNA Loads and Restore Oxidative Phosphorylation Function in Mitochondrial Diseases. Mol Ther 23:1592-9

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