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 #
5R01EY010804-25
Application #
10005433
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
2020-09-01
Budget End
2021-08-31
Support Year
25
Fiscal Year
2020
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
Nissanka, Nadee; Moraes, Carlos T (2018) Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease. FEBS Lett 592:728-742
Pinto, Milena; Nissanka, Nadee; Moraes, Carlos T (2018) Lack of Parkin Anticipates the Phenotype and Affects Mitochondrial Morphology and mtDNA Levels in a Mouse Model of Parkinson's Disease. J Neurosci 38:1042-1053
Peralta, Susana; Goffart, Steffi; Williams, Sion L et al. (2018) ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels. J Cell Sci 131:
Garcia, Sofia; Nissanka, Nadee; Mareco, Edson A et al. (2018) Overexpression of PGC-1? in aging muscle enhances a subset of young-like molecular patterns. Aging Cell 17:
Arguello, Tania; Köhrer, Caroline; RajBhandary, Uttam L et al. (2018) Mitochondrial methionyl N-formylation affects steady-state levels of oxidative phosphorylation complexes and their organization into supercomplexes. J Biol Chem 293:15021-15032
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
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
Tengan, Celia H; Moraes, Carlos T (2017) NO control of mitochondrial function in normal and transformed cells. Biochim Biophys Acta Bioenerg 1858:573-581
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
Luo, Xueting; Ribeiro, Marcio; Bray, Eric R et al. (2016) Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System. Cell Rep 15:398-410

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