Our long-term goal is to develop genetic approaches that could be used for the treatment of mitochondrial disorders associated with mitochondrial DNA (mtDNA) mutations. Although some of the approaches tested in the past showed some promise, they are inefficient and unlikely to reach clinical trials. We propose to develop approaches that are more efficient in improving oxidative phosphorylation in cells harboring heteroplasmic mtDNA mutations (i.e. a mixture of wild-type and mutated mtDNA). The approach is based on the """"""""mtDNA heteroplasmy shift"""""""" concept, where, by genetic manipulation, levels of the wild-type genome are increased in relation to the mutated genome. In the previous funding period we showed that mitochondria-targeted specific endonucleases are powerful tools to achieve mtDNA heteroplasmy shift. The present proposal will continue to develop this approach. We will deliver mitochondria targeted restriction endonucleases systemically to muscle of a mouse model of mtDNA heteroplasmy and expect to see a generalized shift in mtDNA heteroplasmy in skeletal muscle. To expand the use of mitochondria nucleases, we will create novel zinc finger protein nucleases that can target common mtDNA mutations associated with mitochondrial disorders. When this approach moves into the clinical arena, it will be important to avoid secondary effects with potential clinical relevance, such as transient mtDNA depletion. To this end, we will test a model whereby the levels of mtDNA are increased (per cell) before the action of the specific mitochondrial restriction endonuclease. This should minimize a potential bioenergetic crisis associated with partial mtDNA depletion.

Public Health Relevance

Mitochondrial disorders are devastating diseases affecting the central nervous system, eyes, muscle and several other organ systems. At present, there are no treatments for mitochondrial disorders. We propose to develop a genetic approach that could be used as a therapy for a sub-group of mitochondrial disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010804-17
Application #
8264352
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Araj, Houmam H
Project Start
1994-12-01
Project End
2013-09-29
Budget Start
2012-05-01
Budget End
2013-09-29
Support Year
17
Fiscal Year
2012
Total Cost
$363,528
Indirect Cost
$125,928
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
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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
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
Pinto, Milena; Moraes, Carlos T (2015) Mechanisms linking mtDNA damage and aging. Free Radic Biol Med 85:250-8
(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
Reddy, Pradeep; Ocampo, Alejandro; Suzuki, Keiichiro et al. (2015) Selective elimination of mitochondrial mutations in the germline by genome editing. Cell 161:459-69
Pinto, Milena; Moraes, Carlos T (2014) Mitochondrial genome changes and neurodegenerative diseases. Biochim Biophys Acta 1842:1198-207
Bacman, Sandra R; Williams, Sion L; Pinto, Milena et al. (2014) The use of mitochondria-targeted endonucleases to manipulate mtDNA. Methods Enzymol 547:373-97
Moraes, Carlos T; Bacman, Sandra R; Williams, Sion L (2014) Manipulating mitochondrial genomes in the clinic: playing by different rules. Trends Cell Biol 24:209-11

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