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  Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo

Gammage, P. A., Viscomi, C., Simard, M. L., Costa, A. S. H., Gaude, E., Powell, C. A., et al. (2018). Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo. Nat Med, 24(11), 1691-1695. doi:10.1038/s41591-018-0165-9.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-7209-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-73AE-7
Genre: Journal Article

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 Creators:
Gammage, P. A.1, Author
Viscomi, C.1, Author
Simard, M. L.1, Author
Costa, A. S. H.1, Author
Gaude, E.1, Author
Powell, C. A.1, Author
Van Haute, L.1, Author
McCann, B. J.1, Author
Rebelo-Guiomar, P.1, Author
Cerutti, R.1, Author
Zhang, L.1, Author
Rebar, E. J.1, Author
Zeviani, M.1, Author
Frezza, C.1, Author
Stewart, J. B.1, Author
Minczuk, M.1, Author
Affiliations:
1Stewart – Mitochondrial Mutations and Genome Co-evolution, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, DE, ou_1942301              

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 Abstract: Mutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNA(Ala) mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin.

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 Dates: 2018-112018-09-27
 Publication Status: Published in print
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 Identifiers: Other: 30250142
DOI: 10.1038/s41591-018-0165-9
ISSN: 1546-170X (Electronic)1078-8956 (Linking)
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Title: Nat Med
Source Genre: Journal
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Pages: - Volume / Issue: 24 (11) Sequence Number: - Start / End Page: 1691 - 1695 Identifier: -