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Lookup NU author(s): Dr Jim StewartORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
Mutations in the mitochondrial DNA (mtDNA) commonly cause severe encephalopathies. Because most of these mtDNA alterations are heteroplasmic, we used a mitochondrial-targeted TALEN (mitoTALEN) to specifically eliminate the mutant mtDNA in the CNS of a mouse model harboring a heteroplasmic mutation in the mitochondrial tRNA alanine gene (m.5024C>T). Delivery to neurons was achieved by using AAV-PHP.eB and neuronal expression was obtained by using a neuronal-specific synapsin promoter. We found that most CNS regions were effectively transduced and showed a significant reduction in mutant mtDNA. This reduction was accompanied by an increase in mitochondrial tRNA alanine level, which is drastically reduced by the mutation. These results showed, for the first time, that mitochondrial-targeted gene editing can be effective in reducing CNS mutant mtDNA in vivo, paving the way for clinical trials in patients with mitochondrial encephalopathies.
Author(s): Bacman SR, Barrera-Paez JD, Pinto M, Van Booven D, Stewart JB, Griswold AJ, Moraes CT
Publication type: Article
Publication status: Published
Journal: Molecular Therapy Nucleic Acids
Year: 2024
Volume: 35
Issue: 1
Print publication date: 12/03/2024
Online publication date: 02/02/2024
Acceptance date: 29/01/2024
Date deposited: 19/02/2024
ISSN (electronic): 2162-2531
Publisher: Cell Press
URL: https://doi.org/10.1016/j.omtn.2024.102132
DOI: 10.1016/j.omtn.2024.102132
Data Access Statement: Data that are not already included in the manuscript is available upon request.
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