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mitoTALEN Eliminates Mutant mtDNA Genomes in Neurons

Lookup NU author(s): Dr Jim StewartORCiD

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Abstract

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.

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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

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