mitoTALEN reduces the mutant mtDNA load in neurons
Year: 2024
Type: article
Abstract: Mutations within mtDNA frequently give rise to severe encephalopathies. Given that a majority of these mtDNA defects exist in a heteroplasmic state, we harnessed the precision of mitochondrial-targeted TALEN (mitoTALEN) to selectively eliminate mutant mtDNA within the CNS of a murine model harboring a heteroplasmic mutation in the mitochondrial tRNA alanine gene (m.5024C>T). This targeted approach was accomplished by the use of AAV-PHP.eB and a neuron-specific synapsin promoter for effective neuronal delivery and expression of mitoTALEN. 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 levels, which are drastically reduced by the m.5024C>T mutation. These results showed 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.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,900
Awards: G1432373144, Mouse Models of Mitochondrial Encephalomyopathies, MitoCluster: an integrated phenotyping and mouse model generation platform for mitochondrial disease and dysfunction, G3315150621, Developing Gene Therapy Approaches for mtDNA Deletions, G5642384944, G5841794253, G7216941899, G7452299184, G7678110179, G8024407505, G9000268364, Setting the Stage for Replacement of Mitochondrial Genes
OpenAlex ID: W4391474424