Abstract
Mutations within mitochondrial DNA (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 central nervous system (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 utilization 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.
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Moraes and colleagues showed that a mtDNA mutation in a mouse model can be eliminated from neurons harboring heteroplasmic mtDNA. The associated improvement in molecular markers opens the way for much needed therapeutic approaches for mitochondrial encephalomyopathies.
