Precision BioSciences Announces New Study Published in Nature Communications Using Engineered ARCUS Nuclease to Target Mutant Mitochondrial DNA In Vivo
Learnings to be Presented by
The study, “Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo” was led by
Mitochondrial disorders impair the function of mitochondria, the organelles that produce the energy needed by cells. Organs and tissues that require more energy, such as the heart, muscles and brain, are more often affected. Additionally, both mutant and wild-type mtDNA can co-exist within the mitochondria of a cell, a phenomenon called mtDNA heteroplasmy. When specific threshold levels of mutant mtDNA are reached, cell function can be compromised, and disease can manifest1. It is believed that a shift in mtDNA heteroplasmy toward wild-type may provide therapeutic benefit for patients, and not all mutant mtDNA must be eliminated to achieve improvements in symptoms; mutant mtDNA levels just need to be reduced below the disease threshold level.
“In the past, mitochondrial-targeted nucleases have been successful in shifting mtDNA heteroplasmy but have come with unwanted drawbacks, most notably large size, heterodimeric nature, inability to distinguish single base changes, or low flexibility and effectiveness,” said
Researchers involved with the study reported mitoARCUS-induced heteroplasmic shifts of up to 60% in vitro, with changes persisting for up to three weeks. When tested in a heteroplasmic mouse model, mitoARCUS delivered by AAV effectively shifted heteroplasmy towards wild-type in several of the analyzed tissues of juvenile mice, with no depletion in total mtDNA levels at 6, 12, or 24 weeks. In adult mice treated with AAV-mitoARCUS, there was no editing at any of the potential nuclear off-target sites, and liver and skeletal muscle showed robust elimination of mutant mtDNA with concomitant restoration of mitochondrial transfer RNA levels.
“This is the first time ARCUS has been used to edit outside the nuclear genome and has done so with encouraging safety and efficacy in this mouse model,” said
ARCUS® is a proprietary genome editing technology discovered and developed by scientists at
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1 Craven, L., et al., Recent Advances in Mitochondrial Disease. Annu Rev Genomics Hum Genet, 2017. 18: p. 257-275.
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