Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo

Ugne Zekonyte, Sandra R. Bacman, Jeff Smith, Wendy Shoop, Claudia V. Pereira, Ginger Tomberlin, James Stewart, Derek Jantz and Carlos T. Moraes ()
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Ugne Zekonyte: University of Miami Miller School of Medicine
Sandra R. Bacman: University of Miami Miller School of Medicine
Jeff Smith: Precision BioSciences
Wendy Shoop: Precision BioSciences
Claudia V. Pereira: University of Miami Miller School of Medicine
Ginger Tomberlin: Precision BioSciences
James Stewart: Newcastle University
Derek Jantz: Precision BioSciences
Carlos T. Moraes: University of Miami Miller School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Diseases caused by heteroplasmic mitochondrial DNA mutations have no effective treatment or cure. In recent years, DNA editing enzymes were tested as tools to eliminate mutant mtDNA in heteroplasmic cells and tissues. Mitochondrial-targeted restriction endonucleases, ZFNs, and TALENs have been successful in shifting mtDNA heteroplasmy, but they all have drawbacks as gene therapy reagents, including: large size, heterodimeric nature, inability to distinguish single base changes, or low flexibility and effectiveness. Here we report the adaptation of a gene editing platform based on the I-CreI meganuclease known as ARCUS®. These mitochondrial-targeted meganucleases (mitoARCUS) have a relatively small size, are monomeric, and can recognize sequences differing by as little as one base pair. We show the development of a mitoARCUS specific for the mouse m.5024C>T mutation in the mt-tRNAAla gene and its delivery to mice intravenously using AAV9 as a vector. Liver and skeletal muscle show robust elimination of mutant mtDNA with concomitant restoration of mt-tRNAAla levels. We conclude that mitoARCUS is a potential powerful tool for the elimination of mutant mtDNA.

Date: 2021
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DOI: 10.1038/s41467-021-23561-7

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