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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\n                    <jats:italic>I-CreI<\/jats:italic>\n                    meganuclease known as ARCUS\n                    <jats:sup>\u00ae<\/jats:sup>\n                    . 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&gt;T mutation in the mt-tRNA\n                    <jats:sup>Ala<\/jats:sup>\n                    gene and its delivery\u00a0to mice intravenously using AAV9 as a vector. Liver and skeletal muscle show robust elimination of mutant mtDNA with concomitant restoration of mt-tRNA\n                    <jats:sup>Ala<\/jats:sup>\n                    levels. We conclude that mitoARCUS is a potential powerful tool for the elimination of mutant mtDNA.\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-23561-7","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T06:20:17Z","timestamp":1622182817000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo"],"prefix":"10.1038","volume":"12","author":[{"given":"Ugne","family":"Zekonyte","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra R.","family":"Bacman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Shoop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia V.","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginger","family":"Tomberlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2902-4968","authenticated-orcid":false,"given":"James","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Jantz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos T.","family":"Moraes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"23561_CR1","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.tig.2020.06.009","volume":"36","author":"KR Schon","year":"2020","unstructured":"Schon, K. 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C.T.M., D.J., G.T., and W.S. are named in a joint patent application (Patent applicant- Precision BioSciences, Inc. and the University of Miami; application number: 63\/178,269; status: pending) for mitochondria-targeted ARCUS nucleases with Precision BioSciences. Specific aspect of manuscript covered in patent application: ARCUS nuclease sequences and compositions for targeting mitochondria, including delivery vectors; Methods of modifying cells, Treating mitochondrial conditions in vivo using the disclosed ARCUS nucleases. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3210"}}