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To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (\n                    <jats:italic>Ndufs3<\/jats:italic>\n                    \/complex I or\n                    <jats:italic>Cox10<\/jats:italic>\n                    \/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing gene to the CNS of these mice. In both cases, we observed survival extension from 5\u20136 to more than 15 months, with no detectable disease phenotypes. Likewise, molecular and cellular phenotypes were mostly recovered in the treated mice. Surprisingly, these remarkable phenotypic improvements were achieved with only ~30% of neurons expressing the transgene from the AAV-PHP.eB vector in the conditions used. These findings suggest that neurons lacking OXPHOS are protected by the surrounding neuronal environment and that partial compensation for neuronal OXPHOS loss can have disproportionately positive effects.\n                  <\/jats:p>","DOI":"10.1038\/s44321-024-00111-4","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T11:17:15Z","timestamp":1724325435000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9202-3538","authenticated-orcid":false,"given":"Brittni R","family":"Walker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise-Michelle","family":"Theard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Rodriguez-Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra R","family":"Bacman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8077-7092","authenticated-orcid":false,"given":"Carlos T","family":"Moraes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"key":"111_CR1","doi-asserted-by":"publisher","first-page":"2693","DOI":"10.1093\/hmg\/ddg284","volume":"12","author":"H Antonicka","year":"2003","unstructured":"Antonicka H, Leary SC, Guercin G-H, Agar JN, Horvath R, Kennaway NG, Harding CO, Jaksch M, Shoubridge EA (2003) Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. 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