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Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Therapies for Leber hereditary optic neuropathy (LHON), in common with all disorders caused by mutated mitochondrial DNA, are inadequate. We have developed two gene therapy strategies for the disease: mitochondrial-targeted and allotopic expressed and compared them in a mouse model of LHON.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A LHON mouse model was generated by intravitreal injection of a mitochondrialtargeted Adeno-associated virus (AAV) carrying mutant human NADH dehydrogenase 4 gene (<jats:italic>hND4\/m.11778G&amp;gt;A<\/jats:italic>) to induce retinal ganglion cell (RGC) degeneration and axon loss, the hallmark of the human disease. We then attempted to rescue those mice using a second intravitreal injection of either mitochondrial-targeted or allotopic expressed wildtype human <jats:italic>ND4<\/jats:italic>. The rescue of RGCs and their axons were assessed using serial pattern electroretinogram (PERG) and transmission electron microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to non-rescued LHON controls where PERG amplitude was much reduced, both strategies significantly preserved PERG amplitude over 15 months. However, the rescue effect was more marked with mitochondrial-targeted therapy than with allotopic therapy (<jats:italic>p<\/jats:italic> = 0.0128). Post-mortem analysis showed that mitochondrial-targeted human <jats:italic>ND4<\/jats:italic> better preserved small axons that are preferentially lost in human LHON.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results in a pre-clinical mouse model of LHON suggest that mitochondrially-targeted AAV gene therapy, compared to allotopic AAV gene therapy, is more efficient in rescuing the LHON phenotype.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2023.1119724","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T04:55:18Z","timestamp":1679892918000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model"],"prefix":"10.3389","volume":"17","author":[{"given":"Sindhu","family":"Velmurugan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsung-Han","family":"Chou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy D.","family":"Eastwood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vittorio","family":"Porciatti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William W.","family":"Hauswirth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Guy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/S1055-7903(03)00194-5","article-title":"Evolution of mitochondrial gene content: gene loss and transfer to the nucleus.","volume":"29","author":"Adams","year":"2003","journal-title":"Mol. 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