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Med"],"abstract":"<jats:p>Adeno-associated virus (AAV) vectors are currently used in four approved gene therapies for Leber congenital amaurosis (Luxturna), spinal muscular atrophy (Zolgensma), aromatic L-amino acid decarboxylase deficiency (Upstaza) and Haemophilia A (Roctavian), with several more therapies being investigated in clinical trials. AAV gene therapy has long been considered extremely safe both in the context of immunotoxicity and genotoxicity, but recent tragic deaths in the clinical trials for X-linked myotubular myopathy and Duchenne\u2019s muscular dystrophy, together with increasing reports of potential hepatic oncogenicity in animal models have prompted re-evaluation of how much trust we can place on the safety of AAV gene therapy, especially at high doses. In this review we cover genome and capsid engineering strategies that can be used to improve safety of the next generation AAV vectors both in the context of immunogenicity and genotoxicity and discuss the gaps that need filling in our current knowledge about AAV vectors.<\/jats:p>","DOI":"10.3389\/fmmed.2022.1054069","type":"journal-article","created":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T06:14:30Z","timestamp":1667283270000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Strategies to improve safety profile of AAV vectors"],"prefix":"10.3389","volume":"2","author":[{"given":"Tuisku","family":"Suoranta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nihay","family":"Laham-Karam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppo","family":"Yl\u00e4-Herttuala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e76310","DOI":"10.1371\/journal.pone.0076310","article-title":"Analysis of transduction efficiency, tropism and axonal transport of AAV serotypes 1, 2, 5, 6, 8 and 9 in the mouse brain","volume":"8","author":"Aschauer","year":"2013","journal-title":"PLoS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3908","DOI":"10.1016\/j.vaccine.2012.03.079","article-title":"High-efficiency transduction of human monocyte-derived dendritic cells by capsid-modified recombinant AAV2 vectors","volume":"30","author":"Aslanidi","year":"2012","journal-title":"Vaccine"},{"key":"B3","doi-asserted-by":"publisher","first-page":"59142","DOI":"10.1371\/journal.pone.0059142","article-title":"Optimization of the capsid of recombinant adeno-associated virus 2 (AAV2) vectors: The final threshold?","volume":"8","author":"Aslanidi","year":"2013","journal-title":"PLoS One"},{"key":"B4","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1126\/science.149.3685.754","article-title":"Adenovirus-associated defective virus particles","volume":"149","author":"Atchison","year":"1965","journal-title":"Science"},{"key":"B5","unstructured":"A second patient has tragically died on the AT132 gene therapy trial for XLMTM - letter to XLMTM Patient Community2020"},{"key":"B6","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1089\/hum.2014.057","article-title":"Manufacturing and characterization of a recombinant adeno-associated virus type 8 reference standard material","volume":"25","author":"Ayuso","year":"2014","journal-title":"Hum. 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