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As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno\u2010associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon\u2010optimized human <jats:italic>PAH<\/jats:italic> gene, with or without an intron spacer, to the <jats:italic>Pah<\/jats:italic><jats:sup><jats:italic>enu2<\/jats:italic><\/jats:sup> mouse model of PKU. Dose\u2010dependent transduction of the liver and expression of <jats:italic>PAH<\/jats:italic> mRNA were present with both vectors, resulting in significant and durable reduction of circulating phenylalanine, reaching near control levels in males. Coat color of treated <jats:italic>Pah<\/jats:italic><jats:sup><jats:italic>enu2<\/jats:italic><\/jats:sup> mice reflected an increase in pigmentation from brown to the black color of control animals, further indicating functional restoration of phenylalanine metabolism and its byproduct melanin. There were no adverse effects associated with administration of AAV up to 5\u2009\u00d7\u200910<jats:sup>12<\/jats:sup> VG\/kg, the highest dose tested. Only minor and\/or transient variations in some liver enzymes were observed in some of the AAV\u2010dosed animals which were not associated with pathology findings in the liver. Finally, there was no impact on cell turnover or apoptosis as evaluated by Ki\u201067 and TUNEL staining, further supporting the safety of this approach. This study demonstrates the therapeutic potential of AAV Anc80 to safely and durably cure PKU in a mouse model, supporting development for clinical consideration.<\/jats:p>","DOI":"10.1002\/jimd.12392","type":"journal-article","created":{"date-parts":[[2021,4,25]],"date-time":"2021-04-25T11:25:06Z","timestamp":1619349906000},"page":"1369-1381","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Use of an adeno\u2010associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1411-1513","authenticated-orcid":false,"given":"Robert A.","family":"Kaiser","sequence":"first","affiliation":[{"name":"Children's Hospitals and Clinics of Minnesota  Minneapolis Minnesota USA"},{"name":"Department of Surgery Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas D.","family":"Weber","sequence":"additional","affiliation":[{"name":"Vivet Therapeutics S.L.  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laia","family":"Trigueros\u2010Motos","sequence":"additional","affiliation":[{"name":"Vivet Therapeutics S.L.  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari L.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Surgery Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Genetics Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Surgery Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin J.","family":"VanLith","sequence":"additional","affiliation":[{"name":"Department of Surgery Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori G.","family":"Hillin","sequence":"additional","affiliation":[{"name":"Department of Surgery Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Douar","sequence":"additional","affiliation":[{"name":"Vivet Therapeutics S.A.S.  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1600-4562","authenticated-orcid":false,"given":"Gloria","family":"Gonz\u00e1lez\u2010Aseguinolaza","sequence":"additional","affiliation":[{"name":"Vivet Therapeutics S.L.  Pamplona Spain"},{"name":"Division of Gene Therapy and Regulation of Gene Expression CIMA Universidad de Navarra  Pamplona Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdISNA)  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Aldabe","sequence":"additional","affiliation":[{"name":"Division of Gene Therapy and Regulation of Gene Expression CIMA Universidad de Navarra  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph B.","family":"Lillegard","sequence":"additional","affiliation":[{"name":"Children's Hospitals and Clinics of Minnesota  Minneapolis Minnesota USA"},{"name":"Department of Surgery Mayo Clinic  Rochester Minnesota USA"},{"name":"Pediatric Surgical Associates  Minneapolis Minnesota 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