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However, somewhat unanticipated improvement in neuropsychiatric outcome upon long-term treatment of adults with PKU with enzyme substitution therapy might slowly change this assumption. In parallel, PKU was for a long time considered to be an excellent test system for experimental gene therapy of a Mendelian autosomal recessive defect of the liver due to an outstanding mouse model and the easy to analyze and well-defined therapeutic end point, that is, blood\n                    <jats:sc>l<\/jats:sc>\n                    -phenylalanine concentration. Lifelong treatment by targeting the mouse liver (or skeletal muscle) was achieved using different approaches, including (1) recombinant adeno-associated viral (rAAV) or nonviral naked DNA vector-based gene addition, (2) genome editing using base editors delivered by rAAV vectors, and (3) by delivering rAAVs for promoter-less insertion of the\n                    <jats:italic toggle=\"yes\">PAH<\/jats:italic>\n                    -cDNA into the\n                    <jats:italic toggle=\"yes\">Pah<\/jats:italic>\n                    locus. In this article we summarize the gene therapeutic attempts of correcting a mouse model for PKU and discuss the future implications for human gene therapy.\n                  <\/jats:p>","DOI":"10.1089\/hum.2019.111","type":"journal-article","created":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T05:24:25Z","timestamp":1564550665000},"page":"1274-1283","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":40,"title":["State-of-the-Art 2019 on Gene Therapy for Phenylketonuria"],"prefix":"10.1177","volume":"30","author":[{"given":"Hiu Man","family":"Grisch-Chan","sequence":"first","affiliation":[{"name":"Division of Metabolism, University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Schwank","sequence":"additional","affiliation":[{"name":"Department of Biology, Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cary O.","family":"Harding","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Genetics, School of Medicine, Oregon Science and Health University, Portland, Oregon."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beat","family":"Th\u00f6ny","sequence":"additional","affiliation":[{"name":"Division of Metabolism, University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,9,24]]},"reference":[{"key":"e_1_3_3_2_2","volume-title":"The Online Metabolic and Molecular Bases of Inherited Disease","author":"Donlon J","year":"2014","unstructured":"Donlon J, , Sarkissian C, , Levy H, et al. 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