{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:40:54Z","timestamp":1791571254506,"version":"4.3.4"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":101,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:p>Liver\u2010targeted gene therapy based on recombinant adeno\u2010associated viral vectors (rAAV) shows promising therapeutic efficacy in animal models and adult\u2010focused clinical trials. This promise, however, is not directly translatable to the growing liver, where high rates of hepatocellular proliferation are accompanied by loss of episomal rAAV genomes and subsequently a loss in therapeutic efficacy. We have developed a hybrid rAAV\/<jats:italic toggle=\"yes\">piggyBac<\/jats:italic> transposon vector system combining the highly efficient liver\u2010targeting properties of rAAV with stable <jats:italic toggle=\"yes\">piggyBac<\/jats:italic>\u2010mediated transposition of the transgene into the hepatocyte genome. Transposition efficiency was first tested using an enhanced green fluorescent protein expression cassette following delivery to newborn wild\u2010type mice, with a 20\u2010fold increase in stably gene\u2010modified hepatocytes observed 4 weeks posttreatment compared to traditional rAAV gene delivery. We next modeled the therapeutic potential of the system in the context of severe urea cycle defects. A single treatment in the perinatal period was sufficient to confer robust and stable phenotype correction in the ornithine transcarbamylase\u2013deficient <jats:italic toggle=\"yes\">Spfash\n                           <\/jats:italic> mouse and the neonatal lethal argininosuccinate synthetase knockout mouse. Finally, transposon integration patterns were analyzed, revealing 127,386 unique integration sites which conformed to previously published <jats:italic toggle=\"yes\">piggyBac<\/jats:italic> data. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Using a hybrid rAAV\/<jats:italic toggle=\"yes\">piggyBac<\/jats:italic> transposon vector system, we achieved stable therapeutic protection in two urea cycle defect mouse models; a clinically conceivable early application of this technology in the management of severe urea cycle defects could be as a bridging therapy while awaiting liver transplantation; further improvement of the system will result from the development of highly human liver\u2010tropic capsids, the use of alternative strategies to achieve transient transposase expression, and engineered refinements in the safety profile of <jats:italic toggle=\"yes\">piggyBac<\/jats:italic> transposase\u2010mediated integration. (H<jats:sc>epatology<\/jats:sc> 2015;62:417\u2013428<\/jats:p>","DOI":"10.1002\/hep.27842","type":"journal-article","created":{"date-parts":[[2015,4,9]],"date-time":"2015-04-09T17:04:35Z","timestamp":1428599075000},"page":"417-428","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":47,"title":["Modeling correction of severe urea cycle defects in the growing murine liver using a hybrid recombinant adeno\u2010associated virus\/piggyBac transposase gene delivery system"],"prefix":"10.1097","volume":"62","author":[{"given":"Sharon C.","family":"Cunningham","sequence":"first","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead,Westmead,New South Wales,Australia"},{"name":"University of Sydney Medical School,Sydney,New South Wales,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Siew","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead,Westmead,New South Wales,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus V.","family":"Hallwirth","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead,Westmead,New South Wales,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Bolitho","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead,Westmead,New South Wales,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsuki","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead,Westmead,New South Wales,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gagan","family":"Garg","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead,Westmead,New South Wales,Australia"},{"name":"Department of Chemistry and Biomolecular Sciences,Macquarie University,Macquarie Park,New South Wales,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iacovos P.","family":"Michael","sequence":"additional","affiliation":[{"name":"Lunenfeld\u2010Tanenbaum Research Institute, Mount Sinai Hospital,Toronto,Ontario,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola A.","family":"Hetherington","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead,Westmead,New South Wales,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Biochemical Genetics, The Children's Hospital at Westmead, Westmead,Sydney,New South Wales,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"de Alencastro","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead,Westmead,New South Wales,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andras","family":"Nagy","sequence":"additional","affiliation":[{"name":"Lunenfeld\u2010Tanenbaum Research Institute, Mount Sinai Hospital,Toronto,Ontario,Canada"},{"name":"Institute of Medical Science and Department of Obstetrics & Gynaecology,University of Toronto,Toronto,Ontario,Canada"},{"name":"Department of Obstetrics & Gynaecology,University of 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