{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:09:15Z","timestamp":1792001355042,"version":"4.4.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2019,6,26]],"date-time":"2019-06-26T00:00:00Z","timestamp":1561507200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,6,26]],"date-time":"2019-06-26T00:00:00Z","timestamp":1561507200000},"content-version":"tdm","delay-in-days":0,"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":[[2019,12]]},"abstract":"<jats:p>\n                    Recombinant adeno\u2010associated viral (rAAV) vectors are highly promising vehicles for liver\u2010targeted gene transfer, with therapeutic efficacy demonstrated in preclinical models and clinical trials. Progressive familial intrahepatic cholestasis type 3 (PFIC3), an inherited juvenile\u2010onset, cholestatic liver disease caused by homozygous mutation of the ABCB4 gene, may be a promising candidate for rAAV\u2010mediated liver\u2010targeted gene therapy. The\n                    <jats:italic toggle=\"yes\">Abcb4<\/jats:italic>\n                    <jats:sup>\u2010\/\u2010<\/jats:sup>\n                    mice model of PFIC3, with juvenile mice developing progressive cholestatic liver injury due to impaired biliary phosphatidylcholine excretion, resulted in cirrhosis and liver malignancy. Using a conventional rAAV strategy, we observed markedly blunted rAAV transduction in adult\n                    <jats:italic toggle=\"yes\">Abcb4\u2010\/\u2010<\/jats:italic>\n                    mice with established liver disease, but not in disease\u2010free, wild\u2010type adults or in homozygous juveniles prior to liver disease onset. However, delivery of predominantly nonintegrating rAAV vectors to juvenile mice results in loss of persistent transgene expression due to hepatocyte proliferation in the growing liver.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    A hybrid vector system, combining the high transduction efficiency of rAAV with\n                    <jats:italic toggle=\"yes\">piggyBac<\/jats:italic>\n                    transposase\u2010mediated somatic integration, was developed to facilitate stable human ABCB4 expression\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    and to correct juvenile\u2010onset chronic liver disease in a murine model of PFIC3. A single dose of hybrid vector at birth led to life\u2010long restoration of bile composition, prevention of biliary cirrhosis, and a substantial reduction in tumorigenesis. This powerful hybrid rAAV\u2010\n                    <jats:italic toggle=\"yes\">piggyBac<\/jats:italic>\n                    transposon vector strategy has the capacity to mediate lifelong phenotype correction and reduce the tumorigenicity of progressive familial intrahepatic cholestasis type 3 and, with further refinement, the potential for human clinical translation.\n                  <\/jats:p>","DOI":"10.1002\/hep.30773","type":"journal-article","created":{"date-parts":[[2019,5,17]],"date-time":"2019-05-17T04:53:29Z","timestamp":1558068809000},"page":"2047-2061","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":41,"title":["Prevention of Cholestatic Liver Disease and Reduced Tumorigenicity in a Murine Model of PFIC Type 3 Using Hybrid AAV\u2010piggyBac Gene Therapy"],"prefix":"10.1097","volume":"70","author":[{"given":"Susan M.","family":"Siew","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and James Fairfax Institute of Pediatric Nutrition,Sydney Children\u2019s Hospitals Network,Westmead,Australia"},{"name":"Gene Therapy Research Unit, Children\u2019s Medical Research Institute, Faculty of Medicine and Health,The University of Sydney and Sydney Children\u2019s Hospitals Network,Westmead,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon C.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children\u2019s Medical Research Institute, Faculty of Medicine and Health,The University of Sydney and Sydney Children\u2019s Hospitals Network,Westmead,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erhua","family":"Zhu","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children\u2019s Medical Research Institute, Faculty of Medicine and Health,The University of Sydney and Sydney Children\u2019s Hospitals Network,Westmead,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szun S.","family":"Tay","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children\u2019s Medical Research Institute, Faculty of Medicine and Health,The University of Sydney and Sydney Children\u2019s Hospitals Network,Westmead,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Venuti","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and James Fairfax Institute of Pediatric Nutrition,Sydney Children\u2019s Hospitals Network,Westmead,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Bolitho","sequence":"additional","affiliation":[{"name":"Gene Therapy Research Unit, Children\u2019s Medical Research Institute, Faculty of Medicine and Health,The University of Sydney and Sydney Children\u2019s Hospitals 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