{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:53:06Z","timestamp":1790675586324,"version":"4.1.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2019,3,20]],"date-time":"2019-03-20T00:00:00Z","timestamp":1553040000000},"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":[[2019,7]]},"abstract":"<jats:p>\n                    Gene therapy with an adeno\u2010associated vector (AAV) serotype 8 encoding the human ATPase copper\u2010transporting beta polypeptide (ATP7B) complementary DNA (cDNA; AAV8\u2010ATP7B) is able to provide long\u2010term copper metabolism correction in 6\u2010week\u2010old male Wilson disease (WD) mice. However, the size of the genome (5.2 kilobases [kb]) surpasses the optimal packaging capacity of the vector, which resulted in low\u2010yield production; in addition, further analyses in WD female mice and in animals with a more advanced disease revealed reduced therapeutic efficacy, as compared to younger males. To improve efficacy of the treatment, an optimized shorter AAV vector was generated, in which four out of six metal\u2010binding domains (MBDs) were deleted from the ATP7B coding sequence, giving rise to the miniATP7B protein (\u039457\u2010486\u2010ATP7B). In contrast to AAV8\u2010ATP7B, AAV8\u2010miniATP7B could be produced at high titers and was able to restore copper homeostasis in 6\u2010 and 12\u2010week\u2010old male and female WD mice. In addition, a recently developed synthetic AAV vector, AAVAnc80, carrying the miniATP7B gene was similarly effective at preventing liver damage, restoring copper homeostasis, and improving survival 1 year after treatment. Transduction of approximately 20% of hepatocytes was sufficient to normalize copper homeostasis, suggesting that corrected hepatocytes are acting as a sink to eliminate excess of copper. Importantly, administration of AAVAnc80\u2010miniATP7B was safe in healthy mice and did not result in copper deficiency.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : In summary, gene therapy using an optimized therapeutic cassette in different AAV systems provides long\u2010term correction of copper metabolism regardless of sex or stage of disease in a clinically relevant WD mouse model. These results pave the way for the implementation of gene therapy in WD patients.\n                  <\/jats:p>","DOI":"10.1002\/hep.30535","type":"journal-article","created":{"date-parts":[[2019,2,1]],"date-time":"2019-02-01T09:56:19Z","timestamp":1549014979000},"page":"108-126","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":54,"title":["Liver Expression of a MiniATP7B Gene Results in Long\u2010Term Restoration of Copper Homeostasis in a Wilson Disease Model in Mice"],"prefix":"10.1097","volume":"70","author":[{"given":"Oihana","family":"Murillo","sequence":"first","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, CIMA, FIMA,University of Navarra, Navarra Institute for Health Research (IdisNA),Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Moreno","sequence":"additional","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression 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(IdisNA),Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I\u00f1igo","family":"Navarro","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Soil Sciences,University of Navarra, IdisNA,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iker","family":"Uriarte","sequence":"additional","affiliation":[{"name":"Hepatology Program, CIMA, FIMA,University of Navarra, IdisNA,Pamplona,Spain"},{"name":"CIBERehd,Instituto de Salud Carlos III, Clinica Universidad de Navarra,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Sebastian","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering,Arag\u00f3n Institute of Nanoscience (INA), University of Zaragoza, and Aragon Health Research Institute (IIS Aragon),Zaragoza,Spain"},{"name":"Networking Research Center on Bioengineering, Biomaterials and Nanomedicine,CIBER\u2010BBN,28029\u2010,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Arruebo","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering,Arag\u00f3n Institute of Nanoscience (INA), University of Zaragoza, and Aragon Health Research Institute (IIS Aragon),Zaragoza,Spain"},{"name":"Networking Research Center on Bioengineering, Biomaterials and Nanomedicine,CIBER\u2010BBN,28029\u2010,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Ferrer","sequence":"additional","affiliation":[{"name":"Vivet Therapeutics SAS,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"B\u00e9nichou","sequence":"additional","affiliation":[{"name":"Vivet Therapeutics SAS,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Philippe","family":"Combal","sequence":"additional","affiliation":[{"name":"Vivet 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