{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T21:13:18Z","timestamp":1777669998559,"version":"3.51.4"},"reference-count":45,"publisher":"SAGE Publications","issue":"10","license":[{"start":{"date-parts":[[2012,7,5]],"date-time":"2012-07-05T00:00:00Z","timestamp":1341446400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2012,10]]},"abstract":"<jats:p>\n                    Crigler-Najjar syndrome is an autosomal recessive disorder with severe unconjugated hyperbilirubinemia due to deficiency of bilirubin UDP-glucuronosyltransferase isozyme 1A1 (UGT1A1) encoded by the\n                    <jats:italic toggle=\"yes\">UGT1A1<\/jats:italic>\n                    gene. Current therapy relies on phototherapy to prevent life-threatening elevations of serum bilirubin levels, but liver transplantation is the only permanent treatment. Muscle-directed gene therapy has several advantages, including easy and safe access through simple intramuscular injections, and has been investigated in human clinical trials. In this study, we have investigated the efficacy of adeno-associated viral (AAV) vector-mediated muscle-directed gene therapy in the preclinical animal model of Crigler-Najjar syndrome, that is the Gunn rat. Serotype 1 AAV vector expressing rat\n                    <jats:italic toggle=\"yes\">UGT1A1<\/jats:italic>\n                    under the control of muscle-specific creatine kinase promoter was injected at a dose of 3\u00d710\n                    <jats:sup>12<\/jats:sup>\n                    genome copies\/kg into the muscles of Gunn rats and resulted in expression of UGT1A1 protein and functionally active enzyme in injected muscles. AAV-injected Gunn rats showed an approximately 50% reduction in serum bilirubin levels as compared with saline-treated controls, and this reduction was sustained for at least 1 year postinjection. Increased excretion of alkali-labile metabolites of bilirubin in bile and urine was detected in AAV-injected animals. High-performance liquid chromatography analysis of bile from AAV-injected Gunn rats showed a metabolite with retention time close to that of bilirubin diglucuronide. Taken together, these data show that clinically relevant and sustained reduction of serum bilirubin levels can be achieved by simple and safe intramuscular injections in Gunn rats. AAV-mediated muscle directed gene therapy has potential for the treatment of patients with Crigler-Najjar syndrome type 1.\n                  <\/jats:p>","DOI":"10.1089\/hum.2012.018","type":"journal-article","created":{"date-parts":[[2012,7,5]],"date-time":"2012-07-05T21:07:43Z","timestamp":1341522463000},"page":"1082-1089","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":7,"title":["Sustained Reduction of Hyperbilirubinemia in Gunn Rats After Adeno-Associated Virus-Mediated Gene Transfer of Bilirubin UDP-Glucuronosyltransferase Isozyme 1A1 to Skeletal Muscle"],"prefix":"10.1177","volume":"23","author":[{"given":"Nunzia","family":"Pastore","sequence":"first","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM)","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edoardo","family":"Nusco","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM)","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Van\u00edkova","sequence":"additional","affiliation":[{"name":"Charles University","place":["Czech Republic"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa Maria","family":"Sepe","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM)","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Vetrini","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM)","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antony","family":"McDonagh","sequence":"additional","affiliation":[{"name":"University of California San Francisco (UCSF)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Auricchio","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM)","place":["Italy"]},{"name":"Federico II University of Naples","place":["Italy"]},{"name":"Federico II University of Naples","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Libor","family":"Vitek","sequence":"additional","affiliation":[{"name":"Charles University","place":["Czech Republic"]},{"name":"Charles University","place":["Czech Republic"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Brunetti-Pierri","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM)","place":["Italy"]},{"name":"Federico II University of Naples","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2012,7,5]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(69)90224-1"},{"key":"e_1_3_3_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-05-1446"},{"key":"e_1_3_3_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-12-261156"},{"key":"e_1_3_3_5_1","first-page":"381","article-title":"Complete correction of hyperbilirubinemia in the Gunn rat model of Crigler-Najjar syndrome type I following transient in vivo adenovirus-mediated expression of human bilirubin UDP-glucuronosyltransferase","volume":"3","author":"Askari F.K.","year":"1996","unstructured":"Askari F.K., , Hitomi Y., , Mao M., , Wilson J.M. 1996. Complete correction of hyperbilirubinemia in the Gunn rat model of Crigler-Najjar syndrome type I following transient in vivo adenovirus-mediated expression of human bilirubin UDP-glucuronosyltransferase. 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