title: Correction of hyperbilirubinemia in gunn rats by surgical delivery of low doses of helper-dependent adenoviral vectors.
abstract: Helper-dependent adenoviral (HDAd) vectors are attractive for liver-directed gene therapy because they can drive sustained high levels of transgene expression without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic delivery because of a nonlinear dose response. Unfortunately, such high doses result in systemic vector dissemination and dose-dependent acute toxicity with potential lethal consequences. We have previously shown in nonhuman primates that delivery of HDAd in surgically isolated livers resulted in a significantly higher hepatic transduction with reduced systemic vector dissemination compared with intravenous delivery and multiyear transgene expression. Encouraged by these data, we have now employed a surgical vector delivery method in the Gunn rat, an animal model for Crigler-Najjar syndrome. After vector delivery into the surgically isolated liver, we show phenotypic correction at the low and clinically relevant vector dose of 1 × 10(11) vp/kg. Correction of hyperbilirubinemia and increased glucuronidation of bilirubin in bile was achieved for up to 1 year after vector administration. Surgical delivery of the vector was well tolerated without signs of acute or chronic toxicity. This method of delivery could thereby be a safer alternative to liver transplantation for long-term treatment of Crigler-Najjar syndrome type I.
authors.affiliation: 1 Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 1064, Centre Hospitalier Universitaire (CHU) Hôtel Dieu , 44093 Nantes, France .
authors.forename: Françoise
authors.initials: F
authors.lastname: Schmitt
authors.forename: Nunzia
authors.initials: N
authors.lastname: Pastore
authors.forename: Cecilia
authors.initials: C
authors.lastname: Abarrategui-Pontes
authors.forename: Maude
authors.initials: M
authors.lastname: Flageul
authors.forename: Anne
authors.initials: A
authors.lastname: Myara
authors.forename: Sophie
authors.initials: S
authors.lastname: Laplanche
authors.forename: Philippe
authors.initials: P
authors.lastname: Labrune
authors.forename: Guillaume
authors.initials: G
authors.lastname: Podevin
authors.forename: Tuan Huy
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001663:Bilirubin / Q000097:blood; D003414:Crigler-Najjar Syndrome / Q000628:therapy; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D006932:Hyperbilirubinemia / Q000628:therapy*; D008099:Liver / Q000378:metabolism / Q000601:surgery; D011401:Promoter Regions, Genetic; D051381:Rats; D011911:Rats, Gunn; D014161:Transduction, Genetic; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme