title: Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector.
abstract: Crigler-Najjar syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by a deficiency of uridine diphospho-glucuronosyl transferase 1A1. Current therapy relies on phototherapy to prevent kernicterus, but liver transplantation presently is the only permanent cure. Gene therapy is a potential alternative, and recent work has shown that helper-dependent adenoviral (HD-Ad) vectors, devoid of all viral coding sequences, induce prolonged transgene expression and exhibit significantly less chronic toxicity than early-generation Ad vectors. We used a HD-Ad vector to achieve liver-restricted expression of human uridine diphospho-glucuronosyl transferase 1A1 in the Gunn rat, a model of the human disorder. Total plasma bilirubin levels were reduced from >5.0 mg/dl to <<1.4 mg/dl for >2 yr after a single i.v. administration of vector expressing the therapeutic transgene at a dose of 3 x 10(12) viral particles per kg. HPLC analysis of bile from treated rats showed the presence of bilirubin glucuronides at normal WT levels >2 yr after one injection of vector, and i.v. injection of bilirubins IIIalpha and XIIIalpha in the same animals revealed excess bilirubin-conjugating capacity. There was no significant elevation of liver enzymes (alanine aminotransferase) and only transient, moderate thrombocytopenia after injection of the vector. A clinically significant reduction in serum bilirubin was observed with a dose as low as 6 x 10(11) viral particles per kg. We conclude that complete, long-term correction of hyperbilirubinemia in the Gunn rat model of Crigler-Najjar syndrome can be achieved with one injection of HD-Ad vector and negligible chronic toxicity.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Toietta
authors.forename: Viraj P
authors.initials: VP
authors.lastname: Mane
authors.forename: Wilma S
authors.initials: WS
authors.lastname: Norona
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.forename: Philip
authors.initials: P
authors.lastname: Ng
authors.forename: Antony F
authors.initials: AF
authors.lastname: McDonagh
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000256:Adenoviridae; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D004247:DNA / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000633:toxicity; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006932:Hyperbilirubinemia / Q000188:drug therapy*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011911:Rats, Gunn; D000099148:UGT1A1 Enzyme
chemical_list: D000410:Alanine Transaminase; D001663:Bilirubin; D004247:DNA; D014453:Glucuronosyltransferase; D012333:RNA, Messenger; D000099148:UGT1A1 Enzyme; C499946:Ugt1a1 protein, rat