GENE-THERAPY WITH BILIRUBIN-UDP-GLUCURONOSYLTRANSFERASE IN THE GUNN RAT MODEL OF CRIGLER-NAJJAR-SYNDROME TYPE-1

Crigler-Najjar syndrome type 1 (CN type 1) is an autosomal recessive d isorder characterized by nonhemolytic jaundice resulting from mutation s to the gene encoding bilirubin-UDP-glucuronosyltransferase (UDPGT), The Gunn rat is an accurate animal model of this disease because the b ilirubin-UDPGT gene in this strain carries a premature stop codon, The primary objective of this study was to complement this deficiency in vivo using liver-directed gene therapy, The efficiency of adenovirus t ype 5 (Ad5)-mediated gene transfer to the neonatal rat liver was first assessed by intravenous (i.v.) injection of an Ad5 vector carrying a nuclear-localized LacZ gene, An Ad5 vector expressing the cDNA encodin g human bilirubin-UDPGT (Ad5/CMV/hUG-Br1) was then generated and injec ted i.v. into neonatal Gunn rats, Plasma samples were collected and bi lirubin levels were determined at regular intervals, Although the mean level of bilirubin in homozygous Gunn rats 1-2 days after birth was a lready 14.5-fold higher than that of heterozygous siblings, treatment with Ad5/CMV/hUG-Br1 reduced plasma bilirubin to normal levels within 1 meek, Plasma bilirubin in the treated homozygous rats remained norma l for 4 weeks before gradually climbing to intermediate levels that we re approximately half that of untreated homozygotes by 12 weeks, Admin istration of Ad5-mediated gene therapy to neonatal Gunn rats effective ly complemented the deficiency in bilirubin-UDPGT, resulting in substa ntial reductions in plasma bilirubin over a 3-month period, The effica cy of Ad5-mediated gene therapy in neonates suggests that this approac h might be effective against other hepatic disorders, including autoso mal recessive deficiencies in lipid metabolism and vascular homeostasi s.