RGD Reference Report - Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector. - Rat Genome Database

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Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector.

Authors: Toietta, G  Mane, VP  Norona, WS  Finegold, MJ  Ng, P  McDonagh, AF  Beaudet, AL  Lee, B 
Citation: Toietta G, etal., Proc Natl Acad Sci U S A 2005 Mar 15;102(11):3930-5. Epub 2005 Mar 7.
RGD ID: 1354702
Pubmed: PMID:15753292   (View Abstract at PubMed)
PMCID: PMC554836   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0500930102   (Journal Full-text)

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.

Disease Annotations    

Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Ugt1a1  (UDP glucuronosyltransferase family 1 member A1)
Ugt1a1j  (UDP glucuronosyltransferase family 1 member A1, jaundice mutant)

Genes (Mus musculus)
Ugt1a1  (UDP glucuronosyltransferase 1 family, polypeptide A1)

Genes (Homo sapiens)
UGT1A1  (UDP glucuronosyltransferase family 1 member A1)

Gunn-Ugt1a1j/BluHsd  (Gunn rat)

Additional Information