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.
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Authors | Gabriele Toietta, Viraj P Mane, Wilma S Norona, Milton J Finegold, Philip Ng, Antony F McDonagh, Arthur L Beaudet, Brendan Lee |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 102
Issue 11
Pg. 3930-5
(Mar 15 2005)
ISSN: 0027-8424 [Print] United States |
PMID | 15753292
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- RNA, Messenger
- Ugt1a1 protein, rat
- DNA
- UGT1A1 enzyme
- Glucuronosyltransferase
- Alanine Transaminase
- Bilirubin
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Topics |
- Adenoviridae
- Alanine Transaminase
(blood)
- Animals
- Bilirubin
(blood)
- DNA
(pharmacology)
- Genetic Therapy
- Genetic Vectors
(toxicity)
- Glucuronosyltransferase
(genetics, metabolism)
- Humans
- Hyperbilirubinemia
(drug therapy)
- RNA, Messenger
(metabolism)
- Rats
- Rats, Gunn
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