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: 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.)

Chemical References

• RNA, Messenger
• Ugt1a1 protein, rat
• DNA
• UGT1A1 enzyme
• Glucuronosyltransferase
• Alanine Transaminase
• Bilirubin

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