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Volume 271, Number 43, Issue of October 25, 1996 pp. 26536-26542
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Long Term Correction of Bilirubin-UDP-glucuronosyltransferase Deficiency in Gunn Rats by Administration of a Recombinant Adenovirus during the Neonatal Period

(Received for publication, May 14, 1996, and in revised form, July 17, 1996)

Minoru Takahashi , Yaron Ilan , Namita Roy Chowdhury , Jack Guida ^¶ , Marshall Horwitz ^¶ and Jayanta Roy Chowdhury

From the Department of  Medicine and Molecular Genetics, Marion Bessin Liver Research Center and the ^¶ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

Injection of a recombinant adenovirus expressing human bilirubin-UGT₁ (Ad-hBUGT₁) (3 × 10⁹ plaque-forming units (pfu) intravenously) in adult bilirubin-UDP-glucuronosyltransferase-1 (BUGT₁)-deficient Gunn rats resulted in biliary excretion of bilirubin glucuronides and a 70% reduction of serum bilirubin levels. However, the effect was transient, and host humoral and cellular immune response prevented transgene expression after subsequent injections. To determine whether injection during the neonatal period would tolerize the host to the recombinant virus, we injected 1 × 10⁸ pfu of Ad-hBUGT₁ or Ad-LacZ (a recombinant adenovirus expressing Escherichia coli -galactosidase) into 1-3-day-old Gunn rats. Two subsequent injections (3 × 10⁹ pfu) were given 56 and 112 days after the initial injection. Injection of Ad-BUGT₁, but not Ad-LacZ, reduced serum bilirubin by 70-76% of the levels in untreated pups (9 ± 1.3 mg/dl), followed by a gradual increase to 3.25 ± 0.3 mg/dl in 56 days; similar or greater reductions occurred after the second and third injection. Serum neutralizing antibody titer and cytotoxic lymphocyte activity against adenovirus-infected hepatocytes were low or undetectable. Thus, tolerization by injection of the virus during the neonatal period permits long term gene therapy by repeated injection of the virus.

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