TY - JOUR
T1 - Long term correction of bilirubin-UDP-glucuronosyltransferase deficiency in Gunn rats by administration of a recombinant adenovirus during the neonatal period
AU - Takahashi, Minoru
AU - Ilan, Yaron
AU - Chowdhury, Namita Roy
AU - Guida, Jack
AU - Horwitz, Marshall
AU - Chowdhury, Jayanta Roy
PY - 1996
Y1 - 1996
N2 - Injection of a recombinant adenovirus expressing human bilirubin-UGT1 (Ad-hBUGT1) (3 x 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 x 108 pfu of Ad- hBUGT1 or Ad-LacZ (a recombinant adenovirus expressing Escherichia coli β- galactosidase) into 1-3-day-old Gunn rats. Two subsequent injections (3 x 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.
AB - Injection of a recombinant adenovirus expressing human bilirubin-UGT1 (Ad-hBUGT1) (3 x 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 x 108 pfu of Ad- hBUGT1 or Ad-LacZ (a recombinant adenovirus expressing Escherichia coli β- galactosidase) into 1-3-day-old Gunn rats. Two subsequent injections (3 x 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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U2 - 10.1074/jbc.271.43.26536
DO - 10.1074/jbc.271.43.26536
M3 - Article
C2 - 8900123
AN - SCOPUS:0029970829
SN - 0021-9258
VL - 271
SP - 26536
EP - 26542
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -