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Abstract
Bilirubin is glucuronidated by bilirubin UDP-glucuronyltransferase (UGT1A1) before
biliary excretion. Because bilirubin is toxic, patients with Crigler-Najjar type I
(CN), who have no UGT1A1 activity, suffer severe brain damage early in childhood.
The Gunn rat is the model for CN type 1. Gunn rat fetuses were injected with 10(7)
transducing units of UGT1A1 lentiviral vector at the end of the third trimester on
embryonic day 19. Serum bilirubin of injected Gunn rats was lowered by 45% compared
to untreated controls. This decrease was highly significant (P < 10(6)) and was sustained
for more than a year. In treated Gunn rats, bilirubin glucuronides were present in
bile and UGT1A1 protein was detected in tissue. Liver, intestine, stomach, pancreas,
and other organs were transduced and mostly contained 1% or less vector copies per
genome. Tissue distribution was variable among experimental animals but high transduction
levels were seen in pancreas and intestine in most animals. Immunohistochemistry of
these organs revealed transduction of pancreatic acinar cells and intestinal epithelium.
Injection of a lentiviral UGT1A1 vector into third-trimester Gunn rat fetuses corrects
the metabolic deficiency and mediates a reduction of serum bilirubin levels that would
be therapeutic in humans.