Objectives: Several inherited liver diseases are associated with a pro
gressive course that begins early in lift. Such disorders may be amena
ble to treatment with gene transfer in the fetal or neonatal period. M
ethods: We used ultrasound guidance to deliver an adenoviral vector to
the liver of 28-day gestation fetal rabbits by cardiocentesis. beta-G
alactosidase reporter gene expression in hepatocytes was analyzed 3, 7
, and 21 days after vector delivery. Using this nonsurgical approach,
the viral vector was efficiently delivered into the fetal circulation.
Results: The liver was the main organ targeted by this route of admin
istration with up to 40% of the hepatocytes beta-galactosidase positiv
e in some animals. The beta-galactosidase expression in hepatocytes gr
adually declined between 3 and 21 days following gene transfer. Associ
ated with the decline in gene expression, an increased number of infla
mmatory cells were noted in the livers of adenoviral vector treated an
imals. This suggests that an immune response limits the duration of ge
ne expression in the fetal rabbit, similar to the findings in postnata
l animals. Conclusions: This animal model and vector delivery method m
ay be useful for evaluating gene transfer to the fetus with viral and
nonviral vectors. Further modifications of the adenoviral vector to re
duce immunogenicity may enhance the duration of expression.