FUNCTIONAL CONSEQUENCES OF ADENOVIRUS-MEDIATED MURINE PANCREATIC GENE-TRANSFER

Pancreatic adenoviral gene transfer can be achieved with high efficien cy; however, questions concerning tissue injury from this commonly use d vector have not been addressed. In these experiments, the effects of adenoviral gene transfer on pancreatic exocrine function were evaluat ed. Direct pancreatic injection with an adenoviral vector containing t he Escherichia coli beta-galactosidase (beta-Gal; lacZ) transgene (H5. 010CBlacZ) resulted in a high level of transgene expression (64 +/- 6% of pancreatic cells expressed beta-Gal) at 3 days following infection . However, amylase levels in four of five different subcellular pancre atic fractions were significantly decreased at this time point. Direct pancreatic injection with either saline or psoralen/UV-inactivated ad enovirus did not have this effect, whereas both transduction with an a denoviral vector containing a different transgene and transduction wit h a homologous transgene resulted in decreased pancreatic amylase. The decrease in subcellular amylase levels persisted at 7 days post-trans duction, and then returned to baseline at 21 days post-transduction. T here was associated histologic damage (increased edema, inflammation, cell destruction, and vacuolization) at 3 and 7 days post-transduction , which resolved by 21 days. In summary, adenoviral transduction of th e pancreas results in increased viral transgene expression and a unifo rm decrease in host amylase production throughout the pancreas. The no rmalization of amylase levels and histology suggest that organ recover y occurs. Gene transfer technology as a novel strategy for pancreatic diseases such as diabetes, pancreatitis, and cystic fibrosis is feasib le but will benefit from continued approaches to limit toxicity.