Functional consequences of adenovirus-mediated murine pancreatic gene transfer.
Pancreatic adenoviral gene transfer can be achieved with high efficiency; however, questions concerning tissue injury from this commonly used vector have not been addressed. In these experiments, the effects of adenoviral gene transfer on pancreatic exocrine function were evaluated. Direct pancreatic injection with an adenoviral vector containing the 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 pancreatic fractions were significantly decreased at this time point. Direct pancreatic injection with either saline or psoralen/UV-inactivated adenovirus did not have this effect, whereas both transduction with an adenoviral vector containing a different transgene and transduction with a homologous transgene resulted in decreased pancreatic amylase. The decrease in subcellular amylase levels persisted at 7 days post-transduction, and then returned to baseline at 21 days post-transduction. There 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 the pancreas results in increased viral transgene expression and a uniform decrease in host amylase production throughout the pancreas. The normalization of amylase levels and histology suggest that organ recovery occurs. Gene transfer technology as a novel strategy for pancreatic diseases such as diabetes, pancreatitis, and cystic fibrosis is feasible but will benefit from continued approaches to limit toxicity.
McClane
S J
SJ
Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Hamilton
T E
TE
Burke
C V
CV
Raper
S E
SE
D000256:Adenoviridae; D000681:Amylases / Q000097:blood / Q000378:metabolism; D000818:Animals; D005260:Female; D018014:Gene Transfer Techniques / Q000009:adverse effects; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000201:enzymology; D019076:Transgenes; D001616:beta-Galactosidase / Q000235:genetics
D000681:Amylases; D001616:beta-Galactosidase