Effect of adenoviral early genes and the host immune system on in vivo pancreatic gene transfer in the mouse.
Gene transfer technology may provide a novel approach to treatment for pancreatic diseases. Recombinant adenovirus achieves efficient gene transfer in vivo. In this study, a murine model of adenoviral-mediated pancreatic gene transfer was developed, and the factors responsible for adenoviral elimination were investigated. Three days after direct pancreatic injection of a replication-defective adenovirus containing the lacZ transgene, a high proportion (76.8 +/- 6.7%) of pancreatic cells expressed beta-galactosidase, the gene product. Gene expression was absent by 28 days posttransduction. In immunodeficient mice, beta-galactosidase expression persisted with 20.0 +/- 6.0% of pancreatic cells staining positive 60 days after viral transduction. To test whether early viral proteins are the antigenic components responsible for the potent antiviral immune response, normal mice were injected with different adenoviral vectors containing early gene deletions. Vectors containing deletions in early region 2 or 4 expressed beta-galactosidase at 28 days. Presently available adenoviral vectors engineered to avoid this response offer minimal improvements in transgene duration. Further vector modifications or alternative strategies are needed to achieve stable pancreatic adenoviral transgene expression.
McClane
S J
SJ
Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, USA.
Hamilton
T E
TE
DeMatteo
R P
RP
Burke
C
C
Raper
S E
SE
D000256:Adenoviridae / Q000235:genetics*; D017502:Adenovirus E2 Proteins / Q000235:genetics; D017504:Adenovirus E4 Proteins / Q000235:genetics; D017456:Adenovirus Early Proteins / Q000235:genetics*; D000818:Animals; D005260:Female; D018014:Gene Transfer Techniques; D005814:Genes, Viral; D005822:Genetic Vectors; D007109:Immunity; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D007962:Leukocytes; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D011994:Recombinant Proteins; D001616:beta-Galactosidase / Q000235:genetics
D017502:Adenovirus E2 Proteins; D017504:Adenovirus E4 Proteins; D017456:Adenovirus Early Proteins; D011994:Recombinant Proteins; D001616:beta-Galactosidase