ADENOVIRUS-MEDIATED TRANSDUCTION OF INTESTINAL-CELLS IN-VIVO

The intestinal tract has many features that make it an attractive targ et for therapeutic gene transfer. In this study, replication-defective adenoviral vectors were used to explore parameters that mag be import ant in administering gene therapy vectors to the intestine. After surg ically accessing the intestine, an E1-, E3-deleted adenoviral vector e ncoding beta-galactosidase (beta-Gal) was directly injected into vario us regions of the small and large intestine of rats and rabbits. Signi ficant transduction of the tissue was observed and histochemical stain ing was used to identify enterocytes as the primary targets of gene tr ansfer. Expression of beta-Gal did not differ substantially when the v irus was administered to the duodenum, ileum, or colon. When the vecto r was directly administered to segments of the distal ileum containing a Peyer's patch, transgene expression was similar to 10-fold higher t han in segments lacking a Peyer's patch. In the Peyer's patches, a hig h level of expression was localized to epithelial cells, potentially M cells, overlying the lymphoid follicle domes. Transduction of these c ells could have application in DNA-mediated oral vaccination, Administ ration of an adenoviral vector encoding a secreted alkaline phosphatas e to the lumen resulted in expression and secretion of this gene produ ct into the circulation. This finding demonstrates the potential of en terocytes to serve as heterotopic sites for the synthesis of heterolog ous gene products that would be secreted into the lumen of the intesti nal tract or into the bloodstream.