GENE-TRANSFER TO THE INTESTINAL-TRACT - A NEW APPROACH USING SELECTIVE INJECTION OF THE SUPERIOR MESENTERIC-ARTERY

Gene transfer to the intestinal tract has many potential applications, including complementation of single gene disorders, genetic immunizat ion, and ectopic production of therapeutic molecules, Because the intr alumenal approach to vector administration has not been highly success ful, we tested whether the circulation can be used as a route to trans fer genes to intestinal cells, The superior mesenteric artery (SMA) an d vein (SMV) of adult Lewis rats were isolated and an adenoviral vecto r expressing the Escherichia coli LacZ gene was injected into the SMA, In one set of experiments, both vessels remained patent throughout th e entire procedure, In a second group of animals, both vessels were oc cluded by clamping the SMA 1 cm distal to the injection site and the S MV proximal to the portal vein, In the absence of vascular clamps, gen e transfer was evident throughout the small bowel, localized near the serosal surface within the muscularis propria, Occlusion of the SMA an d SMV limited gene delivery to a short segment of bowel and shifted P- galactosidase activity toward the mucosal surface, at the level of mic roscopy, most of the transduction events were in the lamina propria; t ransduced mucosal epithelial cells were occasionally observed, These d ata demonstrate that intestinal gene transfer can be accomplished thro ugh the circulation, and that targeting specific regions is feasible.