Gene Transfer to the Intestinal Tract: A New Approach Using Selective Injection of the Superior Mesenteric Artery

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Abstract
Gene transfer to the intestinal tract has many potential applications, including complementation of single gene disorders, genetic immunization, and ectopic production of therapeutic molecules. Because the intralumenal approach to vector administration has not been highly successful, we tested whether the circulation can be used as a route to transfer genes to intestinal cells. The superior mesenteric artery (SMA) and vein (SMV) of adult Lewis rats were isolated and an adenoviral vector expressing the Escherichia coli LacZ gene was injected into the SMA. In one set of experiments, both vessels remained patent throughout the entire procedure. In a second group of animals, both vessels were occluded by clamping the SMA 1 cm distal to the injection site and the SMV proximal to the portal vein. In the absence of vascular clamps, gene transfer was evident throughout the small bowel, localized near the serosal surface within the muscularis propria. Occlusion of the SMA and SMV limited gene delivery to a short segment of bowel and shifted β-galactosidase activity toward the mucosal surface. At the level of microscopy, most of the transduction events were in the lamina propria; transduced mucosal epithelial cells were occasionally observed. These data demonstrate that intestinal gene transfer can be accomplished through the circulation, and that targeting specific regions is feasible. Delivery of genes through the vasculature has been demonstrated for several organs, including the liver, heart, kidney, and lungs. Vectors delivered via this route might potentially reach every cell within an organ. We have found that a replication-deficient adenoviral vector delivered to the intestinal tract by the selective injection of the superior mesenteric artery can transfer genes to epithelial and nonepithelial cells within the intestines.