Recombinant adenovirus administration in rat peritoneum: endothelial expression and safety concerns

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Abstract
Background. Initial studies of adenovirus-mediated gene transfer to the peritoneum have shown transgene expression in the mesothelium from the parietal peritoneum. Using a replication-deficient adenovirus encoding β-galactosidase (AdβGal), we investigated the expression efficiency and the distribution of the transgene to different areas of both visceral and parietal peritoneum and to extra-peritoneal tissues. Methods. Male Wistar rats received an intraperitoneal injection of 15 ml of 0.9% NaCl alone or containing 1 × 109 or 3 × 109 p.f.u. of AdβGal. Evaluations of the histology of the peritoneum, the transgene expression and the safety of adenovirus-mediated gene transfer, using measurement of both βGal activity and staining, were performed 1, 3 and 5 days post-injection. Results. At 1 day post-injection of × 109 p.f.u. of AdβGal, significant βGal activity and staining were detected in the omentum and mesenteric peritoneum. βGal staining was observed in endothelial cells, mesothelial cells and adipocytes. Focal mononuclear infiltrates restricted to the submesothelial area of the visceral peritoneum were also observed. No expression was detected in the mesocolon and parietal peritoneum, where the mesothelium was damaged. Significant βGal activity and staining were observed in lymph nodes, lungs, liver, heart and kidneys, in the absence of inflammatory changes. Conclusions. Intraperitoneal delivery of adenoviral vectors allows highly efficient transgene expression in mesothelial cells, but also in endothelial cells and adipocytes of the visceral peritoneum. Adverse focal mononuclear infiltrates, as well as spreading of the adenoviral vector from the abdominal cavity to the systemic circulation, were observed in parallel. Transgene expression in endothelial cells is potentially important since the latter play a key role in the alterations of the peritoneal membrane associated with long-term peritoneal dialysis. However, these data emphasize the need for less immunogenic adenoviral vectors, ideally containing an endothelial cell-specific promoter, to overcome immune response-related problems and spreading to extra-peritoneal tissues.