Identification of adeno-associated viral vectors suitable for intestinal gene delivery and modulation of experimental colitis

Abstract

Effective gene transfer with sustained gene expression is an important adjunct to the study of intestinal inflammation and future therapy in inflammatory bowel disease. Recombinant adeno-associated virus (AAV) vectors are ideal for gene transfer and long-term transgene expression. The purpose of our study was to identify optimal AAV pseudotypes for transduction of the epithelium in the small intestine and colon, which could be used for studies in experimental colitis. The tropism and transduction efficiencies of AAV pseudotypes 1-10 were examined in murine small intestine and colon 8 wk after administration by real-time PCR and immunohistochemistry. The clinical and histopathological effects of IL-10-mediated intestinal transduction delivered by AAVrh10 were examined in the murine IL-10⁻/⁻ enterocolitis model. Serum IL-10 levels and IL-10 expression were followed by ELISA and real-time PCR, respectively. AAV pseudotypes 4, 7, 8, 9, and 10 demonstrated optimal intestinal transduction. Transgene expression was sustained 8 wk after administration and was frequently observed in enteroendocrine cells. Long-term IL-10 gene expression and serum IL-10 levels were observed following AAV transduction in an IL-10-/- model of enterocolitis. Animals treated with AAVrh10-IL-10 had lower disease activity index scores, higher colon weight-to-length ratios, and lower microscopic inflammation scores. This study identifies novel AAV pseudotypes with small intestine and colon tropism and sustained transgene expression capable of modulating mucosal inflammation in a murine model of enterocolitis.

Intracolonically administered adeno‐associated virus‐bone morphogenetic protein‐7 ameliorates dextran sulphate sodium‐induced acute colitis in rats

“…administration of AAV vectors transducing colonic mucosa, although the tests of the most commonly used AAV vector (i.e. AAV type 2) showed controversial results . In the present study, a fairly high transduction efficiency of type 2 AAV vector in the colonic mucosa was achieved by i.c.…”

The emerging role of miRNAs in inflammatory bowel disease: a review

“…Also using an IL-10 knockout mouse, Polyak and colleagues subsequently demonstrated amelioration of colitis following pseudotype 10 AAV-mediated restorative delivery of IL-10 via superior mesenteric artery (SMA) injection. Further work by Polyak and colleagues tested the tropism and transduction efficiency of AAV serotypes 1-10 via small bowel lavage, enema and SMA injection [Polyak et al 2012]. Only SMA injection resulted in significant intestinal transduction in which case AAV serotypes 4, 7, 8, 9 and 10 demonstrated optimal small intestinal and colonic transduction.…”

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

“…In animal experiments, IL-10 administration was able to prevent colitis, but was ineffective to attenuate already established colitis [110,111]. Interestingly, adenoviral vector-based strategies of IL-10 gene transfer have been shown to improve symptoms of colitis and RA in respective animal models [6,112,113,114,115,116,117].…”