The Wnt pathway and particularly beta-catenin (CTNNB1) have been identified as potential targets for treatment and prevention of colon cancer. RNA interference offers a novel technology which can induce specific suppression of disease related genes, such as CTNNB1 in colon cancer or polyposis. However, the gastrointestinal (GI) tract is a particularly difficult organ for RNAi-based drugs due to its hostile environment of digestive enzymes and microbial flora. We have proposed a method (Xiang S. et al, Nature Biotechnology, 2006), which is ideally suited to deliver RNAi therapeutics into the epithelial cells of the GI tract, transkingdom RNA interference (tkRNAi). This approach is based on nonpathogenic invasive bacteria which produce and deliver shRNA, the mediators of RNA interference. In this work, we demonstrate that silencing of CTNNB1 through oral treatment with tkRNAi is sufficient to prevent polyp formation in the GI tract of live APCmin mice. 38 APCmin mice (a genetic model of human colon cancer and familial adenomatous polyposis), were treated orally for 8-10 weeks with tkRNAi bacteria targeting CTNNB1 (or control bacteria expressing an irrelevant hairpin RNA against green fluorescent protein-GFP) to prevent the formation of polyps. Treatment was well tolerated with no added toxicity. Treatment with tkRNAi lead to a significant reduction of CTNNB1 expression on mRNA as well as protein levels in the GI tract. Treatment also lead to a significant reduction of polyp numbers (Control, 21.8, GFP, 27.1, CTNNB1, 11.4, p<0.05) and sizes. Relative reductions in polyp numbers of up to 80% were observed within matched littermates. Cequent Pharmaceuticals is currently developing a clinical drug candidate for the treatment and prevention of colon polyps in the hereditary syndrome Familial Adenomatous Polyposis based on tkRNAi. IND enabling toxicology studies will begin in Q1/2008 and preliminary data on toxicology findings after 28d oral dosing of CEQ501 in cynomolgus monkeys will also be presented as part of this presentation.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA