Familial Adenomatous Polyposis (FAP) is a devastating inherited disease which results in the formation of hundreds of adenomatous polyps in the colon, and has a near-100% risk of colon cancer. No medical therapy is known to date, and surgery (usually colectomy) is the treatment of choice to prevent colon cancer formation. In FAP, a mutation of the Adenomatous Polyposis coli (APC) gene results in the upregulation of beta-catenin (CTNNB1), which accumulates in the nucleus and is responsible for triggering a number of proliferative genes, allowing adenoma to form. With the advent of RNA interference (RNAi), targeting of CTNNB1 is becoming feasible for anticancer applications. We have developed a method to deliver therapeutic RNAi into the mucosa of the gastrointestinal tract, called transkingdom RNA interference(tkRNAi). tkRNAi uses highly attenuated nonpathogenic bacteria engineered to produce and deliver mediators of RNA interference, short hairpin RNA (shRNA) to the gastrointestinal mucosa after oral application. Here we demonstrate toxicology results in mice and monkeys. Overall, GLP toxicology testing was very favorable and demonstrated safety of a tkRNAi therapeutic targeting CTNNB1 in 28d daily dosing. Surveillance of hematology, coagulation, cytokines, chemistry, gross and histopathology and a range of clinical parameters revealed no drug related side effects. The toxicology study showed efficacy of the orally administered tkRNAi drug in non-human primates. After oral feeding, we observed reductions of 50-60% in CTNNB1 expression levels in the GI mucosa of treated animals. These effects were fully reversible after 21 days and no drug related side effects were observed. This is the first time that any RNAi drug has been shown to have efficacy in non-human primates after oral application. A clinical Phase I trial for FAP patients is scheduled to begin in late-2009 or early 2010.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-123.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO