Development of Novel Engineered Native Bacteria (ENB) for the Treatment of Familial Adenomatous Polyposis

PROJECT SUMMARY Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer death globally. Most CRC develops from a histologically specific type of colon polyp i.e., adenoma. Around 1% of these cases (i.e. approximately 20,000 per year) are attributed to a genetic condition called familial adenomatous polyposis (FAP) and patients with FAP have a 100% chance of developing CRC, typically by 40 years of age. FAP is a hereditary cancer syndrome that is distinguished by the existence of numerous synchronous polyps in the gastrointestinal tract, particularly in the large intestine and due to familial involvement, the condition is often diagnosed early. Polyps typically start to form during childhood and grow in size and quantity until adolescence. Removal of these polyps is a remedy, but not a permanent solution, since they recur frequently. There are drugs for the suppression of these polyps, but they need to be administered long-term and have substantial side effects. Moreover, prevention of FAP through colectomy is costly, invasive, and life-altering. Thus, there is an urgent unmet need for a safe, efficient, cost-effective and sustained therapy to suppress the further progression of colon adenomas, thereby reducing incidence of CRC. Endure Biotherapeutics has developed an innovative technology, where native gut bacteria expressing therapeutic gene products can be engineered to effectively colonize the gut and affect host physiology through the expressed gene products. This platform technology can be used to express bile salt hydrolase (BSH) gene in the gut and potentially suppress FAP. We have previously tested the colonization hypothesis in mouse models by introducing a variety of genes, including those that affect host metabolism and tumorigenesis, into the gut microbiome using a native E. coli strain. Recent, unpublished studies in Dr. Amir Zarrinpar’s Lab with these BSH expressing bacteria have shown a strong suppression of adenomas. Towards developing these engineered native bacteria (ENB) as a commercial therapy for colon adenomas, this Phase I project, will focus on in vivo safety and efficacy studies of the ENBs in a mouse model. We will also establish the safety, extent of colonization, and localization along the gastrointestinal tract of the ENB in Yucatan mini-pigs, as a prelude to the Phase II, which will focus on IND enabling studies like PK/PD, CMC and toxicology in this model. The Phase II project will culminate in the preparation of the application for IND submission.