Project Summary We have developed a candidate product that induces colon epithelial repair in ulcerative colitis (UC) models. UC comprises a major type of inflammatory bowel disease and is characterized by chronic and relapsing inflammation in the gastrointestinal (GI) tract. UC develops in the innermost mucosal layer of the distal GI tract in a continuous manner, usually starting at the rectum and spreading into the colon. The etiology of UC remains elusive; genetic and environmental factors appear to trigger dysregulated mucosal immune responses, leading to chronic inflammation, disrupted intestinal barrier function and epithelial damage in the colon. Lacking a definitive cause, no preventative or curative therapies have been developed for UC. Conventional treatments aim to blunt inflammation, establish and maintain clinical remission, mucosal healing, decrease the risk of complications and improve quality of life. Achieving mucosal healing is recognized as an important clinical endpoint in UC treatment, as it is closely associated with sustained clinical remission, improved quality of life, fewer surgical interventions and cancer incidence, as shown in clinical studies. However, current UC drugs do not effectively induce mucosal healing because merely inhibiting inflammation will not necessarily facilitate tissue repair, which is a complex and dynamic process that must involve the restoration of the intestinal barrier function along with alleviation of detrimental inflammation. Thus, development of an epithelial wound repair agent will fill an important gap for the management of UC. Our lead product, EPICERTIN, is a recombinant protein derived from cholera toxin B subunit that has been modified genetically with a C-terminal peptide containing the KDEL endoplasmic reticulum retention signal. This simple modification instills in EPICERTIN the colon epithelial wound healing activity. EPICERTIN is our lead active pharmaceutical ingredient for managing UC via epithelial barrier recovery. University of Louisville (UofL) researchers invented EPICERTIN and extensively characterized its biological mode of action (MOA) and therapeutic effects in acute and chronic animal models of colitis. The MOA involves an unfolded protein response, and all preliminary studies have underscored high safety and tolerability upon oral or colonic administrations to animals. We have initiated pre-IND discussions with FDA and have received initial Agency guidance, which has substantially reduced regulatory risk. Following FDA’s and NIH reviewers’ recommendations, UofL and its commercial partner GROW Biomedicine LLC are initiating product-focused development of EPICERTIN through this Phase I STTR project with the goals of: (1) further exploring dose-effect relationships in vivo in a rat model of UC to support future pharmacodynamic and toxicity studies, and (2) expanding the range of applications of our bioanalytical method to quantify the drug in canine plasma, and using th...