Date on Master's Thesis/Doctoral Dissertation

12-2025

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Matoba, Nobuyuki

Committee Member

Yaddanapudi, Kavitha

Committee Member

Siskind, Leah

Committee Member

Lawrenz, Matthew

Committee Member

Deng, Zhongbin

Author's Keywords

Ulcerative colitis; 28-day toxicology study; immune cell profile; colon lamina propria; mesenteric lymph node

Abstract

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic, relapsing inflammation of the colon and rectum with limited treatment options. Among them, immunosuppressive agents have a high rate of adverse side effects and do not cure the disease. EPICERTIN (EPT), a recombinant variant of the cholera toxin B subunit (CTB) with a C-terminal hexapeptide extension consisting of a KDEL endoplasmic reticulum (ER) retention motif, is a promising oral biotherapeutic candidate for the treatment of UC. EPT has demonstrated mucosal healing activity in mouse models of colitis and human colonic explants. EPT's mechanism of action involves binding to GM1 ganglioside at the plasma membrane of colon epithelial cells and interaction with the KDEL receptor that activates an adaptive unfolded protein response in the ER, leading to the upregulation of wound-healing pathway genes. Also, EPT recruits innate immune cells to the colon lamina propria (CLP) following oral administration in healthy mice. In this study, we evaluated the safety of EPT through a repeated oral dose toxicity study in C57BL/6J mice. This included clinical evaluations, changes in body weight, complete blood counts (CBC), blood chemistry analyses, gross pathology, and histopathology. The study involved both male and female mice, which received EPT at the therapeutic dose of 3 mg or at a dose ten times higher (30 mg) every three days over 28 days period. EPT was well tolerated, with no sign of toxicity observed. This conclusion is supported by the lack of clinical symptoms, normal CBC and blood chemistry results, absence of gross pathological changes at necropsy, and further confirmation through histopathological examinations of major organs. Moreover, the safety of EPT is reinforced by the lack of significant dose-dependent effects on immune cell profiles in both the CLP and MLN when compared to the parent molecule CTB. These results indicate the safety of EPT under the experimental conditions, providing a solid basis for future preclinical toxicological research intended to promote EPT as a promising oral biotherapy for UC.

Download

Share

COinS