Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease.

Reference

Date, A., Rais, R., Babu, T., Ortiz, J., Kanvinde, P., Thomas, C., Zimmermann, S., Gadiano, A., Halpert, G., Slusher, B., & Ensign, L. (2017). Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease. 263. https://doi.org/10.1016/j.jconrel.2017.01.036

Abstract

Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon. Local administration of 2-PMPA in a hypotonic enema vehicle resulted in increased colorectal tissue absorption at 30min compared to 2-PMPA administered in an isotonic enema vehicle. Furthermore, local delivery of 2-PMPA in hypotonic enema vehicle resulted in prolonged drug concentrations for at least 24h with minimal systemic exposure. Finally, daily treatment with the hypotonic 2-PMPA enema ameliorated macroscopic and microscopic symptoms of IBD in the TNBS-induced colitis mouse model, indicating the potential of FOLH1/GCPII inhibitors for the local treatment of IBD.