FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities

• DOI: 10.1172/jci.insight.88634
• Publication Date: 2016-08-03T15:00:34Z
• Authors: Rana Rais; Weiwei Jiang; Huihong Zhai; Krystyna M. Wozniak; Marigo Stathis; Kristen R. Hollinger; Ajit G. Thomas; Camilo Rojas; James J. Vornov; Michael Marohn; Xuhang Li; Barbara S. Slusher
• Keywords: Glutamate carboxypeptidase II; Intestinal mucosa

Recent gene-profiling analyses showed significant upregulation of the folate hydrolase (FOLH1) gene in affected intestinal mucosa patients with inflammatory bowel disease (IBD). The FOLH1 encodes a type II transmembrane glycoprotein termed glutamate carboxypeptidase (GCPII). To establish that previously reported increased expression was functional, we quantified enzymatic activity 31 surgical specimens and report robust 2.8- to 41-fold increase IBD compared an uninvolved area same or from healthy controls. Using human-to-mouse approach, next similar two well-validated murine models evaluated therapeutic effect potent FOLH1/ GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) (IC50 = 300 pM). In dextran sodium sulfate (DSS) colitis model, 2-PMPA inhibited colonic by over 90% substantially reduced activity. significance target confirmed FOLH1-/- mice who exhibited resistance DSS treatment. IL-10-/- model spontaneous colitis, daily treatment also significantly both macroscopic microscopic severity. These results provide first evidence FOLH1/GCPII inhibition as option for IBD.