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JCI Insight. 2016 Aug 4;1(12). pii: e88634.

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

Author information

1
Department of Neurology, Baltimore, Maryland, USA; Johns Hopkins Drug Discovery, Baltimore, Maryland, USA.
2
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4
Johns Hopkins Drug Discovery, Baltimore, Maryland, USA.
5
Department of Neurology, Baltimore, Maryland, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
6
Johns Hopkins Drug Discovery, Baltimore, Maryland, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
7
Medpace, Cincinnati, Ohio, USA.
8
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
9
Department of Neurology, Baltimore, Maryland, USA; Johns Hopkins Drug Discovery, Baltimore, Maryland, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Abstract

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

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