Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease.
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.
['Date|Abhijit A|AA|', 'Rais|Rana|R|', 'Babu|Taarika|T|', 'Ortiz|Jairo|J|', 'Kanvinde|Pranjali|P|', 'Thomas|Ajit G|AG|', 'Zimmermann|Sarah C|SC|', 'Gadiano|Alexandra J|AJ|', 'Halpert|Gilad|G|', 'Slusher|Barbara S|BS|', 'Ensign|Laura M|LM|']
D000818:Animals D003092:Colitis D003106:Colon D004733:Enema D043425:Glutamate Carboxypeptidase II D015212:Inflammatory Bowel Diseases D007413:Intestinal Mucosa D008297:Male D008807:Mice, Inbred BALB C D009943:Organophosphorus Compounds D014302:Trinitrobenzenesulfonic Acid
2-PMPA Colitis Hypotonic Folate polyglutamate N-acetyl-aspartyl glutamate TNBS