BioCentury
ARTICLE | Distillery Therapeutics

Inhibiting proteolytic activation of the receptor PAR2 for eosinophilic esophagitis

July 29, 2020 3:17 PM UTC

INDICATION: Eosinophilic esophagitis

Inhibiting the extracellular serine protease KLK5 or its substrate PAR2 could treat eosinophilic esophagitis, a food antigen-driven inflammatory disease. Single-cell sequencing revealed aberrant KLK5 expression in multiple cell populations from esophageal tissue of eosinophilic esophagitis patients compared with samples from donors without the disease. In a mouse model of chicken egg albumin-induced eosinophilic esophagitis, trypsin-like activity was elevated in the esophagus; systemic knockout of KLK5 reduced trypsin-like activity and epithelial thickening in the esophagus and the number of eosinophils in the esophagus and blood. Also in the model, a PAR2 antagonist tool compound or AAT -- a protease inhibitor that can block KLK5 -- decreased eosinophil accumulation and epithelial thickening in the esophagus. Ongoing work includes developing small molecule inhibitors of the pathway...