Pharmacological Inhibition of Cathepsin C in Neutrophil-Mediated Inflammatory Diseases

Coordinator of the consortium: Dr Brice Korkmaz, Centre of studies for Respiratory Pathologies (CEPR) / inserm, University of Tours - FR

Summary

nflammation-mediated immune cell alterations are associated with many diseases, including acute, chronic inflammatory diseases and cancer. Current therapies of inflammatory diseases fail to fully control inflammatory processes in patients. There is an unmet need for new therapies that go beyond symptomatic relief and transient delay of disease progression. Neutrophil serine proteases (NSPs) are locally released in response to pathogens and many other non-infectious danger signals. Uncontrolled NSPs are involved in neutrophil mediated inflammatory diseases and are considered as important therapeutic targets. Targeting NSPs by therapeutic inhibitors may appear as a simple, easy to manage approach however, direct inhibition of NSPs has faced unresolved difficulties regarding the choice of proteinase targets or due to physicochemical properties of the inhibitors, prompting proposals for alternative approaches. This project focuses on a novel approach to control the excessive proteolytic activity released at sites of aberrant immune cell activation in inflammatory diseases. Our original and European innovative initiative is dedicated to establishing an efficient anti-proteolytic therapy upstream of NSPs by blocking “directly” or “indirectly” their maturing enzyme, cathepsin C (CatC).
International Cathepsin-C Consortium (ICat-CC) has been set up in 2016 thanks to the participation of world leading specialists from academic labs and industry, working on CatC and its target proteases. ICat-CC is an international innovative consortium employing basic/translational and clinical research to establish proof of concepts for the repositioning of medicinal products blocking NSPs activities. Five participants of ICat-CC have joined forces to implement their initial CatC-specific ideas and to develop an even broader program as a consortium named "Euro-CatC". Main objectives of the proposal are 1. Validation of the pharmacological targeting of CatC in NSPs-mediated inflammatory diseases, 2. Validation of cathepsin S as a new therapeutic target for a better control of CatC-dependent pathways.