Development of a new therapeutic product targeting neuroimmune circuits to treat asthma

Introduction

Asthma affects approximately 3% of the population and results in 1,000 daily deaths. It is characterized by chronic lung inflammation and airway hyperresponsiveness. First lines of treatment have not evolved in the last decades, and actual developments are essentially focusing on severe asthma management (7% of patients) via the targeting of inflammatory mediators. Unfortunately, 60% of asthmatics still suffer from uncontrolled symptoms.

Background

The lungs are innervated by peripheral neurons expressing specific sets of G protein-coupled receptors (GPCR) that contribute to bronchoconstriction and regulate allergic immune response. Among the broad family of GPCRs, the GPCRX has never been studied in a pathological context, albeit human and murine orthologs share a remarkable sequence identity.

Research Development

We have created a new transgenic mouse, GPCRXMut, allowing both to track the receptor expression and to interrogate its function in vivo. The GPCRXMut mouse exhibits normal immune and sensory systems at steady state. Our data demonstrate that:

a) GPCRX is expressed by both peripheral neurons and certain lung-resident immune cells;
b) the selective invalidation of GPCRX completely protects against the development of asthma in various models;
c) lung biopsies from asthmatic patients show high expression of GPCRX in neurons and immune cells.

Project Objectives

The ERC proof of concept project IMMCEPTION 2 aims to develop a selective antagonist for GPCRX to treat asthmatic patients. We will:

1. Miniaturize our established screening system for antagonists;
2. Identify leads capable of specifically blocking GPCRX;
3. Develop a new mouse model humanized for the GPCRX to further validate identified leads in vivo.

Conclusion

The research program has been carefully designed to leverage our expertise in neurobiology, immunology, asthma, and clinical allergy and has the potential to lead to the development of a new oral molecule with a dual mode of action to silence lung neuroimmune circuits.