COPe-IBD - Development of a COmbined P2X4/P2X7 targeting strategy to manage Inflammatory Bowel Diseases: a translational study

Inflammatory bowel diseases (IBD), including ulcerative colitis and Chron’s disease, are chronic gut inflammatory conditions characterized by debilitating symptoms and an unprecedented rise in cases in the last decades. P2X7 receptor emerged as an attractive pharmacological target in IBD as it sustains enteric phlogosis via activation of the NLRP3 inflammasome pathway and release of cytokines. Based on these findings, an inhibitor of P2X7 was administered in a phase IIa clinical study in Crohn's patients, reducing disease activity and increasing patients' wellbeing by decreasing chronic abdominal pain. However, P2X7 blockade failed to reduce inflammatory IBD biomarkers, thus leading to interruption of the clinical trials. The COPe-IBD project is based on the hypothesis that to synergize and complement the effects of P2X7 blockade in IBD, we should jointly antagonize another member of the P2X family of ATP gated ion channels: P2X4. Indeed, we recently proved that P2X4 inhibition reduces IBD symptoms in preclinical models of colitis via downmodulation of inflammatory pathways partially overlapping with those activated by P2X7. Therefore, COPe-IBD's goal will be to give solid evidence that combined administration of P2X4 and P2X7 blockers will prove more efficacious than standalone antagonism of one of the receptors in reducing and preventing IBD symptoms. We will also design, synthesize and test novel dual P2X4/P2X7 antagonists to be patented and ideally addressed to the clinical setting in the years following the end of COPe-IBD. We aim at demonstrating that P2X4 and P2X7 receptors are central in causing the release of IBD promoting molecules from enteric epithelia, glia and macrophages and that these factors include the receptors' ligand ATP and miRNAs. We will test the ability of available receptors antagonists and of newly synthesized dual blockers to interrupt the glia-immune-epithelial cross-talk leading to IBD symptoms exacerbation. We will focus on the role played by P2X4/P2X7 in the release of inflammatory and pain promoting factors together with miRNA containing vesicles. Data emerging from this approach will be central for designing the best-appropriate molecules to investigate in the in vivo preventive and curative models in which we will administer P2X4/P2X7 targeting drugs. These colitis animal models will allow us to explore the therapeutic potential of P2X4/P2X7 blockade in the prevention and the cure of IBD associated loss of barrier permeability and other phlogistic symptoms. COPe-IBD highly interdisciplinary approach bringing together pathologists, pharmacologists and medicinal chemists with a consolidated experience in purinergic signalling has the potential of producing strong preclinical data leading to the development of an innovative therapeutic strategy based on dual P2X4/P2X7 inhibition in IBD.