Validation of novel immunotherapeutic targets against fibrosis in inflammatory bowel diseases

Fibrostenosis is the driving reason for the persistent need in bowel resections in inflammatory bowel diseases (IBD). Current IBD therapies are limited to solely targeting inflammation. While these therapies in some, but not all, cases lead to symptomatic disease remission, recurrent flares interspaced with periods of remission will still result in cumulative gut wall remodeling and fibrosis. Indeed, despite these therapeutic strategies to control inflammation, fibrostenosis incidence and bowel surgical resection is not declining in IBD patients, as no anti-fibrotic drugs are currently available. The aim of this project is to validate fibroblast therapeutic targets for preventing and/or treating fibrosis in IBD-patient-samples with an emphasis on C3 and/or Tyk2/STAT3 and/or NLRP3 in the evolution of intestinal fibrosis. The anti-fibrotic efficacy and mode of action of these novel immunotherapies will be studied preclinically in IBD-patient derived samples and validated in animal models of chronic colitis. In parallel, we aim to develop and validate a clinical diagnostic and prognostic pathway for fibrosis in IBD patients based on the use of non-invasive cross-sectional imaging techniques such as magnetic resonance enterography with elastography and optoacoustic. These results together will allow to design a first-in-human proof of concept randomized trial of immunotherapeutic drugs targeting complement C3 and/or Tyk2/STAT3 and/or NLRP3 pathways in intestinal fibrostenosis. Our aim is to obtain patients and regulatory approval for implementation of these novel non-invasive imaging modalities as diagnostic and prognostic tools for fibrotic IBD to allow vital future therapeutic development for intestinal fibrosis. By providing better molecular and clinical stratification of IBD patients at risk for fibrosis and by identifying and validating novel targets for anti-fibrotic therapy, we aim to pave the way in preventing and treating this invalidating IBD comorbidity.