THERAPEUTIC INNOVATIONS FOR THE TREATMENT OF RADIATION-INDUCED GASTROINTESTINAL SYNDROME – INTRUST

Medical countermeasures under the NRBC risk are still insufficient. Indeed, exposure to ionizing radiation can have serious consequences for the health of exposed people and potentially impact many victims. In humans, doses greater than ˜ 6 Gy over a large volume mainly induce bone marrow destruction (HS hematopoietic syndrome) and digestive injury, resulting in rapid death by gastrointestinal syndrome (GIS). Medical management of SH is complex but possible by stimulating residual hematopoiesis through growth factors administration or, if necessary, bone marrow transplantation. On the other hand, the management of the GIS remains confronted with a therapeutic wall and no scientific consensus on a therapeutic solution for the management of the GIS exists today. The preclinical studies described to treat GIS have all been based on mono-therapeutic approaches. The INTRUST project proposes a paradigm shift and a different conceptual approach based on the assumption that only a global and multimodal approach could be truly effective, robust and accessible to a significant number of victims.
There is a strong rationale for proposing therapeutic strategies for GIS management based in part on pathophysiological features common to inflammatory bowel disease (IBD) and radiation-induced intestinal injury. Indeed, these two diseases share identical symptoms (abdominal pain, frequent diarrhea, bleeding) associated with inflammation of the digestive tract and intestinal epithelium destruction. The contemporary clinical view of IBD is moving towards global or multimodal approaches that could be applied to GIS. Thus we identify 4 essential components to consider for an effective therapeutic strategy: 1) act quickly after irradiation to physically protect the intestinal mucosa, 2) combine therapeutic agents regenerating the digestive mucosa, 3) control intestinal inflammation by immuno-modulators and finally 4) manage the septic/microbiota parameter
The project aims to put in place innovative medical countermeasures for the management of radiological exposure inducing acute intestinal failure. Specifically, the project aims to demonstrate the interest and feasibility of a multimodal therapeutic approach by targeting the first 3 components. Thus we propose 1) to develop innovative biomaterials compatible with regenerative and emergency medicine that can quickly adhere and protect the digestive mucosa (muco-adhesive bio-gels) and find solutions for intestinal delivery. In parallel, innovative biomaterials will also be developed to set up and optimize a tool "mini-organs 3D in vitro" or " human intestinal organoids " to select molecules able to regenerate the intestinal mucosa. Finally 2) we propose to test in vivo multimodal treatment combining muco-adhesive biomaterial administration, selected epithelial regenerating molecules and immuno-modulators that have demonstrated a significant efficacy in IBD. The therapeutic efficacy of this multimodal treatment will be tested on preclinical models of GIS and IBD.
The project benefits from a multidisciplinary consortium that has acquired preliminary results essential to the project’s feasibility. The INTRUST project has a very strong dual military and civilian character because the potential benefits are both for soldiers in operations or civil suffering from GIS and for patients suffering from IBD whose incidence continues to increase in young people or digestive toxicity after radiotherapy for the treatment of cancer.