Discovery of a radiation countermeasure therapeutic for intestinal injury enabled by human organ chips combined with AI

There is a need for better therapies for acute radiation injury (ARI) of the human intestine as current treatments offer limited efficacy. As the ileum is most sensitive to radiation in patients receiving cancer radiation therapy, we created human Organ Chip microfluidic culture models lined by primary patient-derived ileal epithelial cells interfaced with intestinal microvascular endothelium and exposed them to clinically relevant doses of {gamma}-radiation. These Ileum Chips recapitulated key features of ARI, including cell loss, barrier dysfunction, and inflammation, as well as a therapeutic response to a probiotic formulation (VSL#3) that protects against radiation injury in patients. Use of an AI-enabled drug repurposing algorithm (NemoCAD) with transcriptomic data led to the identification of the antifungal agent miconazole as a potential radiation countermeasure drug, and its protective activity was confirmed on-chip. Combination of AI and human Organ Chip studies may offer a powerful way to repurpose drugs for novel disease applications. HighlightsO_LIPrimary human Organ Chips lined by patient-derived ileal epithelial cells interfaced with intestinal microvascular endothelium faithfully recapitulate acute radiation-induced intestinal injury C_LIO_LIUse of the Human Ileum Chip in combination with an AI-based drug repurposing platform led to the identification that the FDA approved antifungal drug miconazole has the potential to be rapidly repurposed as a therapeutic countermeasure against acute radiation injury in the human intestine. C_LI