Development of a Novel Therapeutic for Mitigating Radiation-Induced Microbiome Dysbiosis and Acute Gastrointestinal Syndrome

点击翻译按钮获取中文摘要

SUMMARY A mass casualty radiation event, such as the detonation of an improvised nuclear device or radiological dispersal device, could lead to severe hemorrhage, multi-organ failure, and infection, potentially leading to sepsis and/or death. The hematopoietic system and the gastrointestinal (GI) tract are among the most vulnerable tissues to radiation injury. High-dose radiation results in GI syndrome characterized by microbiome dysbiosis, destruction of mucosal layer, intestinal epithelial barrier dysfunction, and aberrant inflammatory responses that initiate a vicious cycle of further GI tract damage that can lead to rapid death. Although progress has been made to counteract the immediate effects of hematopoietic acute radiation syndrome, no FDA-approved countermeasures exist that can treat radiation-induced GI injury. To meet this critical need, Synedgen Inc., has developed a glycopolymer radiomitigator (MIIST305) that is specifically targeted to the GI tract that could potentially ameliorate the deleterious effects of radiation. The therapeutic drug has been shown to reduce cell death, suppress local and systemic inflammation, and improve tissue regeneration in models associated with inflammatory bowel disease. Our preliminary studies have shown that MIIST305 confers significant survival to mice exposed to high-dose partial body x-irradiation, when administered 24 hours post-irradiation. Furthermore, MIIST305 appears to promote pro-inflammatory resolution and maintain more normal gut microbiota composition in response to GI injury. We hypothesize that MIIST305 maintains the integrity of the mucosal layer thus preserving a healthy microbiome in response to irradiation, minimizing disruption of intestinal epithelial barrier function and alleviating inflammation. To test this hypothesis, we propose two specific aims. In Aim 1, we will perform longitudinal structural and functional studies to determine the impact of acute dose, partial body irradiation with 5% bone marrow sparing on GI architectural integrity, commensal gut microbiota composition and diversity, and inflammation compared to MIIST305-mitigated animals. In Aim 2, we will define the importance of MIIST305-regulated commensal microbiota composition and elucidate the molecular pathways leading to MIIST305 suppression of the pro-inflammatory response and ultimately, mitigation of radiation-induced toxicity, using both transgenic mouse models and cell-based assays. To address the overarching goals of this funding announcement, we propose to (a) explore how the microbiome affects severity of radiation injury, (b) develop novel countermeasures against radiation-induced GI damage with efficacy starting 24 hours after radiation exposure, and (c) define the mechanism of action of the countermeasures, which will provide the necessary information for FDA approval under the Animal Rule.