Development of MIIST305 as a Mitigator for Gastrointestinal Acute Radiation Syndrome and Identification of Biomarkers of Radiation Injury and Drug Efficacy - 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 subsyndrome characterized by the destruction of the mucosal layer, intestinal epithelial barrier dysfunction, and aberrant inflammatory responses that could 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. Development of effective medical countermeasures (MCMs) for mitigation and treatment of GI-acute radiation syndrome (ARS) requires suitable animal models. The minipig model of ARS is becoming considered as an animal model for studying the radiation-induced GI subsyndrome, as it shares many anatomical and physiological parameters with humans. Importantly, GI injury clinical symptoms after radiation exposure are similar between minipigs and humans. In addition, identification of early surrogate markers of candidate radio-mitigators that could potentially be used as secondary endpoints is of large importance. To meet the critical need for GI-specific MCMs, 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. MIIST305 has been shown to reduce cell death, suppress local and systemic inflammation, and confer significant survival in mice and rats exposed to high-dose partial body X-irradiation, when administered 24 hours post-irradiation. The primary objectives of this proposal are to evaluate the efficacy of MIIST305 for mitigating acute GI injury (histopathology) and inhibiting an excessive inflammatory response in the Sinclair miniature swine partial body irradiation (PBI) model (Aim 1), test a protein panel of radiation-responsive GI injury biomarkers of intestinal epithelial tight junction permeability, microbial translocation, and local and systemic inflammation in blood, fecal, and intestinal tissue samples collected from Sinclair minipigs (Aim 2), and use state-of-the-art machine learning methods to identify the top GI biomarkers that correlate with GI injury that can be developed towards a protein bioassay to predict the severity of radiation-induced GI-ARS after administration of MIIST305 (Aim 3). This proposal is relevant to this Notice of Funding Opportunity, since it focuses on the development of a MCM (MIIST305) to mitigate radiation-induced GI injury in a relevant large animal model of ARS, and the identification of early surrogate blood and fecal markers that could accurately predict MIIST305 radiomitigating efficacy. Successful completion of this study combined with our previous work on rodents will help advance MIIST305 for potential MCM marketing approval via the FDA Animal Rule.
