Accidental radiation exposure as a result of terrorism, industrial accidents, or military actions is an increasing global threat. Exposure to IR in the dose range of 0.5 ? 5 Gy and 5 Gy to 10 Gy results in development of the hematopoietic (H-) and gastrointestinal (GI-) subsyndromes, respectively, of the acute radiation syndrome (ARS). The GI syndrome that follows GI-ARS is the leading cause of death following higher doses of radiation even after rescue by bone marrow replacement. Importantly, even with intensive supportive care, individuals may survive the H-ARS and GI-ARS syndromes induced by moderate doses of irradiation, but later succumb to the delayed effects of irradiation (DEARE). There is currently no medical countermeasure (MCM) approved for the GI syndrome. We will use the recently developed ?real world? model to investigate the ability of a potential MCM against GI-ARS and DEARE. The model was developed first in NHP to establish a reality-based model of irradiation injury that would include the likelihood of sparing some bone marrow in a nuclear event. In terms of model development, sparing 5% of the bone marrow allowed for assessment of mortality and morbidity associated with acute GI-ARS induced by TBI (TBI/BM5), while preserving sufficient active bone marrow to ensure survival through the hematopoietic syndrome, which may result in a reduced need for blood transfusions. This ?real world? model received concurrence from the FDA as appropriate for MCM development. PreImplantation Factor (PIF), an evolutionarily conserved 15 amino acid peptide secreted only by viable embryos, is essential for maternal recognition and modulates maternal immunity to induce immune tolerance without immune suppression. Importantly, a stable human grade synthetic PIF (sPIF) is available that mimics the native peptide. The FDA developed and implemented the Animal Rule (21 CFR 314, Subpart I) as an alternative drug approval process, involving the use of appropriate animal models to test and evaluate the efficacy of proposed MCM. The overall goal of this application is to advance the development sPIF as a MCM that addressed both ARS and DEARE in the GI tract with the goal of FDA approval under the animal efficacy rule. In Phase 1, we will perform proof-of-principle studies to demonstrate the efficacy of sPIF to mitigate GI-ARS against increasing doses of TBI/BM5 when first administered 24 hours post irradiation. In phase II, we will determine full PK profiles in mice and NHP to investigate the impact of irradiation on the phamacokinetics of sPIF. In addition, we will determine the efficacy of sPIF to mitigate DEARE-GI when first given 24 hours post-TBI/BM5. Finally, the efficacy of sPIF to mitigate GI-ARS in NHP over 28 days when sPIF is administered 24 hours post exposure to the LD50/15 TBII/BM5. The proposed experiments are aligned clearly with the goals that are critical for progress to an NDA for sPIF as an MCM. .
Accidental radiation exposure as a result of terrorism, industrial accidents, or military actions is an increasing global threat. The gastrointestinal (GI) syndrome is the leading cause of death following higher doses of radiation even after rescue by bone marrow replacement. There is currently no medical countermeasure (MCM) approved for the GI syndrome and thus, the overall goal of this fast track Phase II application is to advance the development of a novel therapy, PreImplantation Factor (PIF), as a MCM the GI syndrome with the goal of FDA approval under the animal efficacy rule.
