Development of a novel therapy for mitigation of the irradiation-inducedgastrointestinal syndrome

Accidental radiation exposure as a result of terrorismindustrial accidentsor military actions is an increasing global threatExposure to IR in the dose range ofGy andGy toGy results in development of the hematopoieticHand gastrointestinalGIsubsyndromesrespectivelyof the acute radiation syndromeARSThe GI syndrome that follows GI ARS is the leading cause of death following higher doses of radiation even after rescue by bone marrow replacementImportantlyeven with intensive supportive careindividuals may survive the H ARS and GI ARS syndromes induced by moderate doses of irradiationbut later succumb to the delayed effects of irradiationDEAREThere is currently no medical countermeasureMCMapproved for the GI syndromeWe will use the recently developedreal worldmodel to investigate the ability of a potential MCM against GI ARS and DEAREThe 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 eventIn terms of model developmentsparingof the bone marrow allowed for assessment of mortality and morbidity associated with acute GI ARS induced by TBITBI BMwhile preserving sufficient active bone marrow to ensure survival through the hematopoietic syndromewhich may result in a reduced need for blood transfusionsThisreal worldmodel received concurrence from the FDA as appropriate for MCM developmentPreImplantation FactorPIFan evolutionarily conservedamino acid peptide secreted only by viable embryosis essential for maternal recognition and modulates maternal immunity to induce immune tolerance without immune suppressionImportantlya stable human grade synthetic PIFsPIFis available that mimics the native peptideThe FDA developed and implemented the Animal RuleCFRSubpart Ias an alternative drug approval processinvolving the use of appropriate animal models to test and evaluate the efficacy of proposed MCMThe 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 ruleIn Phasewe will perform proof of principle studies to demonstrate the efficacy of sPIF to mitigate GI ARS against increasing doses of TBI BMwhen first administeredhours post irradiationIn phase IIwe will determine full PK profiles in mice and NHP to investigate the impact of irradiation on the phamacokinetics of sPIFIn additionwe will determine the efficacy of sPIF to mitigate DEARE GI when first givenhours post TBI BMFinallythe efficacy of sPIF to mitigate GI ARS in NHP overdays when sPIF is administeredhours post exposure to the LDTBII BMThe proposed experiments are aligned clearly with the goals that are critical for progress to an NDA for sPIF as an MCMAccidental radiation exposure as a result of terrorismindustrial accidentsor military actions is an increasing global threatThe gastrointestinalGIsyndrome is the leading cause of death following higher doses of radiation even after rescue by bone marrow replacementThere is currently no medical countermeasureMCMapproved for the GI syndrome and thusthe overall goal of this fast track Phase II application is to advance the development of a novel therapyPreImplantation FactorPIFas a MCM the GI syndrome with the goal of FDA approval under the animal efficacy rule