Evaluation of IPW-5371, a TGFbRI kinase inhibitor, dosed as a single agent or in combination with G-CSF, as a medical countermeasure against the delayed effects of total body irradiation in mice

Abstract Ionizing radiationIRexposure has deleterious effects on multiple organ systems and can be lethal both acutely and later due to the delayed effectsIn the event of a deliberate radiation attack or accidental exposure to radiationa countermeasure can be used to treat exposed populations and prevent death and disabilityNo agent has been approved by the FDA to treat the delayed effects of acute radiation exposureDEAREand our project will address that unmet medical needIPWhas the properties of an ideal radiation countermeasurechemically stable at room temperatureorally bio availableefficacy with once a day dosingtargeting a mechanism of action that has been safely inhibited in human clinical trialsThe results from the experiments in this proposal will advance the development of IPWto protect the organs in the case of an unexpected exposure to radiationWe have previously demonstrated that the Innovation Pathwayssmall molecule TGFinhibitorIPWis effective against DEARE in a thoracic radiation mouse model as measured by improved survival and cardiopulmonary functionwhen dosedhours post IRIn this proposalwe will establish that IPWis effective in treating multiorgan DEARE to the heartlungkidney and intestinein a mouse radiation model as a single agent or in combination with G CSFSpecific AimaDemonstrate that IPWas a single agentcan extend survival of CBLmice exposed to TBIGywhen drug dosingmpk day in chowis initiatedhours post TBI and continued formonthsSpecific aimbDemonstrate that IPWas a single agent can improve secondary endpoints includingdecrease fibrosisprotect functionand block TGFsignaling in multiple organs of CBLmice when measured atandmonths post TBIfollowing an established mouse modelSpecific AimEstablish that IPWG CSFIPWmpk per day in chow formonths and the G CSF will be injected for two weeks dosing initiatedhours post TBIGycan protect against heartlungintestine and kidney DEAREas described in Specific aimband protect against the earlylethal effects of H ARS as measured by survival atdays verses TBIuntreated miceThere will be a total ofmice divided into eight groupsGroups A D are the unirradiated controls with Grp A receiving vehicleSC saline injection fordaysGrp B receiving G CSFand Grp C receiving IPWand Grp D receiving IPWG CSFAll animals receive drug sor vehicle startinghours post TBIIPWadministered in chowmpk day mouseformonths and G CSF is administered daily fordaysSCg kgg mouseqdGroups E H receive TBIGyMice to be exposed to uniform TBI at a dose rate ofGy per minuteGrp E receives vehicleGrp F receives G CSF and Grp G receives IPWand Grp H receives IPWG CSF NARRATIVE Ionizing radiationIRexposure has deleterious effects on multiple organ systems and can be lethal both acutely and later due to the delayed effects of IRA radiation medical countermeasureMCMmust be effective when dosed post radiation exposureas it is unlikely that any advanced warning will be providedInnovation Pathwaysnovel small molecule therapeuticTGFinhibitor IPWhas the potential to mitigate the delayed effects of radiation on multiple organs and be developed as an effective MCM