Evaluation of a Novel Connexin-Based Peptide in the Treatment of Combined Ionizing Radiation and Thermal Burn Injury

PROJECT SUMMARYThe threat of a nuclear attack or disaster resulting in mass casualties is of increasing concernRadiation injury frequently occurs in combination with thermal burnsCombined radiation and thermal burn injuryCRBIresults in impaired wound healingexacerbated symptomsand synergistic increases in mortalityCountermeasures that synergistically address the complex pathophysiology of CRBI at both local and systemic levels remain an unmet needGap junctions and their connexinCxcomponents are indispensable in mediating the cellular coordination required for tissue and organ developmentrepairand homeostasisBased upon thisa small synthetic peptide aCTcomprising the carboxy tail of Cxwhich regulates Cxfunctionwas developedaCTis a systemically stable truncated form of aCTA stableeasy to usetopical formulation of aCTGranexinhas been successfully advanced through extensive preclinical work and three Phasehuman clinical trials with clinically meaningful outcomes for scar reduction and the treatment of chronic woundsGranexinis currently in Phasetrials for the treatment of chronic skin woundsPreclinical studies further support clinical opportunity for aCTwhere daily Granexin treatment prevented injury progression and optimized clinical outcome of thermal burn injuries and acute high dose cutaneous radiation injuriesCxalso has key roles in maintaining intestinal homeostasis and intestinal mucosal repair and early efficacy studies in gastrointestinal targeted murine partial body irradiation models support aCTin reducing mortalityCurrent guidelines in the evaluation of radiation countermeasure support the stepwise translation of acute radiation models to CRBI models and our exciting results support the strategy of synergistically using a topicalGranexinand systemically delivered Cxbased peptideaCTin the mitigation and treatment of CRBI post exposureIn response to the priorities of the Radiological Nuclear Medical Countermeasure Product Development Programour strategy is to develop a broad activity therapeutic strategy that can be readily administered in a mass casualty emergency scenario post exposure and addresses both the cutaneous and systemic symptoms that synergistically result in CRBI associated morbidity and mortalityThe objectives of this Phase I SBIR are to idevelop and fully characterize a murine model of combined partial body radiation and thermal burn injury and iiconduct a proof of concept preclinical efficacy study to evaluate in vivo therapeutic potential and mechanism of action of a combinatorial therapeutic approach involving topical Granexin and systemically delivered aCTin the treatment of CRBIThese studies will lay the foundation for large animal models that will serve as an integral part of an IND submission to the FDAWe hypothesize that application of this two pronged approach will synergistically treat CRBI by effectively reducing the lethality and improving clinical outcomeFurthermorethese studies will validate a combined partial body radiation and burn injury animal model and provide insight into disease biomarkers and additional translational opportunity PROJECT NARRATIVE Medical countermeasures that synergistically address the complex pathophysiology of combined radiation and thermal burn injuryCRBIat both local and systemic levels remain an unmet needOur strategy is to develop a broad activity therapeutic strategy that can be readily administered in a mass casualty emergency scenario post exposure and addresses both the cutaneous and systemic symptoms that synergistically result in CRBIassociated morbidity and mortalityOur effort is highly aligned with NIAID and NIHandapos s responsibility to identifycharacterize and develop new medical countermeasure products against radiological and nuclear incidents that may cause a public health emergency