TP508: A New Drug for Mitigating Lethals Effects of Radiation Exposure

DESCRIPTIONprovided by applicantWith increasing risk of a nuclear accident or detonationthere is a critical need to develop effective medicinal countermeasures that can be delivered to victims after an incident to increase survival and prevent long term effects in those that surviveMajor causes of death following a nuclear incident include acute radiation syndromesARSthat destroy hematopoietic stem cellsH ARSgastrointestinal stem cells in the cryptsGI ARSor bothWe have developed a unique regenerative peptide drugTPrusalatide acetatethat mitigates effects of radiation by restoring endothelial function and activating stem cellsPhaseand Phasestudies demonstrated that TPsignificantly increases survival and delays mortality when injectedh after lethal doses of gamma radiationIn these studiesTPincreased recovery of bone marrow stem cells and stem cells in intestinal and colonic crypts to maintain GI integrityOur studies also showed that TPsystemic injection activates stem cells in the dermis of irradiated animals adjacent to burns and accelerates healing and re epithelization of the burned dermal areaThese life saving effects of TPthereforeappear to be mediated through the protection activation of stem cells or endothelial cells that maintain the stem cell nicheThusin addition to mitigating effects of H ARS and GI ARSTPmay have widespread benefit to prevent delayed effects of radiation by stimulating tissue regenerationTo obtain FDA "animal rulelicensure for TPwe will complete steps necessary for approval employing the established regulatory pathway and animal models for H ARSSpecific Aims for Phaseb are designed to utilize animal studies that will allow us to predict the most efficacious dose of TPto be used in humans following a nuclear incidentWe will establish optimal TPdoses in two strains of mice and conduct GLP PK PD studies in normal and irradiated mice to determine the required systemic bioavailability for maximum efficacySince most exposed individuals will receive supportive care following exposurewe will also determine how supportive care of our animals will affect TPmitigation of radiation induced mortalityAlthough we have information regarding TPeffectsadditional experiments will be used to confirm the key cellular targets and modes of actionThese studies will include experiments with normal and eNOSmice using established assays to quantify TPeffects on hematopoietic cell recoveryDNA repairendothelial cell protectionand stem cell activationFor FDA approvallarge animal studies predictive of human efficacy must also be completedThe large animal "gold standard" for H ARS drugs is demonstration of increased survival of irradiated non human primatesNHPThereforewe will conduct GLP PK PD studies and a pilot efficacy study in NHP using the same formulation and route of administration that will be used in humansCompletion of this PhaseB project will position TPfor pivotal NHP blinded efficacy studies needed for licensure and potential stockpiling of the drug to save thousands of lives in the event of a nuclear disaster