Development of Peptide Inhibitor of Complement to treat neonatal asphyxial brain damage

Abstract The hypothesis for the proposed project is that inhibition of the classical complement pathway with Peptide Inhibitor of complement C PIC will be neuroprotective in a rat model of neonatal hypoxic ischemic encephalopathy HIE HIE is an ischemia reperfusion injury of the brain that occurs around the time of birth with up to mortality and of survivors left with a significant disability The complement system the most potent inflammatory cascade in humans and a critical mediator of inflammation phagocytic cell recruitment and direct cell lysis has been shown to play a major role in the pathogenesis of HIE in animal models and human studies Therapeutic hypothermia the only accepted treatment for neonatal HIE slightly improves short term survival and neurodevelopment in HIE but does not significantly improve long term outcomes To date none of the tested pharmacological adjuvants to therapeutic hypothermia have demonstrated clinical improvement Deficiency of C q the initiator molecule of the classical complement pathway has been shown to be neuroprotective in an animal model of neonatal HIE Our current lead compound of PIC PA CPEG is the product of years of rational drug design yielding a amino acid peptide conjugated with PEG Our compound binds to C q efficiently blocking complement activation at the first step in the cascade Pilot experiments in the well established Vannucci rat model of neonatal HIE have shown that PIC significantly reduces brain infarct volumes and reduces neuronal injury The proposed studies will refine dosing and frequency of PIC in the Vannucci model and conduct fully powered studies to evaluate the efficacy of PIC in reducing brain injury in neonatal HIE The success of the proposed studies will provide critical proof of concept that PIC can prevent complement mediated pathogenesis in an animal model of human disease This will provide the necessary evidence to propel the future pre clinical development of PIC through pharmacokinetic and toxicology studies via SBIR Phase Third party market analysis shows the potential for healthy sales volumes for PIC in HIE Third party regulatory analysis suggests the potential for a stream lined regulatory approach by seeking Orphan Drug and Breakthrough designations The goal of the proposed research project is to conduct proof of concept testing of a promising novel anti inflammatory compound PIC in an animal model of neonatal asphyxial brain injury hypoxic ischemic encephalopathy HIE This compound inhibits a novel pathway of inflammation the classical pathway of the complement cascade which is not targeted by current anti inflammatory drugs The proposed studies will optimize dosing and test whether PIC can decrease brain injury after HIE in an animal model These studies will provide proof of concept data demonstrating the efficacy of PIC to improve neurological outcomes after HIE in humans