Mitigation of Acute Kidney Injury (AKI) using the polymer prodrug, APP-103TM

Project Summary Acute Kidney InjuryAKIis common in hospitalized patients after severe illness or following major surgeriessuch as cardiovascular surgeryThe incidence of AKI in critically ill patients is greater thanPatients who have an AKI event have poor long term outcomes including increased debilitating comorbidities such as chronic kidney disease and increased mortalityIschemia reperfusion injuryIRIan unavoidable consequence of cardiovascular surgeryis a known cause of AKIIRI is partially the result of the formation of reactive oxygen speciesROSin the absence of sufficient antioxidative moietiesand can lead to the induction of inflammationThere is currently no clinically available therapeutic treatment to prevent or treat AKIwhich leaves a large cohort of suffering patients and a high burden on our healthcare systemOur productAPPconsists of effective anti oxidant and anti inflammatory copolymer nanoparticles that have previously been demonstrated to be highly effective in ameliorating damage from oxidative stress in several IRI models of kidneyheartlimb injuryand renal transplantationAPPis a dispersion of polyoxalate vanillyl alcoholVAcopolymer particles that is degraded by hydrogen peroxidethereby reducing the local concentration of ROS and yielding anti inflammatory VAThe polymer chemistry and biology of APPis well understood and indicative of an excellent safety profileWhile easily administered systemicallyit offers site specific anti oxidative and anti inflammatory therapy without expensive and marginally effective targeting moleculesA singlenm diameter APPparticle provides the ability to mitigateROS moleculesand is activated only in the presence of ROSi eAPP activity is self limitingTo datewe have been able to produce APPat the scale necessary for preclinical workand are advancing through IND enabling studies with no toxicityWe have also demonstrated efficacy in pre clinical AKI modelsThe purpose of this proposal is to provide mechanistic insight of APPin kidney IRIdemonstrate proof of concept in a large animal model of AKIand then advance APPfrom lab manufacturing through completion of IND enabling studiesThe milestone of ultimate success will be the submission of an IND in order to bring this exceptionally promising therapy into clinical application Project Narrative Ischemia reperfusionI Rinjury during acute kidney injuryAKIcan result in cellular dysfunction and ultimately the loss of kidney functionincreasing patient morbidity and mortalityWe are developing a polymer based antioxidative anti inflammatory therapyAPPTMthat we have already shown to be highly efficacious in ameliorating damage from oxidative stress in I R models of kidneyheart and limb injury as well as in syngeneic renal transplant models with no signs of toxicityThe overarching goal of this proposal is to demonstrate pre clinical efficacy in a large animal AKI modelto manufacture APPTMand to complete IND enabling studies for IND submission in AKI