Therapy of transplantation-induced oxidative injury using polymeric antioxidants

DESCRIPTION provided by applicant Ischemia reperfusion I R injury during renal transplantation surgery is responsible for oxidative stresses which result in immune activation and graft rejection We are developing an antioxidative therapy that we have already shown to be highly efficacious in ameliorating damage from oxidative stress in various in vitro models as well as I R models of kidney heart and limb injury Importantly no signs of toxicity have been observed in any model We will however undertake a comprehensive safety evaluation as a key component of this grant The product is a dispersion of polyoxalate vanillyl alcohol VA copolymer particles The polymer is degraded by hydrogen peroxide thereby reducing the local concentration of ROS yielding VA a potent antioxidant in its own right We refer to these therapies as Antioxidant Polymer Prodrugs or APPsandquot Their polymer chemistry and biology are well understood and indicative of an excellent safety profile Their site specific antioxidative activity is only produced at the sites of oxidative stress despite systemic administration and without expensive and marginally effective targeting molecules This increases APPsandapos safety profile and efficacy Indeed a single nm diameter APPandquot particle provides the ability to mitigate ROS molecules and will only be active in the presence of ROS i e APP activity is self limiting To date we have produced APP our lead APP product at the scale necessary for preclinical work demonstrated its antioxidative and anti inflammatory activity in vitro determined its release kinetics and demonstrated dose dependent efficacy efficacy and site specificity in vivo in a murine limb I R model efficacy in kidney hepatic and cardiac I R models efficacy against doxorubicin induced cardio and hepato toxicities in vivo and a basic safety profile at high dose Details of these studies are presented in the Research Strategy section Our overarching goal is to move this promising laboratory therapy into the clinic To do this we will scale up APP production develop QA QC assays for particle phenotype and function and demonstrate equivalence of scaled particles in vitro and in vivo determine MTD in healthy mice determine minimum anticipated biological effect level MABEL in rat I R model demonstrate efficacy in rat renal transplant studies and complete preclinical safety testing all culminating in an IND submission for APP PUBLIC HEALTH RELEVANCE Ischemia reperfusion I R injury during kidney transplantation can result in immune activation and graft rejection We are developing a polymer based antioxidative therapy that we have already shown to be highly efficacious in ameliorating damage from oxidative stress in I R models of kidney heart and limb injury and has shown no signs of toxicity The goal of this proposal is to move this promising therapy into the clinic