Targeted Chelation for Reversal of Vascular Calcification

PROJECT SUMMARY Medial arterial calcification is a form of vessel hardening in which calcium deposits are found in the medial layer of elastic and muscular arteriesspecifically on elastic fibersleading to arterial stiffening and tearingAn independent risk factor for cardiovascular diseases in diabetic and chronic kidney disease patientsit predisposes the patients to cardiovascular mortality and lower extremity amputationThere are no treatments to reverse calcificationThe protein which imparts elasticity to elastic fiberselastinhas a half life of overyears and almost no turnoverDuring aging and disease processeselastic fibers degrade and are prone to calcificationbut since elastin production is negligiblethey are not replacedA possible treatment involves removing calcium deposits from vasculature by chelation therapyhoweversystemic exposure to sufficiently high amounts of chelating agents would cause unacceptable side effectsTo address this issuewe have developed unique nanoparticles that can be targeted to degraded elastic lamina in vasculature to deliver chelating agents locallywhile sparing healthy arteries and other elastin rich tissuesOur strong published data show that albumin nanoparticles loaded with EDTA and conjugated to elastin antibodies reverse experimentally created vascular calcification and avoid possible side effects of systemic chelation therapyThis Phase I STTR project is focused on demonstrating feasibility of this approach in a clinically relevant animal model of chronic kidney diseaseby targeting chelating agentsEDTA or EGTAto the degraded and calcified elastin in arteries and removing mineral depositsAs we are advancing a potential therapy through pre clinical developmentwe will utilize human albumin and an antibody against human elastin that we have recently developedIn Specific Aimwe will optimize chelating agent loadingcharacterize particle sizechargein vitro drug release profilestorage conditionsand determine acute toxicity in ratsIn Specific Aimwe will test reversal of vascular calcification with targeted nanoparticles that deliver controlled release of chelating agentsEDTA and EGTAat the site of calcification to improve vascular function irrespective of chronic kidney disease in a rat model of adenine induced uremiaIf successfulwe will humanize our elastin antibody and perform IND enabling studies in a Phase II project PROJECT NARRATIVE Vascular calcification during aging and in diseases like diabetes and chronic kidney disease causes arterial stiffening and increase in blood pressureIt is a significant unresolved health problem that is recognized as a strong predictor of cardiovascular events and mortalityWe are developing a treatment based on targeted nanoparticle based delivery of chelating agentsto remove mineral deposits in arteriesIf successfully translated to humansit will be the first of its kind treatment for vascular calcificationand will considerably improve quality of life for millions of patients