Medial arterial calcification is a form of vessel hardening in which calcium deposits are found in the medial layer of elastic and muscular arteries, specifically on elastic fibers, leading to arterial stiffening and tearing. An independent risk factor for cardiovascular diseases in diabetic and chronic kidney disease patients, it predisposes the patients to cardiovascular mortality and lower extremity amputation. There are no treatments to reverse calcification. The protein which imparts elasticity to elastic fibers - elastin - has a half-life of over 60 years and almost no turnover. During aging and disease processes, elastic fibers degrade and are prone to calcification, but since elastin production is negligible, they are not replaced. A possible treatment involves removing calcium deposits from vasculature by chelation therapy; however, systemic exposure to sufficiently high amounts of chelating agents would cause unacceptable side effects. To address this issue, we have developed unique nanoparticles that can be targeted to degraded elastic lamina in vasculature to deliver chelating agents locally, while sparing healthy arteries and other elastin-rich tissues. Our 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 therapy. This Phase I STTR project is focused on demonstrating feasibility of this approach in a clinically relevant animal model of chronic kidney disease, by targeting chelating agents (EDTA or EGTA) to the degraded and calcified elastin in arteries and removing mineral deposits. As we are advancing a potential therapy through pre-clinical development, we will utilize human albumin and an antibody against human elastin that we have recently developed. In Specific Aim 1, we will optimize chelating agent loading, characterize particle size, charge, in vitro drug release profile, storage conditions, and determine acute toxicity in rats. In Specific Aim 2, we will test reversal of vascular calcification with targeted nanoparticles that deliver controlled release of chelating agents, EDTA and EGTA, at the site of calcification to improve vascular function irrespective of chronic kidney disease in a rat model of adenine-induced uremia. If successful, we will humanize our elastin antibody and perform IND-enabling studies in a Phase II project.
Public Health Relevance Statement: PROJECT NARRATIVE Vascular calcification during aging and in diseases like diabetes and chronic kidney disease causes arterial stiffening and increase in blood pressure. It is a significant unresolved health problem that is recognized as a strong predictor of cardiovascular events and mortality. We are developing a treatment based on targeted nanoparticle-based delivery of chelating agents, to remove mineral deposits in arteries. If successfully translated to humans, it will be the first of its kind treatment for vascular calcification, and will considerably improve quality of life for millions of patients.
Project Terms: Acids; acute toxicity; Address; Adenine; Aging; Albumins; Amputation; Animal Model; Antibodies; arterial stiffness; Arteries; Atherosclerosis; base; Binding; Blood Pressure; Blood Vessels; bone; calcification; Calcium; Cardiovascular Diseases; cardiovascular risk factor; Cardiovascular system; Charge; Chelating Agents; chelation; Chelation Therapy; Chronic Kidney Failure; Clinical; Clinical Trials; clinically relevant; controlled release; Data; Deposition; Diabetes Mellitus; diabetic; Disease; Doppler Ultrasound; dosage; Dose; drug release profile; Drug Targeting; Edetic Acid; Egtazic Acid; Elastic Fiber; Elasticity; Elastin; Elastin Fiber; Ethers; ethylene glycol; Ethylenediamines; Event; Exposure to; Formulation; General Population; Genetic Diseases; Half-Life; Health; heart function; Histology; Human; Hypocalcemia result; improved; In Vitro; in vivo; in vivo monitoring; Infiltration; intima media; intravenous administration; Isolated systolic hypertension; Kidney; Lead; Lethal Dose 50; Lipids; Lower Extremity; macrophage; Measures; Medial; Metabolic Diseases; Methods; Minerals; Modeling; mortality; Muscle; Myocardial Infarction; nanoparticle; nanoparticle delivery; Outcome; particle; Particle Size; Patients; Periodicity; Phase; Physiologic pulse; preclinical development; Process; Production; Proteins; Publishing; Pulse Pressure; Quality of life; Rattus; Serum Albumin; side effect; Site; Small Business Technology Transfer Research; Smooth Muscle Myocytes; Specificity; Surface; Testing; Therapeutic Index; Tissues; Toxic effect; Translating; Uremia; Vascular calcification; Vascular Smooth Muscle
