Research Project
7537318
[unreadable] DESCRIPTION (provided by applicant): Coronary heart disease, the most prevalent manifestation of atherosclerosis, remains the single largest killer of American men and women. The "hallmark" of vascular disease or atherosclerosis is the accumulation of cholesterol in arteries, which can lead to heart attack (coronary heart disease), stroke or peripheral artery disease. The excess cholesterol causes stenosis and disruptions of signaling cascades leading to instability within the plaque. Therefore, a method to rapidly remove cholesterol from the atheromas and reduce the peripheral cholesterol burden may stabilize the plaque. Normally, cholesterol is removed from arteries and delivered to the liver for excretion in bile by a multistage process known as "Reverse Cholesterol Transport" (RCT). In the first stage, high-density lipoprotein (HDL) acquires cholesterol from artery walls. In the second stage, the enzyme lecithin:cholesterol acyltransferase (LCAT) increases the amount of cholesterol carried in HDL by the conversion of cholesterol to cholesteryl ester. The observation that individuals with reduced LCAT function exhibit reduced HDL cholesterol (HDL-C) and increased vascular disease suggests that LCAT function is protective. Moreover, enhancement of LCAT in animal models by gene over-expression is known to increase HDL-C and reduces atherosclerosis. AlphaCore Pharma proposes that the injection of active LCAT will result in the rapid mobilization of vessel and peripheral cholesterol to HDL, and consequent stabilization of arterial atheromas, thereby reducing the risk of primary or secondary vascular events in the patient. The Phase I specific aims are 1) Develop a mammalian cell expression system to produce sufficient quantities of recombinant, active, human LCAT (rhLCAT) and 2) Characterize the pharmacodynamics of rhLCAT infusion in mice expressing human apolipoprotein AI (apoA-ITG). The principle measures will be plasma cholesterol, HDL-C, human apoA-I, plasma LCAT activity and plasma content of rhLCAT. The kinetics of these parameters will be determined following a single infusion. Additionally, a comparison between routes of administration (intravenous, intraperitoneal and intra-muscular) will be performed. The data obtained from these studies will demonstrate the kinetics and magnitudes of HDL-C changes in response to a bolus rhLCAT infusion, which is unprecedented. The results will help define the dose sizes and dose frequency needed to obtain significant elevations in HDL-C. This information will be the foundation for a subsequent study of the effects of rhLCAT infusion on atherosclerosis development in an animal model. The ultimate goal of AlphaCore Pharma is to develop LCAT infusion as an acute therapy for unstable plaque and atherosclerosis. PUBLIC HEALTH RELEVANCE: Coronary heart disease, the most prevalent manifestation of atherosclerosis, remains the single largest killer of American men and women. AlphaCore Pharma proposes that the injection of the enzyme lecithin:cholesterol acyltransferase will result in the rapid mobilization of vessel and peripheral cholesterol to HDL, and consequent stabilization of the arteries, reducing the risk of repeated events in patients who have suffered at least one heart attack. [unreadable] [unreadable] [unreadable]
