Research Project
8133795
DESCRIPTION (provided by applicant): The "hallmark" of atherosclerosis is the accumulation of cholesterol in arteries, resulting in plaque which can lead to a heart attack (myocardial infarction (MI)). The excess cholesterol causes inflammation, promotes plaque instability, and in later stages, narrows the vessel lumen to obstruct blood flow. Normally, cholesterol is removed from arteries and delivered to the liver for excretion into bile by a multistep process known as "Reverse Cholesterol Transport" (RCT). In the first step of RCT, small high-density lipoprotein (HDL) particles called "pre-beta" HDL acquire cholesterol from artery walls. In the second step, the plasma enzyme lecithin:cholesterol acyltransferase (LCAT) increases the amount of cholesterol carried in HDL by the esterification of cholesterol to cholesteryl ester. The recent observation that individuals with heart disease have high pre-beta HDL levels and reduced LCAT activity suggests that LCAT is a critical and perhaps rate-limiting component of RCT. Moreover, enhancement of LCAT in animal models by gene transfer, or more recently by the injection of recombinant LCAT, is known to increase HDL-C, enhance RCT and reduce atherosclerosis. Therefore, it is reasonable that increasing the amount of LCAT in patients who have suffered an MI will rapidly stimulate RCT, stabilize the plaque, and consequently, reduce the likelihood of another adverse clinical event. The long-term commercial objective of AlphaCore Pharma is to gain FDA approval for recombinant human LCAT (rhLCAT) as a therapy for reducing the risk of a repeat (secondary) MI in post-MI patients. Phase I of this project was highly successful. SBIR funding was used for bench-scale production of active rhLCAT and to conduct initial proof-of-concept studies in mice. A single injection of rhLCAT in three relevant mouse models increased HDL cholesterol (principally LCAT-derived cholesteryl esters) and size. Moreover, HDL-C remained elevated for more than 48 hours, which increases the possibility that once-weekly dosing may be achievable in humans. The response to rhLCAT was similar whether the injection route was intravascular, intramuscular or subcutaneous, which suggests different dosing options may be possible in humans, including self- administration. Multiple injections of rhLCAT over several days produced even greater increases in HDL-C, and resulted in enhanced expression of liver genes involved in bile acid production, suggesting enhanced delivery of cholesterol to the liver. The Phase II specific aims are 1) to demonstrate enhancement of macrophage specific RCT after rhLCAT injection, 2) to determine if rhLCAT will induce rapid changes in atherosclerotic lesions in rabbits, 3) to conduct a toxicology study in non-human primates to obtain the data for an Investigational New Drug submission;4) to demonstrate that rhLCAT becomes associated with HDL after injection and is functional. Achievement of these specific aims will enable application to the FDA for approval to test rhLCAT safety and efficacy in humans. The ultimate goal is to make rhLCAT a unique and effective therapy for reducing the unacceptable number of recurrent cardiovascular events in post-infarct patients. 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.
