Coronary heart disease (CHD) is the buildup of a waxy substance called plaque in the arteries that supply blood to the heart. Plaque builds up over time and can eventually narrow arteries and reduce blood flow to the heart, leading to abnormal heart rate, heart attack or heart failure. CHD is the most common type of heart disease and the primary cause of death for men and women in the United States. Having high levels of low-density lipoprotein (LDL) cholesterol — “bad” cholesterol — and low levels of high-density lipoprotein (HDL) cholesterol — “good” cholesterol — increases risk for CHD. Currently, drugs that lower LDL cholesterol are used to help prevent CHD, but they are not completely effective. Scientists have recently explored the therapeutic effects of giving HDL cholesterol to patients with CHD at high risk for a heart attack. These investigators are developing a drug that mimics the effects of apoA-1, a building block of HDL cholesterol. The drug would increase HDL levels in the blood to treat and prevent CHD.
It has become increasingly evident that therapeutic agents for raising HDL would be a useful addition to our current treatment approach for preventing CHD because our existing drugs that lower LDL are not fully adequate for preventing CHD. The recent unraveling of some of the complexities of HDL metabolism has led to the identification of key proteins involved in the biogenesis of HDL, giving new hope and ideas for drug targets. In spite of this, therapies using small molecules to raise HDL have been elusive.
Recently, a potential new treatment strategy for CHD, called acute HDL therapy, has been described. The strategy involves a weekly intravenous infusion of HDL into patients with acute coronary syndrome. A five-week course of this therapy has been shown to rapidly reduce atherosclerotic plaques, as assessed by intravascular ultrasound. The goal of acute HDL therapy is to stabilize patients at great risk for developing a heart attack and to concurrently start them on conventional lipid lowering drugs and other agents for reducing the risk for heart attack.
This project describes a short synthetic peptide mimic of apoA-1, referred to as the 5A peptide, which potentially can be used instead of recombinant apoA-1 in acute HDL therapy. As described below, peptide 5A has several potential advantages over the use of recombinant apoA-1. Peptide 5A is being developed for treatment and prevention of atherosclerotic cardiovascular disease. The 5A attenuates the development of atherosclerotic plaque in pre-clinical models of atherosclerosis, including APOE-deficient mice, and impairs macrophage recruitment and foam cell formation in the rabbit collar model. In vitro assays have demonstrated that 5A specifically interacts with the cholesterol efflux transporter ABCA1 and catalyzes the efflux of cholesterol from macrophages.
Furthermore, the investigators have shown that 5A accelerates the in vivo efflux of cholesterol from tissues to plasma lipoproteins in animal models. This feature of the peptide will be used to inform first-in-human studies following Investigational New Drug (IND) approval from the Food and Drug Administration for rapid assessment of therapeutic proof-of-concept.
National Heart, Lung, and Blood Institute, Bethesda, Maryland
Alan T. Remaley, M.D., Ph.D.
Public Health Impact
Peptide 5A has been shown to reduce atherosclerosis and replicate many of the known benefits of HDL in animal studies, making it an excellent candidate therapy. In spite of good therapies for lowering LDL, atherosclerosis remains a major cause of death worldwide.
Approved studies are ongoing.
- Synthesis of Good Manufacturing Practice (GMP) and non-GMP material
- Formulation development
- Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies
- IND-directed toxicology