Development of an Apoa1 Mimetic Peptide for Treatment of Atherosclerosis
It has become increasingly evident that therapeutic agents for raising high-density lipoproteins (HDL) would be a useful addition to our current treatment approach for preventing coronary heart disease (CHD) because our existing drugs that lower low-density lipoproteins are not fully adequate for preventing CHD. The recent unraveling of some of the complexities of HDL metabolism has led to the identification of new key proteins involved in the biogenesis of HDL, giving new hope and ideas for drug targets. In spite of this, HDL raising small molecule based therapies 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 rapidly stabilize patients at great risk for developing a myocardial infarction and to concurrently start them on conventional lipid lowering drugs and other agents for reducing the risk of myocardial infarction. This application describes a short synthetic peptide mimic of apoA-I, referred to as the 5A peptide, which can potentially be used instead of recombinant apoA-I in acute HDL therapy, and as described below has several potential advantages over the use of recombinant apoA-I. Peptide 5A is being developed for treatment and prevention of atherosclerotic cardiovascular disease. 5A attenuates the development of atherosclerotic plaque in preclinical 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, we have shown by use of a new measurement technology 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 man studies following IND, for rapid assessment of therapeutic proof-of-concept.
Scott Turner, Ph.D.
Public Health Impact
This HDL mimetic, the 5A peptide has been shown to reduce atherosclerosis and replicate many of the known beneficial effects 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 GMP and non-GMP material
- Formulation development
- PK/ADME studies
- IND-directed toxicology