Development of an ApoA-1 Mimetic Peptide for Treatment of Atherosclerosis

National Center For Advancing Translational Sciences

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Abstract

Existing drugs that lower low-density lipoprotein (LDL) are not fully adequate for preventing coronary heart disease (CHD). It has become increasingly evident that therapeutic agents for raising high-density lipoprotein (HDL) would be a useful addition to our current treatment approach. 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. This project involves a short synthetic peptide mimic of apoA-1, (peptide 5A), which potentially can be used instead of recombinant apoA-1 in acute HDL therapy. Peptide 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. The collaboration includes the completion of the following ongoing studies on 5A: - Synthesis of Good Manufacturing Practice (GMP) and non-GMP material - Formulation development - Manufacture of drug product for clinical trials - Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies - IND-directed toxicology