CSL112 Enhances Biomarkers of Reverse Cholesterol Transport After Single and Multiple Infusions in Healthy Subjects
Objective—The ability of apolipoprotein A-I (apoA-I) to transport cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. To gauge the potential of infused apoA-I to transport cholesterol, we quantified cholesterol transport markers in human subjects infused with a novel formulation of apoA-I (CSL112).
Approach and Results—CSL112 was infused into human subjects in single (57 subjects) and multiple (36 subjects) ascending dose trials. Pharmacokinetic and biomarker assessments were conducted before and after infusions. CSL112 caused an immediate, 3-fold elevation of apoA-I and subsequent movement of tissue cholesterol into plasma. Cholesterol appeared first as unesterified cholesterol in the high-density lipoprotein (HDL) fraction and was promptly esterified by lecithin cholesterol acyltransferase. HDL cholesterol increased 81±16.5%. Underlying this movement of cholesterol was an immediate and strong rise in the ability of plasma to promote chole≤sterol efflux from cells ex vivo. CSL112 had its greatest impact on the fraction of efflux mediated by ABCA1, a cholesterol transporter induced in cholesterol-loaded tissues such as plaque. ABCA1-dependent efflux capacity increased ≤630±421% and total efflux capacity by ≤192±40%. In keeping with this finding, we observed a profound rise in very small HDL, also known as preβ1-HDL, the preferred substrate for ABCA1. Very small HDL increased ≤3596±941%. Elevations in apoA-I, cholesterol efflux, and very small HDL were dose-proportional over a wide range. No significant changes in atherogenic lipids were observed at any dose.
Conclusions—Infusion of CSL112 elevates the ability of plasma to withdraw cholesterol from cells. Preferential elevation of ABCA1-dependent efflux may target atherosclerotic plaque for cholesterol removal, making CSL112 a promising candidate therapy for acute coronary syndrome.
- Received March 25, 2014.
- Accepted June 5, 2014.
- © 2014 American Heart Association, Inc.