Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA[S]

• Published in: Journal of lipid research Vol. 56; no. 3; pp. 703 - 712
• Main Authors: Kootte, Ruud S., Smits, Loek P., van der Valk, Fleur M., Dasseux, Jean-Louis, Keyserling, Constance H., Barbaras, Ronald, Paolini, John F., Santos, Raul D., van Dijk, Theo H., Dallinga-van Thie, Geesje M., Nederveen, Aart J., Mulder, WillemJ.M., Hovingh, G.Kees, Kastelein, JohnJ.P., Groen, Albert K., Stroes, ErikS
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2015; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Adult; apolipoprotein A-I; Apolipoprotein A-I - administration & dosage; Carotid Arteries - diagnostic imaging; Carotid Arteries - metabolism; Cholesterol, HDL - blood; familial hypoalphalipoproteinemia; Female; Humans; Hypoalphalipoproteinemias - blood; Hypoalphalipoproteinemias - diagnostic imaging; Hypoalphalipoproteinemias - drug therapy; Magnetic Resonance Angiography; Male; Middle Aged; Patient-Oriented and Epidemiological Research; Phospholipids - administration & dosage; Positron-Emission Tomography; Radiography; Recombinant Proteins - administration & dosage; reverse cholesterol transport; familial hypoalphalipoproteinemia; reverse cholesterol transport; apolipoprotein A-I
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1194/jlr.M055665

Reverse cholesterol transport (RCT) contributes to the anti-atherogenic effects of HDL. Patients with the orphan disease, familial hypoalphalipoproteinemia (FHA), are characterized by decreased tissue cholesterol removal and an increased atherogenic burden. We performed an open-label uncontrolled proof-of-concept study to evaluate the effect of infusions with a human apoA-I-containing HDL-mimetic particle (CER-001) on RCT and the arterial vessel wall in FHA. Subjects received 20 infusions of CER-001 (8 mg/kg) during 6 months. Efficacy was assessed by measuring (apo)lipoproteins, plasma-mediated cellular cholesterol efflux, fecal sterol excretion (FSE), and carotid artery wall dimension by MRI and artery wall inflammation by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography scans. We included seven FHA patients: HDL-cholesterol (HDL-c), 13.8 [1.8–29.1] mg/dl; apoA-I, 28.7 [7.9–59.1] mg/dl. Following nine infusions in 1 month, apoA-I and HDL-c increased directly after infusion by 27.0 and 16.1 mg/dl (P = 0.018). CER-001 induced a 44% relative increase (P = 0.018) in in vitro cellular cholesterol efflux with a trend toward increased FSE (P = 0.068). After nine infusions of CER-001, carotid mean vessel wall area decreased compared with baseline from 25.0 to 22.8 mm2 (P = 0.043) and target-to-background ratio from 2.04 to 1.81 (P = 0.046). In FHA-subjects, CER-001 stimulates cholesterol mobilization and reduces artery wall dimension and inflammation, supporting further evaluation of CER-001 in FHA patients.