title: A cholesterol-lowering VLP vaccine that targets PCSK9.
abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that controls cholesterol homeostasis by enhancing endosomal and lysosomal degradation of the low-density lipoprotein receptor (LDL-R). Mutations that cause increased activity of PCSK9 are associated with hypercholesterolemia, atherosclerosis and early cardiovascular disease (CVD), whereas individuals with loss-of-function mutations in PCSK9 are apparently healthy but are hypocholesterolemic and have a dramatically decreased risk of CVD. In this study, we generated virus-like particle (VLP)-based vaccines targeting PCSK9. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides. A vaccine targeting PCSK9 may, therefore, be an attractive alternative to monoclonal antibody-based therapies.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico, MSC08-4660, Albuquerque, NM 87131, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Crossey
authors.affiliation: Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Building 10 - 2C433, 10 Center Drive, MSC 1666, Bethesda, MD 20892, USA.
authors.forename: Marcelo J A
authors.initials: MJA
authors.lastname: Amar
authors.affiliation: Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Building 10 - 2C433, 10 Center Drive, MSC 1666, Bethesda, MD 20892, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Sampson
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico, MSC08-4660, Albuquerque, NM 87131, USA.
authors.forename: Julianne
authors.initials: J
authors.lastname: Peabody
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Schiller
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico, MSC08-4660, Albuquerque, NM 87131, USA. Electronic address: bchackerian@salud.unm.edu.
authors.forename: Bryce
authors.initials: B
authors.lastname: Chackerian
authors.affiliation: Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Building 10 - 2C433, 10 Center Drive, MSC 1666, Bethesda, MD 20892, USA. Electronic address: aremaley1@nhlbi.nih.gov.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001435:Bacteriophages / Q000235:genetics; D002784:Cholesterol / Q000097:blood*; D004337:Drug Carriers; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D008251:Macaca; D008297:Male; D008807:Mice, Inbred BALB C; D010743:Phospholipids / Q000097:blood; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000276:immunology; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage* / Q000235:genetics
chemical_list: D001323:Autoantibodies; D004337:Drug Carriers; D007074:Immunoglobulin G; D010743:Phospholipids; D014280:Triglycerides; D058425:Vaccines, Virus-Like Particle; D002784:Cholesterol; D043484:Proprotein Convertases
keywords: LDL Cholesterol; PCSK9; Vaccine; Virus-like particles