title: CER-001, a HDL-mimetic, stimulates the reverse lipid transport and atherosclerosis regression in high cholesterol diet-fed LDL-receptor deficient mice.
abstract: OBJECTIVE
  CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and phospholipids that was designed to mimic the beneficial properties of nascent pre-β HDL. In this study, we have evaluated the capacity of CER-001 to perform reverse lipid transport in single dose studies as well as to regress atherosclerosis in LDLr(-/-) mice after short-term multiple-dose infusions.
  
  
  RESULTS
  CER-001 induced cholesterol efflux from macrophages and exhibited anti-inflammatory response similar to natural HDL. Studies with HUVEC demonstrated CER-001 at a concentration of 500 μg/mL completely suppressed the secretion of cytokines IL-6, IL-8, GM-CSF and MCP-1. Following infusion of CER-001 (10mg/kg) in C57Bl/6J mice, we observed a transient increase in the mobilization of unesterified cholesterol in HDL particles containing recombinant human apoA-I. Finally we show that cholesterol elimination was stimulated in CER-001 treated animals as demonstrated by the increased cholesterol concentration in liver and feces. In a familial hypercholesterolemia mouse model (LDL-receptor deficient mice), the infusion of CER-001 caused 17% and 32% reductions in plaque size, 17% and 23% reductions in lipid content after 5 and 10 doses given every 2 days, respectively. Also, there was an 80% reduction in macrophage content in the plaque following 5 doses, and decreased VCAM-1 expression by 16% and 22% in the plaque following 5 and 10 intravenous doses of CER-001, respectively.
  
  
  CONCLUSIONS
  These data demonstrate that CER-001 rapidly enhances reverse lipid transport in the mouse, reducing vascular inflammation and promoting regression of diet-induced atherosclerosis in LDLr(-/-) mice upon a short-term multiple dose treatment.
authors.affiliation: Cerenis Therapeutics SA, 265 rue de la Découverte, 31670 Labege, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Tardy
authors.affiliation: Cerenis Therapeutics SA, 265 rue de la Découverte, 31670 Labege, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Goffinet
authors.affiliation: Cerenis Therapeutics SA, 265 rue de la Découverte, 31670 Labege, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Boubekeur
authors.affiliation: Cerenis Therapeutics Inc., 900 Victor Ways, Ann Arbor, MI 48108, USA.
authors.forename: Rose
authors.initials: R
authors.lastname: Ackermann
authors.affiliation: Cerenis Therapeutics Inc., 900 Victor Ways, Ann Arbor, MI 48108, USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: Sy
authors.affiliation: Cerenis Therapeutics SA, 265 rue de la Découverte, 31670 Labege, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Bluteau
authors.affiliation: Cerenis Therapeutics SA, 265 rue de la Découverte, 31670 Labege, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Cholez
authors.affiliation: Cerenis Therapeutics SA, 265 rue de la Découverte, 31670 Labege, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Keyserling
authors.affiliation: Cerenis Therapeutics Inc., 900 Victor Ways, Ann Arbor, MI 48108, USA.
authors.forename: Narendra
authors.initials: N
authors.lastname: Lalwani
authors.affiliation: Cerenis Therapeutics SA, 265 rue de la Découverte, 31670 Labege, France.
authors.forename: John F
authors.initials: JF
authors.lastname: Paolini
authors.affiliation: Cerenis Therapeutics SA, 265 rue de la Découverte, 31670 Labege, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Dasseux
authors.affiliation: Cerenis Therapeutics SA, 265 rue de la Découverte, 31670 Labege, France.
authors.forename: Ronald
authors.initials: R
authors.lastname: Barbaras
authors.affiliation: Cerenis Therapeutics SA, 265 rue de la Découverte, 31670 Labege, France. Electronic address: baron@cerenis.com.
authors.forename: Rudi
authors.initials: R
authors.lastname: Baron
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy*; D032701:Biomimetics; D016466:CHO Cells; D002448:Cell Adhesion; D002784:Cholesterol / Q000097:blood / Q000737:chemistry; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005243:Feces; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy; D007249:Inflammation; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010743:Phospholipids / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016632:Apolipoprotein A-I; C000591544:CER-001; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D010743:Phospholipids; D011994:Recombinant Proteins; D002784:Cholesterol
keywords: Atherosclerosis regression; HDL mimetics; High density lipoproteins (HDL); Lipoproteins; Reverse lipid transport