title: Effects of an antisense oligonucleotide inhibitor of C-reactive protein synthesis on the endotoxin challenge response in healthy human male volunteers.
abstract: BACKGROUND
  C-reactive protein (CRP) binds to damaged cells, activates the classical complement pathway, is elevated in multiple inflammatory conditions, and provides prognostic information on risk of future atherosclerotic events. It is controversial, however, as to whether inhibiting CRP synthesis would have any direct anti-inflammatory effects in humans.
  
  
  RESULTS
  A placebo-controlled study was used to evaluate the effects of ISIS 329993 (ISIS-CRPR x) on the acute-phase response after endotoxin challenge in 30 evaluable subjects. Healthy adult males were randomly allocated to receive 6 injections over a 22-day period of placebo or active therapy with ISIS 329993 at 400- or 600-mg doses. Eligible subjects were subsequently challenged with a bolus of endotoxin (2 ng/kg). Inflammatory and hematological biomarkers were measured before and serially after the challenge. ISIS-CRPR x was well tolerated with no serious adverse events. Median CRP levels increased more than 50-fold from baseline 24 hours after endotoxin challenge in the placebo group. In contrast, the median increase in CRP levels was attenuated by 37% (400 mg) and 69% (600 mg) in subjects pretreated with ISIS-CRPR x (P<0.05 vs. placebo). All other aspects of the acute inflammatory response were similar between treatment groups.
  
  
  CONCLUSIONS
  Pretreatment of subjects with ISIS-CRPR x selectively reduced the endotoxin-induced increase in CRP levels in a dose-dependent manner, without affecting other components of the acute-phase response. These data demonstrate the specificity of antisense oligonucleotides and provide an investigative tool to further define the role of CRP in human pathological conditions.
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (R.N.).
authors.forename: Robert
authors.initials: R
authors.lastname: Noveck
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (E.G.S.).
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA (J.A.D.F., B.F.B., S.H., M.J.G., R.M.C.).
authors.forename: JoAnn D
authors.initials: JD
authors.lastname: Flaim
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA (J.A.D.F., B.F.B., S.H., M.J.G., R.M.C.).
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Baker
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA (J.A.D.F., B.F.B., S.H., M.J.G., R.M.C.).
authors.forename: Steve
authors.initials: S
authors.lastname: Hughes
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA (J.A.D.F., B.F.B., S.H., M.J.G., R.M.C.).
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA (J.A.D.F., B.F.B., S.H., M.J.G., R.M.C.).
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.affiliation: Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (P.R.).
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
mesh_terms: D000210:Acute-Phase Reaction; D000293:Adolescent; D000328:Adult; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000097:blood / Q000187:drug effects; D019040:E-Selectin / Q000097:blood / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D005338:Fibrin Fibrinogen Degradation Products / Q000187:drug effects; D064368:Healthy Volunteers; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D009841:Oligonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010446:Peptide Fragments / Q000097:blood / Q000187:drug effects; D011516:Prothrombin / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000187:drug effects; D055815:Young Adult
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019040:E-Selectin; D004731:Endotoxins; D005338:Fibrin Fibrinogen Degradation Products; C508600:IL6 protein, human; C000601948:ISIS 329993; D015850:Interleukin-6; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C036309:fibrin fragment D; C045879:prothrombin fragment 1.2; D011516:Prothrombin; D002097:C-Reactive Protein
keywords: C‐reactive protein; acute phase response; antisense inhibitor; endotoxin; healthy volunteers