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. METHODS AND 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. CONCLUSION: 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.
Type
Journal articleSubject
C‐reactive proteinacute phase response
antisense inhibitor
endotoxin
healthy volunteers
Acute-Phase Reaction
Adolescent
Adult
C-Reactive Protein
Chemokine CCL2
E-Selectin
Endotoxins
Fibrin Fibrinogen Degradation Products
Healthy Volunteers
Humans
Interleukin-6
Male
Oligonucleotides
Oligonucleotides, Antisense
Peptide Fragments
Prothrombin
Tumor Necrosis Factor-alpha
Young Adult
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https://hdl.handle.net/10161/11173Published Version (Please cite this version)
10.1161/JAHA.114.001084Publication Info
Noveck, Robert; Stroes, Erik SG; Flaim, JoAnn D; Baker, Brenda F; Hughes, Steve; Graham,
Mark J; ... Ridker, Paul M (2014). Effects of an antisense oligonucleotide inhibitor of C-reactive protein synthesis
on the endotoxin challenge response in healthy human male volunteers. J Am Heart Assoc, 3(4). 10.1161/JAHA.114.001084. Retrieved from https://hdl.handle.net/10161/11173.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Robert Joseph Noveck
Associate Professor of Medicine

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