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Effects of an Antisense Oligonucleotide Inhibitor of C‐Reactive Protein Synthesis on the Endotoxin Challenge Response in Healthy Human Male Volunteers

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...

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Autores principales: Noveck, Robert, Stroes, Erik S. G., Flaim, JoAnn D., Baker, Brenda F., Hughes, Steve, Graham, Mark J., Crooke, Rosanne M., Ridker, Paul M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310401/
https://www.ncbi.nlm.nih.gov/pubmed/25012289
http://dx.doi.org/10.1161/JAHA.114.001084
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author Noveck, Robert
Stroes, Erik S. G.
Flaim, JoAnn D.
Baker, Brenda F.
Hughes, Steve
Graham, Mark J.
Crooke, Rosanne M.
Ridker, Paul M
author_facet Noveck, Robert
Stroes, Erik S. G.
Flaim, JoAnn D.
Baker, Brenda F.
Hughes, Steve
Graham, Mark J.
Crooke, Rosanne M.
Ridker, Paul M
author_sort Noveck, Robert
collection PubMed
description 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‐CRP(R)(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‐CRP(R)(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‐CRP(R)(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‐CRP(R)(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.
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spelling pubmed-43104012015-02-10 Effects of an Antisense Oligonucleotide Inhibitor of C‐Reactive Protein Synthesis on the Endotoxin Challenge Response in Healthy Human Male Volunteers Noveck, Robert Stroes, Erik S. G. Flaim, JoAnn D. Baker, Brenda F. Hughes, Steve Graham, Mark J. Crooke, Rosanne M. Ridker, Paul M J Am Heart Assoc Original Research 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‐CRP(R)(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‐CRP(R)(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‐CRP(R)(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‐CRP(R)(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. Blackwell Publishing Ltd 2014-07-10 /pmc/articles/PMC4310401/ /pubmed/25012289 http://dx.doi.org/10.1161/JAHA.114.001084 Text en © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/3.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Noveck, Robert
Stroes, Erik S. G.
Flaim, JoAnn D.
Baker, Brenda F.
Hughes, Steve
Graham, Mark J.
Crooke, Rosanne M.
Ridker, Paul M
Effects of an Antisense Oligonucleotide Inhibitor of C‐Reactive Protein Synthesis on the Endotoxin Challenge Response in Healthy Human Male Volunteers
title Effects of an Antisense Oligonucleotide Inhibitor of C‐Reactive Protein Synthesis on the Endotoxin Challenge Response in Healthy Human Male Volunteers
title_full Effects of an Antisense Oligonucleotide Inhibitor of C‐Reactive Protein Synthesis on the Endotoxin Challenge Response in Healthy Human Male Volunteers
title_fullStr Effects of an Antisense Oligonucleotide Inhibitor of C‐Reactive Protein Synthesis on the Endotoxin Challenge Response in Healthy Human Male Volunteers
title_full_unstemmed Effects of an Antisense Oligonucleotide Inhibitor of C‐Reactive Protein Synthesis on the Endotoxin Challenge Response in Healthy Human Male Volunteers
title_short Effects of an Antisense Oligonucleotide Inhibitor of C‐Reactive Protein Synthesis on the Endotoxin Challenge Response in Healthy Human Male Volunteers
title_sort effects of an antisense oligonucleotide inhibitor of c‐reactive protein synthesis on the endotoxin challenge response in healthy human male volunteers
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310401/
https://www.ncbi.nlm.nih.gov/pubmed/25012289
http://dx.doi.org/10.1161/JAHA.114.001084
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