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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.

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