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Inhibiting C-reactive protein for the treatment of cardiovascular disease: promising evidence from rodent models
Alexander J Szalai1, Mark A McCrory1, Dongqi Xing2
1Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, 1825 University Boulevard, SHEL 214, Birmingham, Al 35294-2182, USA.
Insights
Antisense oligonucleotides (ASOs) targeting C-reactive protein (CRP) reduced CRP levels in rodents. This reduction improved cardiovascular function and pathology, suggesting CRP
Area of Science:
- Biomedical research
- Cardiovascular science
- Drug development
Background:
- Elevated C-reactive protein (CRP) predicts cardiovascular events, but its causal role remains unproven.
- Pharmacological inhibition is ideal for causal inference but lacks CRP-specific drugs.
- Antisense oligonucleotide (ASO) drugs target gene expression and accumulate in the liver, the primary site of CRP synthesis.
Purpose of the Study:
- To evaluate the efficacy of CRP-specific antisense oligonucleotides (ASOs) in reducing CRP levels and improving cardiovascular outcomes in preclinical models.
- To determine if pharmacological inhibition of CRP can mitigate cardiovascular damage.
Main Methods:
- Developed and administered rat and human CRP-specific ASOs to rodents with experimentally induced cardiovascular damage (myocardial infarction and carotid artery ligation).
- Measured blood CRP levels, assessed cardiac function and pathology post-myocardial infarction, and evaluated carotid artery patency after ligation.
Main Results:
- Rat CRP-specific ASO treatment for 4 weeks reduced blood CRP by over 60% and improved cardiac function and pathology after myocardial infarction.
- Human CRP-specific ASO treatment for 2 weeks in human CRP transgenic mice reduced blood CRP by over 70% and improved carotid artery patency.
- Demonstrated successful reduction of CRP and associated cardiovascular benefits using ASO technology.
Conclusions:
- CRP-specific ASOs effectively lower CRP levels in vivo.
- Pharmacological inhibition of CRP using ASOs shows promise in improving cardiovascular outcomes in preclinical models.
- These findings support the potential for CRP-specific ASOs in future placebo-controlled trials to elucidate CRP's causal role in cardiovascular disease.
Abstract:
Raised blood C-reactive protein (CRP) level is a predictor of cardiovascular events, but whether blood CRP is causal in the disease process is unknown. The latter would best be defined by pharmacological inhibition of the protein in the context of a randomized case-control study. However, no CRP specific drug is currently available so such a prospective study cannot be performed. Blood CRP is synthesized primarily in the liver and the liver is an organ where antisense oligonucleotide (ASO) drugs accumulate. Taking advantage of this we evaluated the efficacy of CRP specific ASOs in rodents with experimentally induced cardiovascular damage. Treating rats for 4 weeks with a rat CRP-specific ASO achieved >60% reduction of blood CRP. Notably, this effect was associated with improved heart function and pathology following myocardial infarction (induced by ligation of the left anterior descending artery). Likewise in human CRP transgenic mice treated for 2 weeks with a human CRP-specific ASO, blood human CRP was reduced by >70% and carotid artery patency was improved (2 weeks after surgical ligation). CRP specific ASOs might pave the way towards a placebo-controlled trial that could clarify the role of CRP in cardiovascular disease.
