Abstract
Due to their ability to promote positive effects across all of the lipoprotein classes, cholesteryl ester transfer protein (CETP) inhibitors are currently being developed as therapeutic agents for cardiovascular disease. In these studies, we compared an antisense oligonucleotide (ASO) inhibitor of CETP to the CETP small molecule inhibitor anacetrapib. In hyperlipidemic CETP transgenic (tg) mice, both drugs provided comparable reductions in total plasma cholesterol, decreases in CETP activity, and increases in HDL cholesterol. However, only mice treated with the antisense inhibitor showed an enhanced effect on macrophage reverse cholesterol transport, presumably due to differences in HDL apolipoprotein composition and decreases in plasma triglyceride. Additionally, the ASO-mediated reductions in CETP mRNA were associated with less accumulation of aortic cholesterol. These preliminary findings suggest that CETP ASOs may represent an alternative means to inhibit that target and to support their continued development as a treatment for cardiovascular disease in man.
Highlights
Due to their ability to promote positive effects across all of the lipoprotein classes, cholesteryl ester transfer protein (CETP) inhibitors are currently being developed as therapeutic agents for cardiovascular disease
Plasma samples from mice treated with the CETP antisense oligonucleotide (ASO) were more effective in inhibiting the exchange of radiolabeled cholesteryl ether from donor HDL to native apoB-bound lipoproteins over a 12 h period. These results suggest that the additional reductions in total cholesterol and TG in mice treated with the ASO could limit substrate available for exchange and provide a secondary means to inhibit CETP activity, and along with the enhanced association of apoA-I on HDL, might potentially account for the enhanced reverse cholesterol transport (RCT)
Once an optimal dose of CETP ASO was determined, further studies explored the effects on plasma lipids, HDL cholesterol (HDL-C), RCT, and aortic cholesterol accumulation
Summary
Due to their ability to promote positive effects across all of the lipoprotein classes, cholesteryl ester transfer protein (CETP) inhibitors are currently being developed as therapeutic agents for cardiovascular disease In these studies, we compared an antisense oligonucleotide (ASO) inhibitor of CETP to the CETP small molecule inhibitor anacetrapib. A large-scale meta-analysis of 92 studies with 113,833 subjects found increases in HDL-C associated with reductions in CETP protein and activity were atheroprotective [10] These observations were upheld in a genome-wide association study from the Women’s Genome Health Study in which single nucleotide polymorphisms in the CETP gene were associated with an increase in HDL-C and a lower risk of developing CVD [11]. Potent CETP SMIs such as anacetrapib and evacetrapib, drugs that do not possess obvious harmful side effects and exert positive effects across all lipoprotein subclasses [20, 21], still hold promise as beneficial therapeutic agents
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