Abstract 1204: Endothelial Lipase Antisense Inhibitors Increase Plasma HDL Levels in Hyperlipidemic Mice
The inverse correlation between plasma high density lipoprotein (HDL-C) levels and coronary artery disease supports the potential therapeutic benefit of agents specifically designed to raise HDL-C. Several new targets are currently being evaluated in an effort to raise HDL levels, and endothelial lipase (EL) represents one such example. EL is a member of the lipase family and is known to modulate phospholipid content of HDL-C by catalyzing the hydrolysis of HDL-C, thus accelerating it’s clearance from the circulation. Studies in EL knockout mice revealed that, in addition to increasing plasma HDL-C levels, these mice also display a marked decrease in the atherosclerotic progression relative to normal animals. For this reason, we designed a series of antisense oligonucleotides (ASO) complementary to both mouse and hamster EL genes to determine their pharmacological effects. Following systemic administration, ASO predominantly distribute to the liver, but also accumulate within atherosclerotic plaques and other tissues. In our first study, we administered murine-specific EL ASOs intraperitoneally (i.p.) twice-weekly at 50 mg/kg/wk for 6 weeks. This treatment regimen resulted in an 80% reduction in hepatic EL mRNA expression, while a 50% reduction was achieved in heart EL mRNA. In addition, this degree of EL suppression produced a 23% increase in HDL-C and a 42% reduction in plasma triglyceride levels. A second study was recently performed in lean hamsters where a 72% reduction in hepatic and heart mRNA levels was observed after 6 week i.p. administration using hamster-specific EL ASOs (50 mg/kg/week). In conclusion, data generated from multiple species provide compelling evidence that EL may indeed represent a promising new therapeutic strategy for increasing atheroprotective HDL-C levels in man. Future studies will evalute the effect of antisense inhibition of EL in appropriate models of atherosclerosis.