High blood cholesterol, or hypercholesterolemia, is a major risk factor for atherosclerosis and heart disease. Some patients using current cholesterol-lowering therapies are still unable to reach target LDL level recommendations, demonstrating the need for additional therapeutic targets to further reduce hypercholesterolemia. Proprotein convertase subtilisin-like kexin type 9 (PCSK9), a protease that decreases LDL receptor levels in the liver, is an interesting potential target since PCSK9 gain-of-function mutations increase plasma cholesterol levels, and PCSK9 loss-of-function mutations decrease cholesterol levels.
Frank-Kamenetsky et al. demonstrate the therapeutic potential of RNAi to target PCSK9 in rat and mouse models, including transgenics expressing the human PCSK9 gene. The siRNA treatment effectively lowered LDL via specific silencing of PCSK9. RNAi silencing of PCSK9 also effectively lowered LDL in cynomolgus monkeys, without affecting HDL or triglyceride levels. These results indicate potential for RNAi therapies and the targeting of PCSK9 as a way to treat high cholesterol.
