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Alnylam Pharmaceuticals, Inc. Message Board

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  • thirdmeinvestor thirdmeinvestor Jul 23, 2006 12:27 PM Flag

    PCSK9 revisited

    The lesson of PCSK9 is clear. If we are to attain an 88% reduction in the incidence of coronary heart disease, we must lower LDL levels well before atherosclerosis has become advanced. If we start early enough, it may be sufficient to lower LDL-C concentration only to 100 mg/dl, a goal that should be attainable for most people. These individuals must be prepared for lifetime treatment. Early intervention is designed to prevent a heart attack that might not occur for many years.
    Statin drugs (and possibly apoB targeting RNA drugs) lower LDL, but they also increase the level of PCSK9 in liver cells.
    Admittedly, our knowledge of the pathogenesis of atherosclerosis is incomplete, and more research is needed. We do not know precisely how LDL particles cause the inflammatory and proliferative lesions of the atherosclerotic plaque. Although we measure LDL by its cholesterol content, the most toxic component may be its fatty acids or phospholipids. Also, we cannot be certain that the atherogenic effect of PCSK9 is due solely to its LDL-elevating action. It is possible that PCSK9 also exerts a direct toxic effect on the arterial wall and that loss-of-function mutations reduce atheroscle-rosis by avoiding this toxicity as well as by lowering LDL levels. Despite these unanswered questions, the data on PCSK9 are consistent with the extensive genetic, epidemiologic, experimental, and therapeutic data that justify an aggressive public health program aimed at lowering LDL levels before the atherosclerotic process has become advanced. Early intervention may well put an end to the epidemic of coronary heart disease that ravaged Western populations in the 20th century.

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