Living the PCSK9 Adventure: from the Identification of a New Gene in Familial Hypercholesterolemia Towards a Potential New Class of Anticholesterol Drugs
Living the PCSK9 Adventure: from the Identification of a New Gene in Familial Hypercholesterolemia Towards a Potential New Class of Anticholesterol Drugs
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DOI：
10.1007/s11883-014-0439-8
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发表时间：
2014-09-01
影响因子：
5.8
通讯作者：
Boileau, Catherine
中科院分区：
文献类型：
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作者：
Abifadel, Marianne;Elbitar, Sandy;Boileau, Catherine
在我们通过鉴定第一个导致高胆固醇血症的突变发现蛋白转化酶枯草杆菌/酶切蛋白9型（PCSK9）参与胆固醇代谢的十年后，PCSK9已成为胆固醇和心血管疾病中最有希望的靶点之一。这项具有挑战性的高胆固醇血症遗传学研究为世界各地的大量研究铺平了道路，这些研究允许表征PCSK9，其表达，其对降低LDL受体丰度的影响，以及识别低胆固醇血症中的功能丧失突变。我们强调了这一冒险的不同步骤，并回顾了已发表的临床试验，特别是抗pcsk9抗体evolocumab （AMG 145）和alirocumab (SAR236553/REGN727)，它们处于III期试验。降低低密度脂蛋白胆固醇水平的有希望的结果增加了PCSK9冒险的希望，在大规模和长期进行的III期研究评估疗效和安全性之后，将导致新的抗胆固醇药物类别。
A decade after our discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in cholesterol metabolism through the identification of the first mutations leading to hypercholesterolemia, PCSK9 has become one of the most promising targets in cholesterol and cardiovascular diseases. This challenging work in the genetics of hypercholesterolemia paved the way for a plethora of studies around the world allowing the characterization of PCSK9, its expression, its impact on reducing the abundance of LDL receptor, and the identification of loss-of-function mutations in hypocholesterolemia. We highlight the different steps of this adventure and review the published clinical trials especially those with the anti-PCSK9 antibodies evolocumab (AMG 145) and alirocumab (SAR236553/REGN727), which are in phase III trials. The promising results in lowering LDL cholesterol levels raise hope that the PCSK9 adventure will lead, after the large and long-term ongoing phase III studies evaluating efficacy and safety, to a new anticholesterol pharmacological class.