El Khoury Petra, Elbitar Sandy, Ghaleb Youmna, Khalil Yara Abou, Varret Mathilde, Boileau Catherine, Abifadel Marianne
LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris Cedex 18, France.
Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie Santé, Saint Joseph University, Beirut, Lebanon.
Curr Atheroscler Rep. 2017 Oct 17;19(12):49. doi: 10.1007/s11883-017-0684-8.
In 2003, Abifadel et al. (Nat. Genet. 34:154-156, 2003) identified PCSK9, encoding proprotein convertase subtilisin/kexin type 9, as the third causal gene for autosomal dominant hypercholesterolemia. This review focuses on the main steps from this major breakthrough in familial hypercholesterolemia (FH) to the latest clinical trials with the anti-PCSK9 antibodies.
The year 2015 was remarkable in cardiovascular disease through the field of cholesterol. Nearly 30 years after the discovery of statins, a new class of effective lipid-lowering drugs has emerged: the anti-PCSK9 antibodies. The discovery of the first gain-of-function mutations of PCSK9 in FH rapidly became the center of interest of researchers worldwide. Preclinical and clinical studies launched by pharmaceutical companies led to the first three anti-PCSK9 antibodies, two of which (evolocumab and alirocumab) reduce LDL cholesterol levels by 50-60% and received FDA and European Medicines Agency approvals in 2015 on top of statin therapy. Recently, results of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, the outcome trial of evolocumab over 2.2 years, showed a reduction of 15-20% in the risk of major cardiovascular outcomes in high-risk patients receiving statin therapy. Results of ODYSSEY OUTCOMES trial, evaluating the effect of alirocumab in 18,000 patients with established CVD are also eagerly awaited in 2018. The evolution of research on PCSK9, starting from the discovery of the first set of mutations in PCSK9 in FH in 2003, is an amazing example of successful translational research. It shows how rigorous and powered genetic analyses can lead to the discovery of a new class of lipid-lowering drugs that give hope in fighting high cholesterol levels and their cardiovascular complications.
2003年，阿比法德尔等人（《自然遗传学》，2003年第34卷：第154 - 156页）确定了编码前蛋白转化酶枯草杆菌蛋白酶/kexin 9型的PCSK9，为常染色体显性高胆固醇血症的第三个致病基因。本综述聚焦于从家族性高胆固醇血症（FH）这一重大突破到抗PCSK9抗体最新临床试验的主要步骤。
2015年在胆固醇领域的心血管疾病方面意义非凡。在他汀类药物发现近30年后，一类新的有效降脂药物出现了：抗PCSK9抗体。FH中PCSK9首个功能获得性突变的发现迅速成为全球研究人员关注的焦点。制药公司开展的临床前和临床研究催生了首批三种抗PCSK9抗体，其中两种（依洛尤单抗和阿利西尤单抗）可使低密度脂蛋白胆固醇水平降低50 - 60%，并于2015年在他汀类药物治疗基础上获得了美国食品药品监督管理局（FDA）和欧洲药品管理局的批准。最近，“PCSK9抑制剂在高危受试者中进一步心血管结局研究（FOURIER）”试验的结果显示，在接受他汀类药物治疗的高危患者中，依洛尤单抗进行2.2年的结局试验使主要心血管结局风险降低了15 - 20%。“ODYSSEY OUTCOMES”试验评估阿利西尤单抗对18000例已确诊心血管疾病患者的疗效，其结果也在2018年备受期待。从2003年FH中PCSK9首批突变的发现开始，PCSK9的研究进展是成功转化研究的一个惊人范例。它展示了严谨且有力的基因分析如何能促成一类新的降脂药物的发现，这类药物为对抗高胆固醇水平及其心血管并发症带来了希望。
