由PCSK9功能获得性突变引起的常染色体显性高胆固醇血症的特征及其用PCSK9单克隆抗体阿利西尤单抗的特异性治疗。
Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody.
作者信息
Hopkins Paul N, Defesche Joep, Fouchier Sigrid W, Bruckert Eric, Luc Gérald, Cariou Bertrand, Sjouke Barbara, Leren Trond P, Harada-Shiba Mariko, Mabuchi Hiroshi, Rabès Jean-Pierre, Carrié Alain, van Heyningen Charles, Carreau Valérie, Farnier Michel, Teoh Yee P, Bourbon Mafalda, Kawashiri Masa-Aki, Nohara Atsushi, Soran Handrean, Marais A David, Tada Hayato, Abifadel Marianne, Boileau Catherine, Chanu Bernard, Katsuda Shoji, Kishimoto Ichiro, Lambert Gilles, Makino Hisashi, Miyamoto Yoshihiro, Pichelin Matthieu, Yagi Kunimasa, Yamagishi Masakazu, Zair Yassine, Mellis Scott, Yancopoulos George D, Stahl Neil, Mendoza Johanna, Du Yunling, Hamon Sara, Krempf Michel, Swergold Gary D
出版信息
Circ Cardiovasc Genet. 2015 Dec;8(6):823-31. doi: 10.1161/CIRCGENETICS.115.001129. Epub 2015 Sep 15.
BACKGROUND
Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported.
METHODS AND RESULTS
We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001).
CONCLUSIONS
PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients.
CLINICAL TRIAL REGISTRATION
URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.
背景
携带前蛋白转化酶枯草溶菌素9（PCSK9）基因功能获得性（GOF）突变的患者患有罕见的常染色体显性高胆固醇血症。然而，缺乏关于其临床特征和地理分布的研究数据。此外，尚未有针对该人群的随机治疗研究报告。
方法与结果
我们在一项跨国回顾性横断面观察性研究中汇总了PCSK9 GOF突变携带者的临床特征。然后，我们对13例患者进行了一项随机安慰剂对照、双盲研究，这些患者代表4种不同的PCSK9 GOF突变，在基线时接受当前降脂治疗，低密度脂蛋白胆固醇（LDL-C）≥70 mg/dL，每2周皮下注射150 mg阿利西尤单抗。观察性研究：在164例患者中，分布于整个基因的16种不同PCSK9 GOF突变与未治疗的LDL-C水平的不同严重程度相关。冠状动脉疾病很常见（33%；平均发病年龄49.4岁），与低密度脂蛋白受体（LDLR）突变携带者（n = 2126）或载脂蛋白B（n = 470）基因匹配携带者相比，未治疗的LDL-C浓度更高。干预性研究：在随机分配接受阿利西尤单抗治疗的PCSK9 GOF突变患者中，2周时LDL-C较基线平均降低百分比为62.5%（P < 0.0001），与接受安慰剂治疗的PCSK9 GOF突变患者相比降低了5３.7%（P = 0.0009；主要终点）。在所有受试者接受8周阿利西尤单抗治疗后，LDL-C较基线降低了73%（P < 0.0001）。
结论
PCSK9 GOF突变携带者的LDL-C水平升高，有过早发生心血管疾病的高风险。PCSK9抗体阿利西尤单抗可显著降低LDL-C水平，且在这些患者中似乎耐受性良好。
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