No small task: therapeutic targeting of Lp(a) for cardiovascular disease.
No small task: therapeutic targeting of Lp(a) for cardiovascular disease.
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任务艰巨：Lp(a) 治疗心血管疾病的靶向治疗。
DOI：
10.1016/s0140-6736(16)31329-0
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Feinberg,MarkW
中科院分区：
文献类型：
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作者：
Feinberg,MarkW
尽管作出了一级和二级预防努力，但缺血性心血管疾病仍然是全世界发病率和死亡率的主要原因。全基因组关联研究在过去十年中已经揭示了数十个与冠状动脉疾病风险增加相关的基因座，这些基因座可能成为潜在的治疗新靶点。其中包括影响低密度脂蛋白代谢的基因，如LPA，它编码糖蛋白载脂蛋白(A)，这是类低密度脂蛋白颗粒脂蛋白(A)(Lp[a])的主要成分。一些观察表明，靶向Lp(A)可以提供一种独特的策略来降低残余心血管风险。血浆Lp(A)浓度的增加与冠状动脉疾病风险的增加显著相关，1孟德尔基因随机研究检测LPA基因或其附近的单核苷酸多态(SNPs)强烈表明，遗传增加的Lp(A)会导致冠状动脉疾病风险的增加。2、3对尽管低密度脂蛋白-胆固醇(LDL-C)低于100 mg/dL，但脂蛋白(A)浓度较高的患者进行的血液学研究显示，显著减少了主要心血管不良事件，这一效果归因于Lp(A)的降低，而不是低密度脂蛋白-C。4、5最后，对他汀类药物的研究表明，尽管低密度脂蛋白-C和主要不良心血管事件显著降低，但Lp(A)血浆浓度并未降低。6，7 Gwas还发现LPA基因及其附近的SNP与心肌梗死、卒中和钙化性主动脉瓣疾病显著相关，提示Lp(A)可能参与了广泛的心血管疾病状态。8在《柳叶刀》杂志上，Nicholas Viney和他的同事9报告了两个针对Lp(A)的反义寡核苷酸(ASO)的随机、安慰剂对照试验的结果，这些试验使用不同的改良化学物质。在第一项研究中，2期试验中，每周一次皮下注射100-300毫克的Ionis-APO(A)Rx(剂量为100-300毫克)连续12周，与服用安慰剂的受试者相比，脂蛋白(A)、氧化磷脂、低密度脂蛋白-C和载脂蛋白B(ApoB)浓度的下降幅度更大；值得注意的是，三分之二的受试者已经在服用他汀类药物或调脂治疗。Ionis-APO(A)Rx还减少了单核细胞迁移(加入培养物中跨内皮细胞迁移的单核细胞的百分比)，这表明在导致动脉粥样硬化的关键炎症过程中有有益的效果。在第二项研究中，1/2a期第一人试验招募了58名Lp(A)浓度升高的健康参与者，22天内单次和多次皮下注射Ionis-APO(A)-LRx与安慰剂相比降低了Lp(A)浓度。在多剂量队列中的Apo(A)-LRx治疗导致10毫克组(平均降低66%[SD 21.8])、20毫克组(80%[13.7])和40毫克组(92%[6.5])的Lp(A)浓度在第36天内显著降低(与安慰剂组相比，p=0.0007)。这些减少持续了3-4个月，单剂量组中近一半的参与者和多剂量组中高达五分之四的参与者持续了这些减少。Ionis-APO(A)-LRx的效力似乎比Ionis-APO(A)Rx高30倍。最高单剂量(120毫克)和多剂量(20毫克和40毫克)组的受试者氧化磷脂、低密度脂蛋白和载脂蛋白B的平均降幅也显著高于安慰剂组。新出现的认识是氧化磷脂和载脂蛋白B共同诱导血管壁炎症，这表明
Despite primary and secondary prevention efforts, ischaemic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Genome-wide association studies (GWAS) over the past decade have revealed dozens of loci associated with increased risk of coronary artery disease that could serve as potential new targets for therapy. Among them are genes that affect LDL metabolism such as LPA, which encodes for the glycoprotein apolipoprotein (a), a principle component of the LDL-like particle lipoprotein (a)(Lp [a]). Several observations suggest that targeting of Lp (a) could offer a unique strategy to decrease residual cardiovascular risk. Increased plasma concentrations of Lp (a) are significantly associated with increased risk of coronary artery disease, 1 and mendelian gene randomisation studies examining single nucleotide polymorphisms (SNPs) in or nearby the LPA gene strongly suggest that genetically increased Lp (a) results in increased risk of coronary artery disease. 2, 3 Apheresis studies of patients with high Lp (a) concentrations, despite LDL cholesterol (LDL-C) lower than 100 mg/dL, demonstrate significantly reduced major adverse cardiovascular events, an effect ascribed to lowering of Lp (a) and not LDL-C. 4, 5 Finally, studies of statins have revealed that despite a significant reduction in LDL-C and major adverse cardiovascular events, Lp (a) plasma concentrations are not reduced. 6, 7 GWAS have also identified SNPs in or nearby the LPA gene to be significantly associated with myocardial infarction, stroke, and calcific aortic valve disease, suggesting the potential involvement of Lp (a) in a broad range of cardiovascular disease states. 8 In The Lancet, Nicholas Viney and colleagues9 report findings from two randomised, placebo-controlled trials of two antisense oligonucleotides (ASOs) with different modified chemistries targeting Lp (a). In the first study, a phase 2 trial, subcutaneous IONIS-APO (a) Rx (dose100–300 mg) once a week for 12 weeks led to greater reductions in Lp (a), oxidised phospholipids, LDL-C, and apolipoprotein B (apoB) concentrations than did placebo in 64 participants with high or very high Lp (a) concentrations; noteworthy since two-thirds were already taking statins or lipid-modulating therapies. IONIS-APO (a) Rx also reduced monocyte migration (percentage of monocytes added to the culture that transmigrated across the endothelium), suggesting beneficial effects on a key inflammatory process leading to atherogenesis.In the second study, a phase 1/2a first-in-man trial enrolling 58 healthy participants with elevated Lp (a) concentrations, both single and multiple doses of subcutaneous IONIS-APO (a)-LRx over 22 days reduced Lp (a) concentrations compared with placebo. APO (a)-LRx treatment in the multiple-dose cohort resulted in potent reductions in Lp (a) concentrations in the 10 mg group (mean reduction 66%[SD 21· 8]), 20 mg group (80%[13· 7]), and 40 mg group (92%[6· 5]) by day 36 (p= 0· 0007 for all vs placebo). These reductions were sustained over 3–4 months by nearly half of participants in the single-dose groups and up to four-fifths of those in multiple-dose groups. IONIS-APO (a)-LRx seemed to have an up to 30-times higher potency than IONIS-APO (a) Rx. Participants in the highest singledose (120 mg) and multiple-dose (20 mg and 40 mg) groups also had significantly greater mean reductions in oxidised phospholipids, LDL-C, and apoB than had those assigned to placebo. The emerging recognition that oxidised phospholipids and apoB conspire to induce inflammation in the vessel wall suggests that