RNA-targeted therapeutics for management of circulating cholesterol concentration: current state and perspectives
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摘要: 低密度脂蛋白胆固醇(LDL-C)是防治动脉粥样硬化性心血管疾病的主要靶点。随着LDL-C目标值不断降低，现有的包括他汀类、依折麦布在内的小分子降胆固醇药物的作用短暂、特异性差，已不能满足临床需求。相反，基于基因沉默或基因编辑机制，特别是利用小干扰RNA(siRNA)或反义寡核苷酸(ASO)选择性沉默在脂质代谢过程中起关键作用的基因(如PCSK9)的核酸疗法，可实现长期有效甚至治愈。先进的肝脏靶向递送技术(如核酸与N-乙酰半乳糖胺耦联)更是极大提高了靶向RNA药物的稳定性、特异性和安全性，降低了药物剂量，也减少了脱靶效应。目前已有多种靶向RNA的降胆固醇药物应用于临床，标志着精准降脂的新时代已经到来，期待后续的临床研究在解决与血脂相关的剩余心血管风险方面取得重大突破。Abstract: Low density lipoprotein cholesterol(LDL-C) remained the main target for the prevention and treatment of atherosclerotic cardiovascular disease. With the continuous reduction of LDL-C target value, the existing small molecule cholesterol-lowering drugs, including statins and ezetimibe, have a transient effects and poor specificity, and can no longer meet the clinical needs. Conversely, nucleic acid therapeutics based on gene silencing or gene editing mechanisms, particularly using small interference RNA or antisense oligonucleotides to selectively silence genes(such as PCSK9) that play a key role in lipid metabolism, can achieve long-term effectiveness and even cure. Advanced liver-targeted delivery techniques greatly improved the stability, specificity, and safety of RNA-targeted drugs, such as the coupling of nucleic acids to N-acetyl-galactosamine, which reduced drug doses and off-target effects. At present, a variety of RNA-targeted cholesterol-lowering drugs have been applied to the clinic, marking the arrival of a new era of accurate lipid-lowering. It is expected that the follow-up clinical research will make a major breakthrough in solving the residual cardiovascular risks associated with blood lipids.
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表 1 美国FDA批准的基于RNA的疗法
Table 1. RNA-based therapies approved by FDA
药物 批准日期 适应证 Fomivirsen 1998年 巨细胞病毒性视网膜炎 Pegaptinib 2004年 新生血管性年龄相关性黄斑变性 Mipomersen 2013年 家族性高胆固醇血症 Etplirsen 2016年 杜氏肌营养不良 Defibrotide 2016年 肝小静脉闭塞性疾病 Patisiran 2018年 遗传性转甲状腺素蛋白介导的淀粉样变性的多发性神经病 Givosiran 2019年 急性肝卟啉症 Inclisiran 2021年 杂合子家族性高胆固醇血症或临床动脉粥样硬化性心血管疾病 
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表 2 Inclisiran与PCSK9单克隆抗体的比较
Table 2. Comparison of Inclisiran and PCSK9 monoclonal antibodies
项目 Inclisiran 依洛尤单抗和阿利西尤单抗 作用机制 抑制PCSK9的翻译 抑制PCSK9与LDLR的结合 靶点位置 肝细胞内 细胞外 给药方式 皮下注射 皮下注射 给药频率 1次/6个月 1次/2~4周 对PCSK9水平的影响 减少 增加 LDLR：低密度脂蛋白受体。
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表 3 Inclisiran的重要临床研究
Table 3. Important clinical studies of Inclisiran
研究 阶段 研究对象 主要终点 对照 随访时间 状态 ORION-1 Ⅱ LDL-C增高的ASCVD等危者 LDL-C ↓% 无 180 d 完成 ORION-2 Ⅱ HoFH LDL-C ↓% 无 180 d 完成 ORION-3 Ⅱ 完成ORION-1者 第210天LDL-C ↓% 依洛尤单抗 4年 准备 ORION-4 Ⅲ ASCVD MACE 安慰剂 5年 招募 ORION-5 Ⅲ HoFH LDL-C ↓% 安慰剂 720 d 准备 ORION-6 Ⅰ 肝损害 不同肝功能时的药代 无 180 d 完成 ORION-7 Ⅰ 肾损害 不同肾功能时的药代 无 60 d 完成 ORION-8 Ⅲ 开放标签，ORION-5、9、10和11的延续 LDL-C＜70 mg/dL和100 mg/dL的% 安慰剂 1080 d 准备 ORION-9 Ⅲ HeFH和LDL-C增高 LDL-C ↓% 安慰剂 510 d 完成 ORION-10 Ⅲ LDL-C高的ASCVD LDL-C ↓% 安慰剂 510 d 完成 ORION-11 Ⅲ LDL-C高的ASCVD或等危 LDL-C ↓% 安慰剂 510 d 完成 ORION-12 Ⅰ 健康人 Q-T间期和ECG变化 安慰剂 180 d 进行 ORION-13 Ⅲ 12~18岁的HoFH LDL-C ↓% 安慰剂 720 d 招募 ORION-14 Ⅰ 降脂治疗后LDL-C仍高的中国人 中国人的药代和LDL-C ↓% 安慰剂 90 d 招募 ORION-15 Ⅱ LDL-C高的日本人 日本人的药代和LDL-C ↓% 安慰剂 180 d 招募 ORION-16 Ⅲ 青少年HeFH，且LDL-C高 LDL-C ↓% 安慰剂 720 d 招募 ORION-17 Ⅲ 一级预防 ORION-18 Ⅲ LDL-C高的ASCVD或等危的亚洲人 LDL-C ↓% 安慰剂 360 d 招募 VICTORION-INITIATE Ⅲ LDL-C>70 mg/dL的ASCVD或等危 LDL-C ↓%和终止用他汀 常规 330 d 招募 VICTORION-INCEPTION Ⅲ 5周内发生ACS者 LDL-C ↓%，＜70 mg/dL的% 常规 360 d 招募 VICTORION-2 PREVENT Ⅲ 确诊的心血管病患者 3P-MACE(心血管死亡、非致死性心肌梗死和缺血性卒中) 安慰剂 6年 准备 ACS：急性冠状动脉综合征；ECG：心电图；MACE：主要心血管不良事件。
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表 4 血脂管理相关的RNA治疗
Table 4. RNA therapy related to lipid management
基于RNA的治疗 靶点 性质 修饰 CiVi007[13] PCSK9 ASO LNA Inclisiran [14] PCSK9 siRNA GalNAc偶联物 Mipomersen [15] Apo B100 ASO 添加2'-O-甲氧基乙基修饰的核糖 Pelacarsen[16] Apo(a) ASO GalNAc偶联物 Olpasiran [17] Apo(a) siRNA GalNAc偶联物 Vupanorsen[18] ANGPTL3 ASO GalNAc偶联物 ARO-ANG3[19] ANGPTL3 siRNA GalNAc偶联物 Volanesorsen [20] Apo C3 ASO 添加2'-O-甲氧基乙基修饰的核糖 ARO-APOC3[19] Apo C3 siRNA GalNAc偶联物 LNA：锁核酸。
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