Gareri Clarice, Polimeni Alberto, Giordano Salvatore, Tammè Laura, Curcio Antonio, Indolfi Ciro
Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy.
Mediterranea Cardiocentro, 80138 Naples, Italy.
J Clin Med. 2022 Jul 4;11(13):3884. doi: 10.3390/jcm11133884.
The burden of atherosclerotic disease worldwide necessitates implementing the treatment of its risk factors. Among them, hypercholesterolemia has a central role. In addition to conventional small organic compounds and the recently introduced monoclonal antibodies, new technologies are arising such as the antisense oligonucleotides and small interfering RNAs (siRNAs) that operate upstream, blocking the mRNA translation of the proteins specifically involved in lipid metabolism. In this review, we briefly explain the mechanisms of action of these molecules and discuss the difficulties related to their in vivo use as therapeutical agents. We go over the oligonucleotides tested in clinical trials that could potentially revolutionize the care of patients by acting on proteins involved in the lipoprotein metabolism and regulation, namely: angiopoietin-like protein 3 (ANGPTL3); lipoprotein a (Lp(a)); apolipoprotein B (Apo B); apolipoprotein C III (Apo C-III); and proprotein convertase subtilisin-kexin type 9 (PCSK9). Finally, the differences between ASOs and siRNAs, their future possible clinical applications, and the role of Inclisiran, a siRNA direct against PCSK9 to reduce LDL-C, were reviewed in detail.
全球范围内动脉粥样硬化疾病的负担使得有必要对其风险因素进行治疗。其中，高胆固醇血症起着核心作用。除了传统的小分子有机化合物和最近推出的单克隆抗体外，诸如反义寡核苷酸和小干扰RNA（siRNA）等新技术也不断涌现，它们作用于上游，阻断特定参与脂质代谢的蛋白质的mRNA翻译。在本综述中，我们简要解释这些分子的作用机制，并讨论其作为治疗药物在体内使用时所面临的困难。我们回顾了在临床试验中测试的寡核苷酸，这些寡核苷酸可能通过作用于参与脂蛋白代谢和调节的蛋白质，即血管生成素样蛋白3（ANGPTL3）、脂蛋白a [Lp(a)]、载脂蛋白B（Apo B）、载脂蛋白C III（Apo C-III）和枯草溶菌素9型前蛋白转化酶（PCSK9），从而彻底改变患者的治疗方式。最后，详细综述了反义寡核苷酸（ASO）和小干扰RNA（siRNA）之间的差异、它们未来可能的临床应用，以及针对PCSK9以降低低密度脂蛋白胆固醇（LDL-C）的小干扰RNA药物Inclisiran的作用。
