Fazoli Renata Tj, Drager Luciano F, Kalil-Filho Roberto, Generoso Giuliano
Centro de Cardiologia, Hospital Sirio-Libanes, São Paulo, Brasil.
Instituto do Coração, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil.
Drugs Context. 2024 Aug 20;13. doi: 10.7573/dic.2024-3-1. eCollection 2024.
The discovery of RNA interference in 1998 opened avenues for the manipulation of gene expression, leading to the development of small interfering RNA (siRNA) drugs. Patisiran, the first FDA-approved siRNA medication, targets hereditary transthyretin amyloidosis with polyneuropathy. Givosiran, lumasiran and nedosiran further expand siRNA applications in treating rare genetic diseases, demonstrating positive outcomes. In cardiology, inclisiran, approved for hypercholesterolaemia, showcases sustained reductions in LDL cholesterol levels. However, ongoing research aims to establish its impact on cardiovascular outcomes. Lipoprotein(a), an independent risk factor for atherosclerotic cardiovascular disease, has become a focus of siRNA therapies, precipitating the development of specific siRNA drugs like olpasiran, zerlasiran and lepodisiran, with promising reductions in lipoprotein(a) levels. Research to assess the effectiveness of these medications in reducing events is currently under way. Zodasiran and plozasiran address potential risk factors for cardiovascular diseases, targeting triglyceride-rich lipoproteins. Zilebesiran, which targets hepatic angiotensinogen mRNA, has demonstrated a dose-related reduction in serum angiotensinogen levels, thereby lowering blood pressure in patients with systemic arterial hypertension. The evolving siRNA methodology presents a promising future in cardiology, with ongoing studies assessing its effectiveness in various conditions. In the future, larger studies will provide insights into improvements in cardiovascular outcomes, long-term safety and broader applications in the general population. This review highlights the historical timeline of the development of siRNA-based drugs, their clinical indications, potential side-effects and future perspectives.
1998年RNA干扰的发现为基因表达调控开辟了道路，推动了小干扰RNA（siRNA）药物的发展。首款获美国食品药品监督管理局（FDA）批准的siRNA药物帕替拉韦，用于治疗遗传性转甲状腺素蛋白淀粉样变多发性神经病。吉沃西坦、鲁马西坦和内多西坦进一步拓展了siRNA在治疗罕见遗传病方面的应用，并显示出积极效果。在心脏病学领域，获批用于治疗高胆固醇血症的英克西兰可使低密度脂蛋白胆固醇水平持续降低。然而，正在进行的研究旨在确定其对心血管结局的影响。脂蛋白(a)是动脉粥样硬化性心血管疾病的独立危险因素，已成为siRNA疗法的重点研究对象，促使olpasiran、zerlasiran和lepodisiran等特异性siRNA药物的研发，有望降低脂蛋白(a)水平。目前正在开展评估这些药物降低心血管事件有效性的研究。佐达西坦和普洛西坦针对富含甘油三酯的脂蛋白这一心血管疾病潜在危险因素。靶向肝血管紧张素原mRNA的齐乐贝西坦已证明可使血清血管紧张素原水平呈剂量依赖性降低，从而降低系统性动脉高血压患者的血压。不断发展的siRNA技术在心脏病学领域展现出广阔前景，正在进行的研究评估其在各种情况下的有效性。未来，规模更大的研究将深入了解心血管结局的改善情况、长期安全性以及在普通人群中的更广泛应用。本综述重点介绍了基于siRNA的药物的发展历史、临床适应证、潜在副作用及未来展望。
