Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
Biochem Pharmacol. 2021 Jul;189:114432. doi: 10.1016/j.bcp.2021.114432. Epub 2021 Jan 26.
More than two decades after the natural gene-silencing mechanism of RNA interference was elucidated, small interfering RNA (siRNA)-based therapeutics have finally broken into the pharmaceutical market. With three agents already approved and many others in advanced stages of the drug development pipeline, siRNA drugs are on their way to becoming a standard modality of pharmacotherapy. The majority of late-stage candidates are indicated for rare or orphan diseases, whose patients have an urgent need for novel and effective therapies. Additionally, there are agents that have the potential to meet the need of a broader population. Inclisiran, for instance, is being developed for hypercholesterolemia and has shown benefit in patients who are uncontrolled even after maximal statin therapy. This review provides a brief overview of mechanisms of siRNA action, physiological barriers to its delivery and activity, and the most common chemical modifications and delivery platforms used to overcome these barriers. Furthermore, this review presents comprehensive profiles of the three approved siRNA drugs (patisiran, givosiran, and lumasiran) and the seven other siRNA candidates in Phase 3 clinical trials (vutrisiran, nedosiran, inclisiran, fitusiran, teprasiran, cosdosiran, and tivanisiran), summarizing their modifications and delivery strategies, disease-specific mechanisms of action, updated clinical trial status, and future outlooks.
在 RNA 干扰的天然基因沉默机制被阐明二十多年后，基于小干扰 RNA（siRNA）的治疗终于进入了制药市场。已有三种药物获得批准，还有许多其他药物处于药物开发管道的后期阶段，siRNA 药物正在成为一种标准的药物治疗模式。大多数晚期候选药物针对的是罕见病或孤儿病，这些患者迫切需要新型有效疗法。此外，还有一些药物有潜力满足更广泛人群的需求。例如，inclisiran 正在开发用于高胆固醇血症，并且在即使在最大剂量他汀类药物治疗后仍未得到控制的患者中显示出益处。本文简要概述了 siRNA 的作用机制、其递送至靶细胞的生理障碍，以及用于克服这些障碍的最常见的化学修饰和递药平台。此外，本文还全面介绍了三种已批准的 siRNA 药物（patisiran、givosiran 和 lumasiran）和七种处于 3 期临床试验的其他 siRNA 候选药物（vutrisiran、nedosiran、inclisiran、fitusiran、teprasiran、cosdosiran 和 tivanisiran），总结了它们的修饰和递药策略、针对特定疾病的作用机制、最新临床试验状态和未来展望。
