RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Nat Rev Drug Discov. 2024 May;23(5):341-364. doi: 10.1038/s41573-024-00912-9. Epub 2024 Apr 3.
More than 25 years after its discovery, the post-transcriptional gene regulation mechanism termed RNAi is now transforming pharmaceutical development, proved by the recent FDA approval of multiple small interfering RNA (siRNA) drugs that target the liver. Synthetic siRNAs that trigger RNAi have the potential to specifically silence virtually any therapeutic target with unprecedented potency and durability. Bringing this innovative class of medicines to patients, however, has been riddled with substantial challenges, with delivery issues at the forefront. Several classes of siRNA drug are under clinical evaluation, but their utility in treating extrahepatic diseases remains limited, demanding continued innovation. In this Review, we discuss principal considerations and future directions in the design of therapeutic siRNAs, with a particular emphasis on chemistry, the application of informatics, delivery strategies and the importance of careful target selection, which together influence therapeutic success.
RNAi 是一种在后转录水平调控基因的机制，自发现以来已有 25 年以上的历史，目前正改变着药物研发领域，这一点已被最近 FDA 批准的多种针对肝脏的小干扰 RNA（siRNA）药物所证明。触发 RNAi 的合成 siRNA 具有以空前的效力和持久性特异性沉默几乎任何治疗靶标的潜力。然而，将这种创新药物带给患者充满了巨大的挑战，其中首要的就是输送问题。有几类 siRNA 药物正在临床评估中，但它们在治疗肝外疾病方面的应用仍然有限，这需要持续的创新。在这篇综述中，我们讨论了治疗性 siRNA 设计中的主要考虑因素和未来方向，特别强调了化学、信息学的应用、输送策略以及仔细选择靶标，这些因素共同影响着治疗的成功。
