基于 RNAi 的治疗药物的现状和未来方向。

The current state and future directions of RNAi-based therapeutics.

机构信息

Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.

Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA, USA.

出版信息

Nat Rev Drug Discov. 2019 Jun;18(6):421-446. doi: 10.1038/s41573-019-0017-4.

DOI:10.1038/s41573-019-0017-4

PMID:30846871

Abstract

The RNA interference (RNAi) pathway regulates mRNA stability and translation in nearly all human cells. Small double-stranded RNA molecules can efficiently trigger RNAi silencing of specific genes, but their therapeutic use has faced numerous challenges involving safety and potency. However, August 2018 marked a new era for the field, with the US Food and Drug Administration approving patisiran, the first RNAi-based drug. In this Review, we discuss key advances in the design and development of RNAi drugs leading up to this landmark achievement, the state of the current clinical pipeline and prospects for future advances, including novel RNAi pathway agents utilizing mechanisms beyond post-translational RNAi silencing.

摘要

RNA 干扰 (RNAi) 途径几乎在所有人类细胞中调节 mRNA 的稳定性和翻译。小双链 RNA 分子可以有效地触发特定基因的 RNAi 沉默，但它们的治疗用途面临着涉及安全性和效力的众多挑战。然而，2018 年 8 月标志着该领域的一个新时代，美国食品和药物管理局批准了 patisiran，这是第一种基于 RNAi 的药物。在这篇综述中，我们讨论了导致这一里程碑式成就的 RNAi 药物设计和开发方面的关键进展，当前临床流水线的状况以及未来进展的前景，包括利用超越翻译后 RNAi 沉默的机制的新型 RNAi 途径药物。