核酸治疗时代的RNA干扰
RNA interference in the era of nucleic acid therapeutics.
作者信息
Jadhav Vasant, Vaishnaw Akshay, Fitzgerald Kevin, Maier Martin A
机构信息
Research & Development, Alnylam Pharmaceuticals, Cambridge, MA, USA.
出版信息
Nat Biotechnol. 2024 Mar;42(3):394-405. doi: 10.1038/s41587-023-02105-y. Epub 2024 Feb 26.
PMID:38409587
Abstract
Two decades of research on RNA interference (RNAi) have transformed a breakthrough discovery in biology into a robust platform for a new class of medicines that modulate mRNA expression. Here we provide an overview of the trajectory of small-interfering RNA (siRNA) drug development, including the first approval in 2018 of a liver-targeted siRNA interference (RNAi) therapeutic in lipid nanoparticles and subsequent approvals of five more RNAi drugs, which used metabolically stable siRNAs combined with N-acetylgalactosamine ligands for conjugate-based liver delivery. We also consider the remaining challenges in the field, such as delivery to muscle, brain and other extrahepatic organs. Today's RNAi therapeutics exhibit high specificity, potency and durability, and are transitioning from applications in rare diseases to widespread, chronic conditions.
摘要
二十年来对RNA干扰（RNAi）的研究已将一项生物学上的突破性发现转化为一个强大的平台，用于开发一类调节mRNA表达的新型药物。在此，我们概述了小干扰RNA（siRNA）药物的研发历程，包括2018年脂质纳米颗粒包裹的肝脏靶向性siRNA干扰（RNAi）疗法首次获批，以及随后另外五种RNAi药物的获批，这些药物使用了代谢稳定的siRNAs并结合N - 乙酰半乳糖胺配体用于基于偶联物的肝脏递送。我们还探讨了该领域尚存的挑战，比如向肌肉、大脑和其他肝外器官的递送。如今的RNAi疗法具有高特异性、高效力和持久性，正从罕见病应用向广泛的慢性病应用转变。
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本文引用的文献
1
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J Hepatol. 2023 Oct;79(4):924-932. doi: 10.1016/j.jhep.2023.05.023. Epub 2023 Jun 7.
2
Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial.降脂新药 inclisiran 在高心血管风险和高 LDL 胆固醇患者中的长期疗效和安全性（ORION-3）：ORION-1 试验 4 年开放标签扩展的结果。
Lancet Diabetes Endocrinol. 2023 Feb;11(2):109-119. doi: 10.1016/S2213-8587(22)00353-9. Epub 2023 Jan 5.
3
Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial.用于治疗遗传性转甲状腺素蛋白介导的淀粉样变性多发性神经病患者的 vutrisiran 的疗效和安全性：一项随机临床试验。
Amyloid. 2023 Mar;30(1):1-9. doi: 10.1080/13506129.2022.2091985. Epub 2022 Jul 23.
4
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5
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7
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8
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