King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK.
Eur Heart J. 2022 Nov 14;43(43):4548-4561. doi: 10.1093/eurheartj/ehac463.
Novel bio-therapeutic agents that harness the properties of small, non-coding nucleic acids hold great promise for clinical applications. These include antisense oligonucleotides that inhibit messenger RNAs, microRNAs (miRNAs), or long non-coding RNAs; positive effectors of the miRNA pathway (short interfering RNAs and miRNA mimics); or small RNAs that target proteins (i.e. aptamers). These new therapies also offer exciting opportunities for cardiovascular diseases and promise to move the field towards more precise approaches based on disease mechanisms. There have been substantial advances in developing chemical modifications to improve the in vivo pharmacological properties of antisense oligonucleotides and reduce their immunogenicity. Carrier methods (e.g. RNA conjugates, polymers, and lipoplexes) that enhance cellular uptake of RNA therapeutics and stability against degradation by intracellular nucleases are also transforming the field. A number of small non-coding RNA therapies for cardiovascular indications are now approved. Moreover, there is a large pipeline of therapies in clinical development and an even larger list of putative therapies emerging from pre-clinical studies. Progress in this area is reviewed herein along with the hurdles that need to be overcome to allow a broader clinical translation.
新型生物治疗药物利用小非编码核酸的特性，为临床应用带来了巨大的希望。这些药物包括抑制信使 RNA、微小 RNA（miRNA）或长非编码 RNA 的反义寡核苷酸；miRNA 途径的正效应物（短干扰 RNA 和 miRNA 模拟物）；或靶向蛋白质的小 RNA（即适体）。这些新疗法还为心血管疾病提供了令人兴奋的机会，并有望使该领域朝着基于疾病机制的更精确方法发展。在开发化学修饰以改善反义寡核苷酸的体内药理学性质和降低其免疫原性方面已经取得了实质性进展。增强 RNA 治疗剂细胞摄取和抵抗细胞内核酸酶降解的稳定性的载体方法（例如 RNA 缀合物、聚合物和脂质体）也正在改变该领域。目前已有多种用于心血管适应症的小非编码 RNA 疗法获得批准。此外，还有大量疗法正在临床开发中，还有更多的潜在疗法正在从临床前研究中涌现。本文综述了这一领域的进展，以及为了实现更广泛的临床转化需要克服的障碍。
