Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China.
Drug Des Devel Ther. 2021 Feb 22;15:721-733. doi: 10.2147/DDDT.S288859. eCollection 2021.
RNAi therapeutics have been growing. Patisiran and givosiran, two siRNA-based drugs, were approved by the Food and Drug Administration in 2018 and 2019, respectively. However, there is rare news on the advance of miRNA drugs (another therapeutic similar to siRNA drug). Here we report the existing obstacles of miRNA therapeutics by analyses for resources available in a drug target perspective, despite being appreciated when it began. Only 10 obtainable miRNA drugs have been in clinical trials with none undergoing phase III, while over 60 siRNA drugs are in complete clinical trial progression including two approvals. We mechanically compared the two types of drug and found that their major distinction lay in the huge discrepancy of the target number of two RNA molecules, which was caused by different complementary ratios. One miRNA generally targets tens and even hundreds of genes. We named it "too many targets for miRNA effect" (TMTME). Further, two adverse events from the discontinuation of two miRNA therapeutics were exactly answered by TMTME. In summary, TMTME is inevitable because of the special complementary approach between miRNA and its target. It means that miRNA therapeutics would trigger a series of unknown and unpreventable consequences, which makes it a considerable alternative for application.
RNAi 疗法不断发展。Patisiran 和 givosiran 是两种基于 siRNA 的药物，分别于 2018 年和 2019 年获得美国食品和药物管理局的批准。然而，miRNA 药物（另一种与 siRNA 药物类似的治疗方法）的进展鲜有报道。尽管 miRNA 疗法在开始时受到了重视，但我们从药物靶点的角度分析了现有的资源，报告了 miRNA 疗法存在的障碍。尽管 miRNA 疗法在开始时受到了重视，但只有 10 种可获得的 miRNA 药物在临床试验中进行，没有一种进入 III 期，而超过 60 种 siRNA 药物在完全的临床试验进展中，包括两种批准。我们从机械的角度比较了这两种药物，发现它们的主要区别在于两种 RNA 分子的靶点数量存在巨大差异，这是由于互补比例不同造成的。一个 miRNA 通常靶向数十甚至数百个基因。我们称之为“miRNA 效应的靶点太多”（TMTME）。此外，两种 miRNA 疗法因停药而出现的两种不良事件也正好被 TMTME 所解释。总之，由于 miRNA 与其靶标之间的特殊互补方式，TMTME 是不可避免的。这意味着 miRNA 疗法将引发一系列未知且不可预防的后果，这使得它成为一种值得考虑的替代应用。
