Université Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000, Versailles, France.
SQY Therapeutics, Université de Versailles St-Quentin, Montigny le Bretonneux, France.
Drugs. 2020 Sep;80(14):1397-1415. doi: 10.1007/s40265-020-01363-3.
Neuromuscular disorders include a wide range of diseases affecting the peripheral nervous system, which are primarily characterized by progressive muscle weakness and wasting. While there were no effective therapies until recently, several therapeutic approaches have advanced to clinical trials in the past few years. Among these, the antisense technology aiming at modifying RNA processing and function has remarkably progressed and a few antisense oligonucleotides (ASOs) have now been approved. Despite these recent clinical successes, several ASOs have also failed and clinical programs have been suspended, in most cases when the route of administration was systemic, highlighting the existing challenges notably with respect to effective ASO delivery. In this review we summarize the recent advances and current status of antisense based-therapies for neuromuscular disorders, using successful as well as unsuccessful examples to highlight the variability of outcomes depending on the target tissue and route of administration. We describe the different ASO-mediated therapeutic approaches, including splice-switching applications, steric-blocking strategies and targeted gene knock-down mediated by ribonuclease H recruitment. In this overview, we discuss the merits and challenges of the current ASO technology, and discuss the future of ASO development.
神经肌肉疾病包括一系列影响周围神经系统的疾病，其主要特征是进行性肌肉无力和萎缩。虽然直到最近都没有有效的治疗方法，但过去几年中，已有几种治疗方法进入临床试验阶段。在这些方法中，针对 RNA 加工和功能修饰的反义技术取得了显著进展，已有几种反义寡核苷酸 (ASO) 获得批准。尽管这些最近的临床成功，一些 ASO 也失败了，临床项目也被暂停，在大多数情况下，当给药途径是全身性时，这突显了目前在有效 ASO 递送上存在的挑战。在这篇综述中，我们总结了神经肌肉疾病反义治疗的最新进展和现状，使用成功和失败的例子来强调根据目标组织和给药途径的不同，结果的可变性。我们描述了不同的 ASO 介导的治疗方法，包括剪接转换应用、空间位阻策略和通过核糖核酸酶 H 募集介导的靶向基因敲低。在这个综述中，我们讨论了当前 ASO 技术的优点和挑战，并讨论了 ASO 开发的未来。
