Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, Box 8111, 115 Biotechnology Bldg, 660 S. Euclid Ave, MO, 63110, St. Louis, USA.
Neurotherapeutics. 2022 Jul;19(4):1145-1158. doi: 10.1007/s13311-022-01247-2. Epub 2022 Jun 2.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss. ALS is now associated with mutations in numerous genes, many of which cause disease in part through toxic gain-of-function mechanisms. Antisense oligonucleotides (ASOs) are small sequences of DNA that can reduce expression of a target gene at the post-transcriptional level, making them attractive for neutralizing mutant or toxic gene products. Advancements in the medicinal chemistries of ASOs have improved their pharmacodynamic profile to allow safe and effective delivery to the central nervous system. ASO therapies for ALS have rapidly developed over the last two decades, and ASOs that target SOD1, C9orf72, FUS, and ATXN2 are now in clinical trials for familial or sporadic forms of ALS. This review discusses the current state of ASO therapies for ALS, outlining their successes from preclinical development to early clinical trials.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是运动神经元丧失。目前，ALS 与许多基因突变有关，其中许多基因突变通过毒性获得功能机制在一定程度上导致疾病。反义寡核苷酸（ASO）是一小段 DNA，可以在转录后水平降低靶基因的表达，使其成为中和突变或毒性基因产物的有吸引力的方法。ASO 的药物化学的进步改善了它们的药效学特征，从而可以安全有效地递送到中枢神经系统。在过去的二十年中，针对 ALS 的 ASO 疗法迅速发展，针对 SOD1、C9orf72、FUS 和 ATXN2 的 ASO 现已进入针对家族性或散发性 ALS 的临床试验。本文讨论了 ALS 的 ASO 疗法的现状，概述了它们从临床前开发到早期临床试验的成功。
