Wen Xiangjin, Lan Tianxiang, Su Weiming, Cao Bei, Wang Yi, Chen Yongping
Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
Neural Regen Res. 2025 May 6. doi: 10.4103/NRR.NRR-D-24-01266.
Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions. They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage. The main types include amyotrophic lateral sclerosis, progressive muscular atrophy, primary lateral sclerosis, and progressive bulbar palsy, the pathological processes of which are largely identical, with the main disparity lying in the location of the lesions. Amyotrophic lateral sclerosis is the representative condition in this group of diseases, while other types are its variants. Hence, this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases. Although the precise pathogenesis remains elusive, recent advancements have shed light on various theories, including gene mutation, excitatory amino acid toxicity, autoimmunology, and neurotrophic factors. The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis: riluzole, edaravone, AMX0035, and tofersen, with the latter being the most recent to receive approval. However, following several phase III trials that failed to yield favorable outcomes, AMX0035 has been voluntarily withdrawn from both the US and Canadian markets. This article presents a comprehensive summary of drug trials primarily completed between January 1, 2023, and June 30, 2024, based on data sourced from clinicaltrials.gov. Among these trials, five are currently in phase I, seventeen are in phase II, and eleven are undergoing phase III evaluation. Notably, 24 clinical trials are now investigating potential disease-modifying therapy drugs, accounting for the majority of the drugs included in this review. Some promising drugs being investigated in preclinical studies, such as ATH-1105, are included in our analysis, and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases. This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs, with the aim of highlighting the latest potentialities for clinical therapy.
运动神经元病是散发性或遗传性的致命性神经退行性疾病。它们选择性地影响大脑和脊髓中的上运动神经元和/或下运动神经元，其特征是起病缓慢，病程亚急性，取决于损伤部位。主要类型包括肌萎缩侧索硬化症、进行性肌肉萎缩症、原发性侧索硬化症和进行性延髓麻痹，它们的病理过程基本相同，主要差异在于病变部位。肌萎缩侧索硬化症是这组疾病中的代表性病症，而其他类型是其变体。因此，本文主要关注肌萎缩侧索硬化症药物研究的进展和挑战，但也简要介绍了其他几种重要的退行性运动神经元疾病。尽管确切的发病机制仍然不明，但最近的进展为各种理论提供了线索，包括基因突变、兴奋性氨基酸毒性、自身免疫和神经营养因子。美国食品药品监督管理局已批准四种药物用于延缓肌萎缩侧索硬化症的进展：利鲁唑、依达拉奉、AMX0035和托弗森，后者是最近获得批准的。然而，在几项未能产生有利结果的III期试验之后，AMX0035已从美国和加拿大市场自愿撤出。本文基于来自clinicaltrials.gov的数据，全面总结了主要在2023年1月1日至2024年6月30日期间完成的药物试验。在这些试验中，五项目前处于I期，十七项处于II期，十一项正在进行III期评估。值得注意的是，24项临床试验正在研究潜在的疾病修饰治疗药物，占本综述所涵盖药物的大多数。我们的分析包括了一些在临床前研究中正在研究的有前景的药物，如ATH-1105，并且在基因治疗和免疫治疗前沿的另一篇综述已经证明了它们对运动神经元疾病的治疗潜力。本文旨在概述与运动神经元病药物相关的研究趋势和治疗前景，以突出临床治疗的最新潜力。
