Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by degeneration of motor neurons. As with all major neurodegenerative disorders, development of disease-modifying therapies has proven challenging for multiple reasons. Nevertheless, ALS is one of the few neurodegenerative diseases for which disease-modifying therapies are approved. Significant discoveries and advances have been made in ALS preclinical models, genetics, pathology, biomarkers, imaging and clinical readouts over the last 10–15 years. At the same time, novel therapeutic paradigms are being applied in areas of high unmet medical need, including neurodegenerative disorders. These developments have evolved our knowledge base, allowing identification of targeted candidate therapies for ALS with diverse mechanisms of action. In this Review, we discuss how this advanced knowledge, aligned with new approaches, can enable effective translation of therapeutic agents from preclinical studies through to clinical benefit for patients with ALS. We anticipate that this approach in ALS will also positively impact the field of drug discovery for neurodegenerative disorders more broadly.

肌萎缩侧索硬化症 （ALS） 是一种由运动神经元退化引起的毁灭性疾病。与所有主要的神经退行性疾病一样，由于多种原因，疾病修饰疗法的开发已被证明具有挑战性。尽管如此，ALS 是少数获批疾病缓解疗法的神经退行性疾病之一。在过去的 10-15 年里，ALS 临床前模型、遗传学、病理学、生物标志物、成像和临床读数方面取得了重大发现和进展。与此同时，新的治疗范式正在应用于高度未满足的医疗需求领域，包括神经退行性疾病。这些发展发展了我们的知识库，从而能够识别具有不同作用机制的 ALS 靶向候选疗法。在这篇综述中，我们讨论了这些先进知识如何与新方法保持一致，使治疗药物从临床前研究的有效转化为 ALS 患者的临床益处。我们预计 ALS 中的这种方法也将对神经退行性疾病的药物发现领域产生更广泛的积极影响。