Introduction

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease involving both upper and lower motor neurons and resulting in increasing disability and death 3–5 years after onset of symptoms. Over 40 large clinical trials for ALS have been negative, except for Riluzole that offers a modest survival benefit, and Edaravone that modestly reduces disease progression in patients with specific characteristics. Thus, the discovery of efficient disease modifying therapy is an urgent need.

Areas covered

Although the cause of ALS remains unclear, many studies have demonstrated that neuroinflammation, proteinopathies, glutamate-induced excitotoxicity, microglial activation, oxidative stress, and mitochondrial dysfunction may play a key role in the pathogenesis. This review highlights recent discoveries relating to these diverse mechanisms and their implications for the development of therapy. Ongoing phase 2 clinical trials aimed to interfere with these pathophysiological mechanisms are discussed.

Expert opinion

This review describes the challenges that the discovery of an efficient drug therapy faces and how these issues may be addressed. With the continuous advances coming from basic research, we provided possible suggestions that may be considered to improve performance of clinical trials and turn ALS research into a ‘fertile ground’ for drug development for this devastating disease.

中文翻译：

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用于治疗肌萎缩性侧索硬化症的新兴药物：以近期的2期试验为重点。

介绍

肌萎缩性侧索硬化症（ALS）是一种快速进展的神经退行性疾病，涉及上，下运动神经元，导致症状发作后3-5年内残疾和死亡增加。超过40项关于ALS的大型临床试验均是阴性的，除了Riluzole提供适度的生存获益，以及Edaravone适度降低具有特定特征的患者的疾病进展。因此，迫切需要发现有效的疾病改变疗法。

覆盖区域

尽管尚不清楚ALS的病因，但许多研究表明神经炎症，蛋白病，谷氨酸诱导的兴奋性毒性，小胶质细胞活化，氧化应激和线粒体功能障碍可能在发病机理中起关键作用。这篇综述重点介绍了与这些不同机制有关的最新发现及其对治疗发展的意义。讨论了旨在干扰这些病理生理机制的正在进行的2期临床试验。

专家意见

这篇综述描述了有效药物治疗的发现面临的挑战以及如何解决这些问题。随着基础研究的不断进步，我们提供了可能的建议，可以考虑这些建议以改善临床试验的性能，并将ALS研究转变为这种毁灭性疾病药物开发的“沃土”。