NEuroMuscular Omnicentre, Fondazione Serena Onlus , Milan, Italy.
Dept. Biomedical Sciences of Health, University of Milan , Milan, Italy.
Expert Opin Emerg Drugs. 2020 Jun;25(2):145-164. doi: 10.1080/14728214.2020.1769067. Epub 2020 May 27.
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.
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.
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.
肌萎缩侧索硬化症（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，导致症状出现后 3-5 年内残疾和死亡逐渐增加。除了提供适度生存益处的利鲁唑和对具有特定特征的患者适度减缓疾病进展的依达拉奉外，已有 40 多项大型 ALS 临床试验均为阴性。因此，迫切需要发现有效的疾病修正治疗方法。
尽管 ALS 的病因仍不清楚，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、小胶质细胞激活、氧化应激和线粒体功能障碍可能在发病机制中起关键作用。这篇综述强调了与这些不同机制相关的最新发现及其对治疗开发的意义。正在进行的旨在干预这些病理生理机制的 2 期临床试验也进行了讨论。
这篇综述描述了发现有效药物治疗方法所面临的挑战，以及如何解决这些问题。随着基础研究的不断进步，我们提出了可能的建议，可以考虑这些建议来提高临床试验的效果，使 ALS 研究成为开发这种毁灭性疾病药物的“肥沃土壤”。
