Pathogenic variants in the superoxide dismutase 1 (SOD1) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of SOD1 ALS. The understanding that SOD1 ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of SOD1 ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest SOD1 ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of SOD1 ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.

中文翻译：

---

SOD1 变异引起的肌萎缩侧索硬化症：从基因发现到疾病预防


1993 年，超氧化物歧化酶 1 （SOD1） 基因的致病性变异是肌萎缩侧索硬化症 （ALS） 首次确定的遗传原因。这一发现使用于研究 SOD1 ALS 生物学的转基因啮齿动物模型的开发成为可能。SOD1 ALS 是由毒性功能获得性突变驱动的理解导致了旨在降低 SOD1 蛋白浓度的治疗策略，这一努力因 SOD1 ALS 的表型异质性而变得复杂。成功开发降低 SOD1 表达的基因靶向疗法，以及对症状前疾病的更好理解以及发现神经丝轻蛋白作为预测表型转换的易感性/风险生物标志物，开创了旨在预防临床表现的 SOD1 ALS 试验的新时代。从基因发现到基因治疗的 30 年历程不仅揭示了 SOD1 ALS 的病理生理学，还促进了生物标志物的开发，这些生物标志物应该有助于所有形式 ALS 的治疗开发。