Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
The Friends of Garrett Cumming Research & Muscular Dystrophy Canada HM Toupin Neurological Sciences Research, Edmonton, AB T6G 2H7, Canada.
Genes (Basel). 2024 Oct 20;15(10):1342. doi: 10.3390/genes15101342.
Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in (), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by mutations, therapeutic strategies aimed at suppressing gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.
肌萎缩侧索硬化症（ALS）是一种难治性神经退行性疾病，其特征是运动神经元变性和丢失，通常在发病后五年内导致死亡。目前治疗方法有限，因此开发有效的治疗方法是一项紧迫的挑战。遗传突变被认为是 ALS 的一个促成因素，其中（）的突变，中和了有害的活性氧超氧化物，约占所有 ALS 病例的 2%。为了对抗由（）突变引起的毒性功能获得，旨在抑制（）基因表达的治疗策略显示出了希望。反义寡核苷酸（ASO）是一种人工合成的、短的、单链 DNA/RNA 分子，可与靶 RNA 结合以改变基因表达，代表了下一代治疗方法。2023 年，托法替布成为首个获 FDA 批准用于 ALS 的 ASO 药物。鞘内给药时，托法替布特异性结合（）mRNA，抑制毒性 SOD1 蛋白的产生，从而改善 ALS 的生物标志物。托法替布的长期疗效和安全性需要进一步验证，开发更优化的治疗方案至关重要。一系列与（）突变相关的研究和治疗进展，推进了对 ALS 病理生理学的认识，并为中枢神经系统疾病的治疗策略做出了重大贡献。本综述重点介绍（）突变的概述和托法替布的开发过程，旨在深化对 ALS 研究进展的理解，并讨论 ASO 治疗的未来挑战和方向。
