McDowall Simon, Aung-Htut May, Wilton Steve, Li Dunhui
School of Human Sciences, The University of Western Australia, Crawley, WA, Australia.
Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands, WA, Australia.
Front Neurosci. 2024 Sep 23;18:1414658. doi: 10.3389/fnins.2024.1414658. eCollection 2024.
Rare diseases affect almost 500 million people globally, predominantly impacting children and often leading to significantly impaired quality of life and high treatment costs. While significant contributions have been made to develop effective treatments for those with rare diseases, more rapid drug discovery strategies are needed. Therapeutic antisense oligonucleotides can modulate target gene expression with high specificity through various mechanisms determined by base sequences and chemical modifications; and have shown efficacy in clinical trials for a few rare neurological conditions. Therefore, this review will focus on the applications of antisense oligonucleotides, in particular splice-switching antisense oligomers as promising therapeutics for rare neurological diseases, with key examples of Duchenne muscular dystrophy and spinal muscular atrophy. Challenges and future perspectives in developing antisense therapeutics for rare conditions including target discovery, antisense chemical modifications, animal models for therapeutic validations, and clinical trial designs will also be briefly discussed.
全球约有5亿人受罕见病影响，主要是儿童，常导致生活质量严重受损且治疗成本高昂。虽然在为罕见病患者开发有效治疗方法方面已取得重大进展，但仍需要更快速的药物发现策略。治疗性反义寡核苷酸可通过由碱基序列和化学修饰决定的各种机制，以高特异性调节靶基因表达；并且在一些罕见神经疾病的临床试验中已显示出疗效。因此，本综述将重点关注反义寡核苷酸的应用，特别是剪接转换反义寡聚物作为罕见神经疾病的有前景治疗方法，以杜氏肌营养不良症和脊髓性肌萎缩症为例。还将简要讨论开发针对罕见病的反义疗法所面临的挑战和未来展望，包括靶点发现、反义化学修饰、治疗验证的动物模型以及临床试验设计。
