反义寡核苷酸——神经系统遗传病治疗的新策略  

Antisense oligonucleotide as novel therapies for neurogenetic disorders

作　　者：范丽苑 Fan Liyuan(University of Hong Kong Shenzhen Hospital,Shenzhen,Guangdong 518053,China)

机构地区：[1]香港大学深圳医院,深圳518053

出　　处：《中华医学遗传学杂志》2025年第1期102-113,共12页Chinese Journal of Medical Genetics

摘　　要：作为一种分子生物学工具,反义寡核苷酸(ASO)已在基础研究中应用数十年。近年来,ASO在神经系统疾病治疗中的潜力受到广泛的关注。研究者已开发出多种治疗性ASO药物。包括eteplirsen、golodirsen、viltolarsen、nusinersen和inotersen在内的多款药物已获得美国食品药品监督管理局(FDA)的批准应用于临床,并取得了显著的疗效。此外还有大量的候选药物正处于实验研究阶段。作为一种精准医疗手段,ASO治疗的探索有望推动罕见病治疗模式的革新。在遗传咨询的过程中,咨询师有责任向患者及其家属详细解释这些新型靶向疗法的效果、潜在的不良反应以及价格。由于这类疗法在实施前通常需要精确的基因诊断,遗传咨询师以及其他医疗专业的人员在筛选并将患者与合适的ASO药物相匹配方面扮演关键的角色。对这一环节的专业支持对于实现个性化的治疗方案至关重要。本文概述了ASO疗法的基本原理、化学修饰特性、潜在的不良反应以及给药方式,并系统总结了获得FDA批准的ASO疗法及其在多种神经系统疾病临床试验中的应用,此外还讨论了ASO疗法在实际市场推广中可能遇到的局限性和挑战,并分析了遗传咨询师在临床实践中应当关注的问题。Antisense oligonucleotide(ASO)was discovered several decades ago and initially used only as a research tool in the laboratory.In recent years,several ASO therapeutics have been developed for neurological disorders.Some of these therapeutics,including eteplirsen,golodirsen,viltolarsen,nusinersen and inotersen,have been approved by the Food and Drug Administration(FDA)and begun to draw the public′s attention as an effective therapeutic approach.These novel therapeutics have shown great performance,while many similar therapeutics are under investigation and in clinical trials.This n-of-1 precision medicine may start a new chapter in the paradigm of therapeutics.Clinicians,clinical geneticists,and genetic counselors may know about this novel therapy,but very few may understand the background in details.During genetic counseling,they have the responsibility to convey the effectiveness,side effects and cost of such therapies to patients and their families.As these target therapies will require precise genetic diagnosis before treatment,healthcare professionals and genetic counselors play a vital role in relating the patients to the corresponding ASO drugs.This review has elaborated the mechanism of ASO therapies,including basic rationales,modifications,side effects and delivery routes.It also systemically summarized the FDA-approved ASO therapeutics and their applications for various neurological disorders,and discussed the limitations and challenges the real-world market may face and issues genetic counselor should take into consideration in the near future.

关 键 词：反义寡核苷酸 神经系统疾病 遗传咨询 精准医疗 基因治疗 罕见病治疗 药物疗效 靶向疗法 基因诊断 药物化学修饰 

分 类 号：R741[医药卫生—神经病学与精神病学]