基于Duchenne型肌营养不良症动物模型的核酸药物与基因治疗研究进展  

Advances in Nucleic Acid Drugs and Gene Therapies based on Animal Models of Duchenne Muscular Dystrophy

作　　者：刘思雨 赖跃昭 郭文婷 陈学进 LIU Siyu;LAI Yuezhao;GUO Wenting;CHEN Xuejin(State Key Laboratory of Primate Biomedical Research,Institute of Primate Translational Medicine,Kunming University of Science and Technology,Kunming 650500,China;School of Medicine,The Chinese University of Hong Kong,Shenzhen 518172,China)

机构地区：[1]昆明理工大学灵长类转化医学研究院,省部共建非人灵长类生物医学国家重点实验室,昆明650500 [2]香港中文大学(深圳)医学院,深圳518172

出　　处：《实验动物与比较医学》2024年第6期613-625,共13页Laboratory Animal and Comparative Medicine

基　　金：2024年度云南省高校服务重点产业科技项目“利用猴模型评价Utrophin基因激活疗法的有效性和安全性研究”(FWCY-ZD2024006)。

摘　　要：Duchenne型肌营养不良症(Duchenne muscular dystrophy,DMD)是一种严重的X连锁隐性遗传疾病,由DMD基因突变引起,是最常见的遗传性肌营养不良类型之一。DMD基因是已知的人类基因组中最大的基因之一,编码抗肌萎缩蛋白(dystrophin)。目前已知的DMD基因突变类型复杂多样,包括外显子的缺失、重复、点突变,以及小片段插入或缺失等,为DMD的治疗带来了巨大挑战。目前尚无根治DMD的方法,其主要治疗手段以症状管理为主,且无法逆转或阻止疾病的进展。近年来,随着生物技术的进步,核酸药物和基因治疗成为DMD治疗研究的前沿领域。此类治疗方法旨在通过修复或替代突变的基因来恢复抗肌萎缩蛋白的表达,从而改善肌肉功能或延缓肌肉退化。在临床前动物模型研究和前期临床试验中,这些治疗方法已显现出一定的疗效,为DMD患者带来了新的希望。本文在简述DMD病理机制及遗传特征的基础上,详细介绍了DMD治疗领域的最新研究进展,特别聚焦于DMD核酸药物(包括基于外显子跳跃疗法的反义寡核苷酸药物和核糖体跳跃促进剂)以及基因治疗方法(包括基因替代疗法和基因编辑疗法)。这些治疗方法的开发和应用不仅为DMD患者提供了新的治疗选择,也为其他遗传性疾病的治疗积累了宝贵经验。然而,DMD治疗的临床转化也面临诸多挑战,未来研究需要进一步优化现有的治疗方法,提高治疗的有效性和适用性,同时探索新的治疗策略,以期为DMD患者带来更有效且可持续的治疗方案。Duchenne muscular dystrophy(DMD)is a severe X-linked recessive genetic disorder caused by mutations in the DMD gene,making it one of the most common forms of hereditary muscular dystrophy.The DMD gene,which encodes dystrophin,is the largest known gene in the human genome.Mutations in the DMD gene are highly diverse,including exon deletions,duplications,point mutations,and small insertions or deletions,posing significant challenges for treatment.Currently,there is no cure for DMD,and existing treatment strategies focus primarily on symptom management,which cannot reverse or halt disease progression.Advances in biotechnology position nucleic acid drugs and gene therapies at the forefront of DMD treatment research.These treatments aim to restore dystrophin expression by repairing or replacing mutated genes,thereby improving muscle function or slowing muscle degeneration.Preclinical studies in animal models and early-phase clinical trials demonstrate promising efficacy and offer new hope for DMD patients.This review briefly outlines the pathological mechanisms and genetic characteristics of DMD before delving into recent progress in therapeutic strategies,with a particular focus on nucleic acid drugs(including antisense oligonucleotides for exon skipping therapy and translation readthrough inducers)and gene therapy approaches(including gene replacement therapy and gene editing).The development and application of these therapies not only provide new treatment options for DMD patients,but also offer valuable insights for addressing other genetic disorders.However,numerous challenges impede the clinical translation of DMD treatments.Future studies must optimize existing therapeutic strategies,improve their efficacy and applicability,and explore innovative approaches to deliver more effective and sustainable treatments for DMD patients.

关 键 词：DUCHENNE型肌营养不良症 抗肌萎缩蛋白 核酸药物 反义寡核苷酸 基因治疗 外显子跳跃 

分 类 号：R-332[医药卫生] R966