反义寡核苷酸类药物在Duchenne型肌营养不良中的治疗进展  

Progress in the Treatment of Antisense Oligonucleotides in Duchenne Muscular Dystrophy

作　　者：许婷婷 左玮[1] 刘鑫[1] 范倩倩[1] 高杨 梁春苏 张波[1] XU Tingting;ZUO Wei;LIU Xin;FAN Qianqian;GAO Yang;LIANG Chunsu;ZHANG Bo(Department of Pharmacy,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100730,China)

机构地区：[1]中国医学科学院北京协和医院药剂科,北京100730

出　　处：《罕见病研究》2022年第2期199-205,共7页Journal of Rare Diseases

基　　金：中国医学科学院医学与健康科技创新工程项目(2021-I2M-1-003)。

摘　　要：近年来,反义寡核苷酸(ASO)药物在罕见病研发领域十分活跃,特别在Duchenne型肌营养不良症(DMD)中取得了重大突破。DMD主要是由抗肌萎缩蛋白(dystrophin)基因突变导致的儿童罕见性肌病,因此目前国际上批准的4种治疗DMD的ASO类药物均是针对抗肌萎缩蛋白这一靶点的,包括Eteplirsen、Golodirsen、Viltolarsen和Casimersen。它们均属于磷酰二胺吗啉代低聚物(PMO)反义寡核苷酸药物,因此,它们的药代动力学特征相似。在静脉给药后很快分布到其他组织中,由于PMO结构的电中性,其与血浆蛋白结合率低,因此,它们很快被肾脏代谢以原型经尿排出。此外,该类药物发生药物-药物相互作用的可能性也很低。现有的临床研究结果表明,它们具有一定的临床获益性和良好的耐受性,为DMD治疗带来新的选择。因此,本文主要对用于治疗DMD的ASO药物药理作用、药代动力学特点、有效性和安全性进行讨论,希望能为临床合理、安全地应用这类药物提供科学参考。In recent years, antisense oligonucleotide(ASO) has been very active in the field of rare disease research and development, especially in Duchenne muscular dystrophy, where it made a major breakthrough. Duchenne muscular dystrophy(DMD) is a rare childhood myopathy caused by mutations in the dystrophin gene. Currently, the four ASO drugs approved internationally for DMD are all targeted at dystrophin, including eteplirsen, golodirsen, viltolarsen and casimersen. They all belong to phosphorodiamidate morpholino oligomers(PMO) antisense oligonucleotide drugs, so that their pharmacokinetic characteristics are similar. The drugs quickly spread to other tissues after intravenous administration. Because of the electrical neutrality of the PMO, they have a low binding rate to plasma proteins and are quickly metabolized by the kidney and excreted in the urine as archetypes. In addition, the likelihood of drug-drug interactions of ASO is low. Existing clinicalstudies have shown that they have certain clinical benefits and good tolerability, bringing new options for DMD treatment. This paper mainly discusses the pharmacological effects, pharmacokinetic characteristics, efficacy, and safety of ASO drugs for the treatment of DMD, hoping to provide scientific reference for the rational and safe clinical use of such drugs.

关 键 词：反义寡核苷酸类药物 DUCHENNE型肌营养不良症 罕见病 药代动力学 有效性和安全性 

分 类 号：R72[医药卫生—儿科]