寡核苷酸药物非临床安全性评价的一般考虑及案例分析  

General considerations and case analysis of non-clinical studies of oligonucleotide therapeutics

作　　者：冯政 岳岩 李德利 刘其耀 樊阿莉 黄芳华 宫新江 FENG Zheng;YUE Yan;LI De-li;LIU Qi-yao;FAN A-li;HUANG Fang-hua;GONG Xin-jiang(TriApex Laboratories Co.,Ltd,Nanjing 211800,China;Center for Drug Evaluation,National Medical Products Administration,Beijing 100022,China)

机构地区：[1]江苏鼎泰药物研究(集团)股份有限公司,南京211800 [2]国家药品监督管理局药品审评中心,北京100022

出　　处：《中国新药杂志》2024年第23期2446-2455,共10页Chinese Journal of New Drugs

基　　金：南京市生命健康科技专项一临床前技术突破:细胞与基因治疗药物成药性评价的关键技术研发及其平台构建(202205009)。

摘　　要：作为一种新兴的治疗方法,寡核苷酸药物(oligonucleotide therapeutics,ONTs)在罕见病和某些慢性疾病领域展现出了良好的应用前景和开发潜力。目前,全球范围内已有20种ONTs上市,主要包括反义寡核苷酸(antisense oligonucleotides,ASO)、小干扰RNA(small interfering RNAs,siRNA)和适配体(aptamer)等,并有越来越多的ONTs进入临床开发阶段。业界已对ONTs的序列设计、化学修饰和递送系统等积累了较多的经验,但对于非临床安全性评价尚缺乏系统认识,也尚未形成全球监管的一致要求。本文系统调研了ONTs的主要毒性来源及其影响因素、美国FDA已批准上市的ASO和siRNA药物研究案例,在此基础上阐述了ONTs非临床安全性评价的研究内容、关注要点的一般考虑,以期为我国ONTs的研发提供参考。As an emerging therapeutic approach,oligonucleotide therapeutics(ONTs)have shown good application prospects and development potential in the fields of rare diseases and some chronic diseases.At present,20 ONTs have been approved globally,mainly including antisense oligonucleotides(ASO),small interfering RNAs(siRNA),and aptamer,with more and more ONTs entering the clinical development stage.The industry has accumulated relatively rich experience in ONTs sequence design,chemical modification,delivery system,etc.,but there is still a lack of systematic understanding of non-clinical safety evaluation,and no consistent global regulatory requirements have been formed yet.This article comprehensively investigated the main sources of toxicity of ONTs and their causing factors,as well as the non-clinical experiences of FDA-approved ASO and siRNA drugs,and elaborated the research contents and general considerations of ONTs non-clinical safety evaluation,in order to provide reference for the research and development of ONTs in China.

关 键 词：寡核苷酸药物 非临床研究 安全性评价 一般考虑 

分 类 号：R95[医药卫生—药学]