AAV载体基因药物临床生物样本分析要点及挑战

The Challenges and Key-points of Clinical Bioanalysis of AAV Vector Gene Therapy

细胞和基因治疗已进入高速发展期,多种病毒和非病毒载体被应用于细胞和基因治疗领域。其中,腺相关病毒(adeno-associated virus, AAV)载体因其对治疗基因的高效转导率、持久的表达能力和良好的安全性等特点,在遗传病的体内基因治疗领域得到广泛应用。随着越来越多的AAV载体基因药物进入临床研究阶段,AAV载体药物的生物分析也越来越受关注,涉及药物代谢动力学(pharmacokinetics, PK)、药效学(pharmacodynamics, PD)、免疫原性、病毒脱落和基因整合监测等方面,目前均缺乏标准化的分析方法、标准品和对照品,在分析方法验证方案、接受标准等方面亦尚无统一规定。囿于AAV载体药物组成和作用机制的复杂性,无论是分析方法、结果解释,还是监管机构的建议和要求等方面均不同于传统小分子和蛋白药物。本研究结合AAV载体基因药物特点、监管机构建议和已发表的临床研究,概述AAV载体基因药物临床生物样本给药前、给药后分析工作要点及面临的挑战,以期为临床上AAV载体基因治疗药物的研究开发提供借鉴和参考。

Cell and gene therapy has entered a period of rapid development,and a variety of viral and non-viral vectors have been applied to the field of cell and gene therapy.Among them,adeno-associated virus(AAV)vectors have been widely used in the field of in vivo gene therapy for genetic diseases because of their potent transduction efficiency,durable expression ability and good safety.As more and more AAV vector gene therapy products enter the clinical trials,the bioanalysis related to AAV vector has also attracted more and more attention,which involves pharmacokinetics(PK),pharmacodynamics(PD),immunogenicity,viral shedding and gene integration monitoring,etc.At present,there are no standardized analytical methods,standards and reference materials,and there are no uniform regulations on the verification scheme and acceptance standard of analytical methods.Due to the complexity of the structure and mechanism of AAV vector products,the bioanalytic methods,interpretation of results or regulatory recommendations is different from the bioanalysis of traditional small molecule and protein drugs.This study overviewed the key points and challenges of clinical bioanalysis products before and after administration of AAV vectors gene therapy based on the characteristics of AAV vector,the current regulatory recommendations and the published data of clinical trails,to provide reference for the development of AAV vector gene therapy in clinic.