Pilaro A M, Serabian M A
United States Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutics Research and Review, Rockville, Maryland 20852, USA.
Toxicol Pathol. 1999 Jan-Feb;27(1):4-7. doi: 10.1177/019262339902700102.
With over 220 investigational new drug applications currently active, gene therapy represents one of the fastest growing areas in biotherapeutic research. Initially conceived for replacing defective genes in diseases such as cystic fibrosis or inborn errors of metabolism with genes encoding the normal, or wild-type, gene product, gene therapy has expanded into other novel applications such as treatment of cancer or cardiovascular disease, where the risk:benefit profiles may be more acceptable in relation to the severity of the disease. Different types of vectors, including modified retroviruses, adenoviruses, adenovirus-associated viruses, and herpesviruses and plasmid DNA, are used to transfer foreign genetic material into patients' cells or tissues. Developing a toxicology program to determine the safety of these agents, therefore, requires a modified approach that encompasses the pharmacology and toxicity of both the gene product itself and the vector system used for delivery in the context of the application for the clinical trial. In general, the issues involved in designing and developing appropriate preclinical testing to determine the safety of these products are similar to those encountered for other recombinant molecules, including protein biotherapeutics. Limitations to some of the typical toxicology studies conducted for a traditional drug development program may exist for these agents, and nontraditional approaches may be required to demonstrate their safety. Many factors may affect the safety and clinical activity of these agents, including the route, frequency, and duration of exposure and the type of vector employed. Other safety considerations include quantitation of the duration and degree of expression of the vector in target and other tissues, the effects of gene expression on organ pathology and/or histology, evaluation of trafficking of gene-transduced cells or vector after injection, and interactions of the host immune system with the transduced cell population. Because of the unique concerns regarding each of these therapies, the Center for Biologics Evaluation and Research encourages sponsors to obtain toxicity data whenever possible while evaluating the pharmacologic activity of the vector in a species or animal model relevant to their clinical indication. Sponsors are encouraged to discuss preclinical study design and results with the Center during product development to facilitate early identification of safety concerns prior to entry of these novel agents into the clinical setting and to ensure an uninterrupted course of development while addressing issues required for licensure.
目前有超过220项研究性新药申请正在进行中，基因治疗是生物治疗研究中发展最快的领域之一。基因治疗最初设想用于用编码正常或野生型基因产物的基因替代诸如囊性纤维化或先天性代谢缺陷等疾病中的缺陷基因，如今已扩展到其他新的应用领域，如癌症或心血管疾病的治疗，在这些疾病中，相对于疾病的严重程度，风险效益比可能更易被接受。不同类型的载体，包括经修饰的逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和质粒DNA，被用于将外源遗传物质转移到患者的细胞或组织中。因此，制定一个毒理学计划以确定这些制剂的安全性，需要一种经过改进的方法，该方法要在临床试验应用的背景下，涵盖基因产物本身以及用于递送的载体系统的药理学和毒性。一般来说，设计和开展适当的临床前测试以确定这些产品安全性所涉及的问题，与其他重组分子（包括蛋白质生物治疗药物）所遇到的问题相似。对于这些制剂，传统药物开发计划中进行的一些典型毒理学研究可能存在局限性，可能需要采用非传统方法来证明其安全性。许多因素可能影响这些制剂的安全性和临床活性，包括暴露途径、频率和持续时间以及所采用的载体类型。其他安全考虑因素包括载体在靶组织和其他组织中的表达持续时间和程度的定量、基因表达对器官病理学和/或组织学的影响、注射后基因转导细胞或载体的转运评估，以及宿主免疫系统与转导细胞群体的相互作用。由于对每种治疗方法都有独特的关注，生物制品评估和研究中心鼓励申办者在评估与临床适应症相关的物种或动物模型中载体的药理活性时，尽可能获取毒性数据。鼓励申办者在产品开发过程中与该中心讨论临床前研究设计和结果，以便在这些新型制剂进入临床环境之前尽早识别安全问题，并确保在解决许可所需问题的同时，开发过程不间断。
