Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, United States of America.
Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Adv Drug Deliv Rev. 2021 Mar;170:214-237. doi: 10.1016/j.addr.2021.01.017. Epub 2021 Jan 21.
While protein therapeutics are one of the most successful class of drug molecules, they are expensive and not suited for treating chronic disorders that require long-term dosing. Adeno-associated virus (AAV) mediated in vivo gene therapy represents a viable alternative, which can deliver the genes of protein therapeutics to produce long-term expression of proteins in target tissues. Ongoing clinical trials and recent regulatory approvals demonstrate great interest in these therapeutics, however, there is a lack of understanding regarding their cellular disposition, whole-body disposition, dose-exposure relationship, exposure-response relationship, and how product quality and immunogenicity affects these important properties. In addition, there is a lack of quantitative studies to support the development of pharmacokinetic-pharmacodynamic models, which can support the discovery, development, and clinical translation of this delivery system. In this review, we have provided a state-of-the-art overview of current progress and limitations related to AAV mediated delivery of protein therapeutic genes, along with our perspective on the steps that need to be taken to improve clinical translation of this therapeutic modality.
虽然蛋白质疗法是最成功的一类药物分子之一，但它们价格昂贵，不适合治疗需要长期给药的慢性疾病。腺相关病毒（AAV）介导的体内基因治疗是一种可行的替代方法，它可以将蛋白质治疗药物的基因递送到靶组织中，以产生蛋白质的长期表达。正在进行的临床试验和最近的监管批准表明，人们对这些治疗药物非常感兴趣，然而，人们对它们的细胞分布、全身分布、剂量-暴露关系、暴露-反应关系以及产品质量和免疫原性如何影响这些重要特性缺乏了解。此外，缺乏定量研究来支持药代动力学-药效动力学模型的开发，而这些模型可以支持该输送系统的发现、开发和临床转化。在这篇综述中，我们提供了有关 AAV 介导的蛋白质治疗基因传递的最新进展和局限性的最新概述，以及我们对需要采取哪些步骤来改善这种治疗方式的临床转化的看法。
