The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Hematology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Mol Ther. 2022 Aug 3;30(8):2646-2663. doi: 10.1016/j.ymthe.2022.06.004. Epub 2022 Jun 10.
On August 18, 2021, the American Society of Gene and Cell Therapy (ASGCT) hosted a virtual roundtable on adeno-associated virus (AAV) integration, featuring leading experts in preclinical and clinical AAV gene therapy, to further contextualize and understand this phenomenon. Recombinant AAV (rAAV) vectors are used to develop therapies for many conditions given their ability to transduce multiple cell types, resulting in long-term expression of transgenes. Although most rAAV DNA typically remains episomal, some rAAV DNA becomes integrated into genomic DNA at a low frequency, and rAAV insertional mutagenesis has been shown to lead to tumorigenesis in neonatal mice. Currently, the risk of rAAV-mediated oncogenesis in humans is theoretical because no confirmed genotoxic events have been reported to date. However, because insertional mutagenesis has been reported in a small number of murine studies, there is a need to characterize this genotoxicity to inform research, regulatory needs, and patient care. The purpose of this white paper is to review the evidence of rAAV-related host genome integration in animal models and possible risks of insertional mutagenesis in patients. In addition, technical considerations, regulatory guidance, and bioethics are discussed.
2021 年 8 月 18 日，美国基因与细胞治疗学会（ASGCT）举办了一场关于腺相关病毒（AAV）整合的虚拟圆桌会议，邀请了在临床前和临床 AAV 基因治疗领域的领先专家，以进一步了解和理解这一现象。由于能够转导多种细胞类型，从而实现转基因的长期表达，重组腺相关病毒（rAAV）载体被用于开发多种疾病的治疗方法。尽管大多数 rAAV DNA 通常保持游离状态，但一些 rAAV DNA 以低频率整合到基因组 DNA 中，rAAV 插入突变已被证明会导致新生小鼠发生肿瘤。目前，rAAV 介导的人类致癌风险是理论上的，因为迄今为止尚未报道任何确认的遗传毒性事件。然而，由于在少数小鼠研究中已经报道了插入突变，因此需要对这种遗传毒性进行特征描述，以指导研究、监管需求和患者护理。本白皮书的目的是回顾动物模型中 rAAV 相关宿主基因组整合的证据，以及插入突变在患者中的潜在风险。此外，还讨论了技术考虑因素、监管指导和生物伦理学。
