Evaluating the state of the science for adeno-associated virus integration: An integrated perspective.
Evaluating the state of the science for adeno-associated virus integration: An integrated perspective.
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评价腺相关病毒整合的科学现状：一个综合的观点。
DOI：
10.1016/j.ymthe.2022.06.004
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发表时间：
2022-08-03
影响因子：
12.4
通讯作者：
Yuan, Jing
中科院分区：
文献类型：
--
作者：
Sabatino, Denise E.;Bushman, Frederic D.;Chandler, Randy J.;Crystal, Ronald G.;Davidson, Beverly L.;Dolmetsch, Ricardo;Eggan, Kevin C.;Gao, Guangping;Gil-Farina, Irene;Kay, Mark A.;McCarty, Douglas M.;Montini, Eugenio;Ndu, Adora;Yuan, Jing
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，与会的有临床前和临床AAV基因治疗方面的领先专家，以进一步了解这一现象。由于重组AAV(RAAV)载体能够转导多种细胞类型，从而导致转基因的长期表达，因此可用于多种疾病的治疗。虽然大多数rAAV DNA通常保持上体，但一些rAAV DNA以较低的频率整合到基因组DNA中，rAAV插入突变已被证明导致新生小鼠肿瘤的发生。目前，rAAV介导的人类肿瘤发生的风险是理论上的，因为到目前为止还没有证实的遗传毒性事件的报道。然而，由于插入突变已在少数小鼠研究中被报道，因此有必要对这种遗传毒性进行表征，以便为研究、调节需求和患者护理提供信息。本白皮书的目的是综述动物模型中rAAV相关宿主基因组整合的证据，以及在患者中插入突变的可能风险。此外，还讨论了技术考虑、监管指导和生物伦理。虽然重组AAV DNA主要保持在表型，但它可以整合到靶细胞基因组中。这篇综述讨论了目前对AAV整合的理解以及潜在的遗传毒性风险。我们讨论了可能影响插入突变风险的因素、技术考虑和监管指导。
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. While recombinant AAV DNA remains primarily episomal, it can integrate into the target cell genome. This review discusses the current understanding of AAV integration and the potential risk of genotoxicity. We discuss the factors that may influence the risk of insertional mutagenesis, technical considerations, and regulatory guidance.
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影响因子：
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作者：
Bijlani S;Pang KM;Sivanandam V;Singh A;Chatterjee S
通讯作者：
Chatterjee S
影响因子：
64.8
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影响因子：
4.2
作者：
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通讯作者：
Srivastava, Arun
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20.3
作者：
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通讯作者：
High, KA
影响因子：
56.9
作者：
Cartier, Nathalie;Hacein-Bey-Abina, Salima;Aubourg, Patrick
通讯作者：
Aubourg, Patrick