Evaluating the state of the science for adeno-associated virus integration: An integrated perspective,Molecular Therapy

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Evaluating the state of the science for adeno-associated virus integration: An integrated perspective
Molecular Therapy ( IF 12.1 ) Pub Date : 2022-06-10 , DOI: 10.1016/j.ymthe.2022.06.004
Denise E Sabatino ₁ , Frederic D Bushman ₂ , Randy J Chandler ₃ , Ronald G Crystal ₄ , Beverly L Davidson ₅ , Ricardo Dolmetsch ₆ , Kevin C Eggan ₇ , Guangping Gao ₈ , Irene Gil-Farina ₉ , Mark A Kay ₁₀ , Douglas M McCarty ₁₁ , Eugenio Montini ₁₂ , Adora Ndu ₁₃ , Jing Yuan ₁₄ ,

Affiliation

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.
National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY, USA.
The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
uniQure N.V., Amsterdam, the Netherlands.
BioMarin Pharmaceutical Inc, San Rafael, CA, USA.
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
ProtaGene CGT GmbH, Heidelberg, Germany.
Departments of Pediatrics and Genetics, Stanford University, Stanford, CA, USA.
NeuroGT, Inc., Durham, NC, USA.
San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
BridgeBio Pharma, Inc., Palo Alto, CA, USA.
Drug Safety Research and Development, Pfizer Inc., Cambridge, MA, USA.

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.

中文翻译：

评估腺相关病毒整合的科学现状：综合视角

2021 年 8 月 18 日，美国基因与细胞治疗学会 (ASGCT) 主办了一场关于腺相关病毒 (AAV) 整合的虚拟圆桌会议，由临床前和临床 AAV 基因治疗领域的领先专家参加，以进一步了解和理解这一现象。重组 AAV (rAAV) 载体可用于开发针对多种疾病的疗法，因为它们能够转导多种细胞类型，从而导致转基因的长期表达。尽管大多数rAAV DNA通常保持附加型，但一些rAAV DNA以低频率整合到基因组DNA中，并且rAAV插入诱变已被证明可导致新生小鼠的肿瘤发生。目前，rAAV 介导的人类肿瘤发生的风险是理论上的，因为迄今为止尚未报告证实的基因毒性事件。然而，由于在少数小鼠研究中报道了插入突变，因此需要表征这种遗传毒性，以便为研究、监管需求和患者护理提供信息。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患者插入突变的可能风险。此外，还讨论了技术考虑因素、监管指导和生物伦理学。

更新日期：2022-06-10

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