降低逆转录病毒载体的基因毒性潜力。
Reducing the genotoxic potential of retroviral vectors.
作者信息
Ramezani Ali, Hawley Teresa S, Hawley Robert G
机构信息
Department of Anatomy and Regenerative Biology, The George Washington University Medical Center, Washington, DC, USA.
出版信息
Methods Mol Biol. 2008;434:183-203. doi: 10.1007/978-1-60327-248-3_12.
Abstract
The recent development of leukemia in gene therapy patients with X-linked severe combined immunodeficiency disease because of retroviral vector insertional mutagenesis has prompted reassessment of the genotoxic potential of integrating vector systems. In this chapter, various strategies are described to reduce the associated risks of retroviral genomic integration. These include deletion of strong transcriptional enhancer-promoter elements in the retroviral long terminal repeats, flanking the retroviral transcriptional unit with enhancer blocking sequences and designing vectors with improved RNA 3' end processing. Protocols are provided to evaluate the relative biosafety of the modified vectors based on their ability to immortalize hematopoietic progenitor cells and propensity to trigger clonal hematopoiesis or leukemogenesis following hematopoietic stem cell transplantation.
摘要
因逆转录病毒载体插入诱变导致X连锁重症联合免疫缺陷病基因治疗患者近期发生白血病，促使人们重新评估整合载体系统的基因毒性潜力。在本章中，描述了各种降低逆转录病毒基因组整合相关风险的策略。这些策略包括删除逆转录病毒长末端重复序列中的强转录增强子-启动子元件、用增强子阻断序列侧翼逆转录病毒转录单元以及设计具有改进的RNA 3'端加工的载体。提供了基于其使造血祖细胞永生化的能力以及造血干细胞移植后触发克隆性造血或白血病发生的倾向来评估修饰载体相对生物安全性的方案。
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