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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells
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Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells

机译：逆转录病毒载体整合可破坏基因表达，但对移植的T细胞的生物学和功能没有影响

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摘要

The use of retroviral vectors in gene therapy has raised safety concerns for the genotoxic risk associated with their uncontrolled insertion into the human genome. We have analyzed the consequences of retroviral transduction in T cells from leukemic patients treated with allogeneic stern cell transplantation and donor lymphocytes genetically modified with a suicide gene (HSV-TK). Retroviral vectors integrate preferentially within or near transcribed regions of the genome, with a preference for sequences around promoters and for genes active in T cells at the time of transduction. Quantitative transcript analysis shows that one fifth of these integrations affect the expression of nearby genes. However, transduced T cell populations maintain remarkably stable gene expression profiles, phenotype, biological functions, and immune repertoire in vivo, with no evidence of clonal selection up to 9 yr after administration. Analysis of integrated proviruses in transduced cells before and after transplantation indicates that integrations interfering with normal T cell function are more likely to lead to clonal ablation than expansion in vivo. Despite the potentially dangerous interactions with the T cell genome, retroviral integration has therefore little consequence on the safety and efficacy of T cell transplantation.
机译：逆转录病毒载体在基因治疗中的使用引起了人们对其与人类基因组不受控制的插入相关的遗传毒性风险的安全性关注。我们已经分析了异基因干细胞移植和自杀基因（HSV-TK）基因改造的供体淋巴细胞治疗的白血病患者的T细胞中逆转录病毒转导的后果。逆转录病毒载体优先整合在基因组的转录区内或转录区附近，优先选择启动子周围的序列以及转导时T细胞中活跃的基因。转录本定量分析表明，这些整合的五分之一会影响附近基因的表达。然而，转导的T细胞群体在体内保持了非常稳定的基因表达谱，表型，生物学功能和免疫库，在给药后长达9年没有克隆选择的证据。移植前后在转导细胞中整合原病毒的分析表明，干扰正常T细胞功能的整合比体内扩增更可能导致克隆消融。尽管与T细胞基因组存在潜在的危险相互作用，逆转录病毒整合因此对T细胞移植的安全性和有效性影响不大。

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