Wiskott-Aldrich综合征
遗传增强
造血
生物
病毒学
病毒载体
载体(分子生物学)
干细胞
基因表达
Wiskott–Aldrich综合征蛋白
慢病毒
基因治疗载体
基因
免疫学
遗传学
病毒
病毒性疾病
细胞
重组DNA
细胞骨架
肌动蛋白细胞骨架
作者
Cecilia Frecha,Miguel G. Toscano,Caroline Costa,María José Sáez‐Lara,François‐Loïc Cosset,Els Verhoeyen,Francisco Martı́n
出处
期刊:Gene Therapy
[Springer Nature]
日期:2008-03-06
卷期号:15 (12): 930-941
被引量:32
摘要
Wiskott–Aldrich syndrome (WAS) gene therapy requires highly efficient and well-controlled vectors. Here we studied the performance of a lentiviral vector (LV) harbouring a 500-bp fragment of the WAS proximal promoter (WW), which we previously characterized as haematopoietic-specific and capable of restoring WAS phenotype in patients' T cells. We used an LV (WE) expressing eGFP to evaluate whether this promoter was following the expression pattern of endogenous WASp. Transgene expression was analysed in WE-transduced hCD34+ population and its progeny after in vitro and in vivo differentiation in the Rag2−/−, γc−/− humanized mouse. We revealed very poor expression from the WE internal promoter in macrophages and erythroid cells. Therefore, we designed a novel LV including a fragment of the alternative WAS promoter in WE vector (AWE). This new vector sustained high transgene levels along the whole lymphoid lineage in vivo. Most importantly, the performance of AWE vector was highly superior to WE vector since AWE clearly improved transgene levels in in vitro and in vivo hCD34+-derived macrophages, erythroid cells, megakaryocytes and B cells while supporting a high expression in human T cells. This emphasizes that it is a suitable LV backbone for gene therapy of haematopoietic diseases such as WAS.
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