Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction
Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction
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DOI：
10.1016/j.ymthe.2004.08.008
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发表时间：
2004-11-01
影响因子：
12.4
通讯作者：
Roncarolo, MG
中科院分区：
文献类型：
--
作者：
Dupré, L;Trifari, S;Roncarolo, MG
Wiskott-Aldrich综合征（WAS）是一种X连锁原发性免疫缺陷，由于感染、严重出血和淋巴瘤，中位生存期低于20岁。从HLA相同的同胞供体移植造血干细胞是一种解决方案，但可用于少数患者。遗传校正的自体造血干细胞或T细胞的移植可以代表适用于所有患者的替代治疗。我们研究了用基于MMLV的肿瘤逆转录病毒和基于HIV的慢病毒载体转移WAS基因是否可以恢复患者T细胞的正常功能。用表达来自普遍存在的PGK启动子或组织特异性WASP启动子的WASP蛋白（WASP）的慢病毒载体或用表达来自LTR的WASP的肿瘤逆转录病毒载体转导的T细胞，达到了WASP的正常水平，并纠正了功能缺陷，包括增殖、IL-2产生和脂筏上调。与肿瘤逆转录病毒载体相比，慢病毒载体以更高的速率transluced来自WAS患者的T细胞，并且有效地transluced活化的和幼稚的WAS T细胞。此外，证明了用慢病毒载体校正的T细胞的选择性生长优势。慢病毒载体介导的基因转移导致体外T细胞缺陷的纠正，这一观察结果支持其在WAS患者中用于基因治疗的应用。
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with a median survival below the age of 20 due to infections, severe hemorrhage, and lymphomas. Transplantation of hematopoietic stem cells from HLA-identical sibling donors is a resolutive treatment, but is available for a minority of patients. Transplantation of genetically corrected autologous hematopoietic stem cells or T cells could represent an alternative treatment applicable to all patients. We investigated whether WAS gene transfer with MMLV-based oncoretroviral and HIV-based lentiviral vectors could restore normal functions of patients' T cells. T cells transduced either with lentiviral vectors expressing the WAS protein (WASP) from the ubiquitous PGK promoter or the tissue-specific WASP promoter or with an oncoretroviral vector expressing WASP from the LTR, reached normal levels of WASP with correction of functional defects, including proliferation, IL-2 production, and lipid raft upregulation. Lentiviral vectors transcluced T cells from WAS patients at higher rates, compared to oncoretroviral vectors, and efficiently transcluced both activated and naive WAS T cells. Furthermore, a selective growth advantage of T cells corrected with the lentiviral vectors was demonstrated. The observation that lentiviral vector-mediated gene transfer results in correction of T cell defects in vitro supports their application for gene therapy in WAS patients.