慢性肉芽肿性疾病
遗传增强
生物
病毒载体
插入突变
载体(分子生物学)
烟酰胺腺嘌呤二核苷酸磷酸
突变
基因
免疫学
癌症研究
遗传学
突变
氧化酶试验
重组DNA
生物化学
基因组
酶
作者
Isabelle Barde,Elisa Laurenti,Sonia Verp,Maciej Wiznerowicz,Sandra Offner,A. Viornery,Anne Galy,Andreas Trumpp,Didier Trono
出处
期刊:Gene Therapy
[Springer Nature]
日期:2011-05-05
卷期号:18 (11): 1087-1097
被引量:45
摘要
Insertional mutagenesis represents a serious adverse effect of gene therapy with integrating vectors. However, although uncontrolled activation of growth-promoting genes in stem cells can predictably lead to oncological processes, this is far less likely if vector transcriptional activity can be restricted to fully differentiated cells. Diseases requiring phenotypic correction only in mature cells offer such an opportunity, provided that lineage/stage-restricted systems can be properly tailored. In this study, we followed this reasoning to design lentiviral vectors for the gene therapy of chronic granulomatous disease (CGD), an immune deficiency due a loss of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes, most often secondary to mutations in gp91(phox). Using self-inactivating HIV1-derived vectors as background, we first expressed enhanced green fluorescent protein (eGFP) from a minimal gp91(phox) promoter, adding various natural or synthetic transcriptional regulatory elements to foster both specificity and potency. The resulting vectors were assessed either by transplantation or by lentiviral transgenesis, searching for combinations conferring strong and specific expression into mature phagocytic cells. The most promising vector was modified to express gp91(phox) and used to treat CGD mice. High-level restoration of NADPH activity was documented in granulocytes from the treated animals. We propose that this lineage-specific lentiviral vector is a suitable candidate for the gene therapy of CGD.
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