期刊
MOLECULAR THERAPY
卷 19, 期 1, 页码 122-132出版社
CELL PRESS
DOI: 10.1038/mt.2010.226
关键词
-
资金
- Chronic Granulomatous Disorder Research Trust, London [J4G/04B/GT]
- Deutsche Forschungsgemeinschaft (Bonn, Germany) [GRK 1172]
- Spanish government
- Ministerio de Ciencia e Innovacion [LE2009/0100, SAF2009-07164]
- European Program PERSIST
- Fondo de Investigaciones Sanitarias [RETIC-RD06/241]
- Fundacion Marcelino Botin
- Great Ormond Street Hospital Childrens Charity [V1223] Funding Source: researchfish
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000644, ZIAAI000988, ZIAAI000991, ZIAAI000645] Funding Source: NIH RePORTER
X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency caused by mutations in the CYBB gene encoding the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase catalytic subunit gp91(phox). A recent clinical trial for X-CGD using a spleen focus-forming virus (SFFV)-based gamma-retroviral vector has demonstrated clear therapeutic benefits in several patients although complicated by enhancer-mediated mutagenesis and diminution of effectiveness over time due to silencing of the viral long terminal repeat (LTR). To improve safety and efficacy, we have designed a lentiviral vector that directs transgene expression primarily in myeloid cells. To this end, we created a synthetic chimeric promoter that contains binding sites for myeloid transcription factors CAAT box enhancer-binding family proteins (C/EBPs) and PU.1, which are highly expressed during granulocytic differentiation. As predicted, the chimeric promoter regulated higher reporter gene expression in myeloid than in nonmyeloid cells, and in human hematopoietic progenitors upon granulocytic differentiation. In a murine model of stem cell gene therapy for X-CGD, the chimeric vector resulted in high levels of gp91(phox) expression in committed myeloid cells and granulocytes, and restored normal NADPH-oxidase activity. These findings were recapitulated in human neutrophils derived from transduced X-CGD CD34(+) cells in vivo, and suggest that the chimeric promoter will have utility for gene therapy of myeloid lineage disorders such as CGD.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据