文章基本信息

标题：In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of β-thalassemia
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作者：Annarita Miccio ; Rossano Cesari ; Francesco Lotti 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2008
卷号：105
期号：30
页码：10547-10552
DOI：10.1073/pnas.0711666105
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Gene therapy for {beta}-thalassemia requires stable transfer of a {beta}-globin gene into hematopoietic stem cells (HSCs) and high and regulated hemoglobin expression in the erythroblastic progeny. We developed an erythroid-specific lentiviral vector driving the expression of the human {beta}-globin gene from a minimal promoter/enhancer element containing two hypersensitive sites from the {beta}-globin locus control region. Transplantation of transduced HSCs into thalassemic mice leads to stable and long-term correction of anemia with all red blood cells expressing the transgene. A frequency of 30-50% of transduced HSCs, harboring an average vector copy number per cell of 1, was sufficient to fully correct the thalassemic phenotype. In the mouse model of Cooley's anemia transplantation of transduced cells rescues lethality, leading to either a normal or a thalassemia intermedia phenotype. We show that genetically corrected erythroblasts undergo in vivo selection with preferential survival of progenitors harboring proviral integrations in genome sites more favorable to high levels of vector-derived expression. These data provide a rationale for a gene therapy approach to {beta}-thalassemia based on partially myeloablative transplantation protocols.
关键词：gene therapy ; hematopoietic stem cells ; lentiviral vector