Journal
HUMAN GENE THERAPY
Volume 23, Issue 1, Pages 15-31Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2011.048
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Funding
- European Union [005242]
- EPAN Project Network for the Development of Technology and Application of Gene Therapy in Hematopoietic Disorders
- Greek General Secretariat of Research and Technology [YB/90]
- European Commission
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To address how low titer, variable expression, and gene silencing affect gene therapy vectors for hemoglobinopathies, in a previous study we successfully used the HPFH (hereditary persistence of fetal hemoglobin)-2 enhancer in a series of oncoretroviral vectors. On the basis of these data, we generated a novel insulated self-inactivating (SIN) lentiviral vector, termed GGHI, carrying the (A)gamma-globin gene with the -117 HPFH point mutation and the HPFH-2 enhancer and exhibiting a pancellular pattern of (A)gamma-globin gene expression in MEL-585 clones. To assess the eventual clinical feasibility of this vector, GGHI was tested on CD34(+) hematopoietic stem cells from nonmobilized peripheral blood or bone marrow from 20 patients with beta-thalassemia. Our results show that GGHI increased the production of gamma-globin by 32.9% as measured by high-performance liquid chromatography ( p=0.001), with a mean vector copy number per cell of 1.1 and a mean transduction efficiency of 40.3%. Transduced populations also exhibited a lower rate of apoptosis and resulted in improvement of erythropoiesis with a higher percentage of orthochromatic erythroblasts. This is the first report of a locus control region (LCR)-free SIN insulated lentiviral vector that can be used to efficiently produce the anticipated therapeutic levels of gamma-globin protein in the erythroid progeny of primary human thalassemic hematopoietic stem cells in vitro.
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