Correction of β‐thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients

EA Roselli, R Mezzadra, MC Frittoli… - EMBO molecular …, 2010 - embopress.org
EA Roselli, R Mezzadra, MC Frittoli, G Maruggi, E Biral, F Mavilio, F Mastropietro, A Amato…
EMBO molecular medicine, 2010embopress.org
Abstract β‐Thalassemia is a common monogenic disorder due to mutations in the β‐globin
gene and gene therapy, based on autologous transplantation of genetically corrected
haematopoietic stem cells (HSCs), holds the promise to treat patients lacking a compatible
bone marrow (BM) donor. We recently showed correction of murine β‐thalassemia by gene
transfer in HSCs with the GLOBE lentiviral vector (LV), expressing a transcriptionally
regulated human β‐globin gene. Here, we report successful correction of thalassemia major …
Abstract
β‐Thalassemia is a common monogenic disorder due to mutations in the β‐globin gene and gene therapy, based on autologous transplantation of genetically corrected haematopoietic stem cells (HSCs), holds the promise to treat patients lacking a compatible bone marrow (BM) donor. We recently showed correction of murine β‐thalassemia by gene transfer in HSCs with the GLOBE lentiviral vector (LV), expressing a transcriptionally regulated human β‐globin gene. Here, we report successful correction of thalassemia major in human cells, by studying a large cohort of pediatric patients of diverse ethnic origin, carriers of different mutations and all candidates to BM transplantation. Extensive characterization of BM‐derived CD34+ cells before and following gene transfer shows the achievement of high frequency of transduction, restoration of haemoglobin A synthesis, rescue from apoptosis and correction of ineffective erythropoiesis. The procedure does not significantly affect the differentiating potential and the relative proportion of haematopoietic progenitors. Analysis of vector integrations shows preferential targeting of transcriptionally active regions, without bias for cancer‐related genes. Overall, these results provide a solid rationale for a future clinical translation.
See accompanying article: http://dx.doi.org/10.1002/emmm.201000086
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