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

Emanuela Anna Roselli, Riccardo Mezzadra, Marta Claudia Frittoli, Giulietta Maruggi, Erika Biral, Fulvio Mavilio, Fabrizio Mastropietro, Antonio Amato, Giovanni Tonon, Chiara Refaldi, Maria Domenica Cappellini, Marco Andreani, Guido Lucarelli, Maria Grazia Roncarolo, Sarah Marktel, Giuliana Ferrari

Research output: Contribution to journalArticle

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 toBMtransplantation. 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.

Original languageEnglish
Pages (from-to)315-328
Number of pages14
JournalEMBO Molecular Medicine
Volume2
Issue number8
DOIs
Publication statusPublished - Aug 2010

Keywords

  • Gene therapy
  • Haematopoietic stem cells
  • Haemoglobin
  • Lentiviral vectors
  • Locus control region

ASJC Scopus subject areas

  • Molecular Medicine
  • Medicine(all)

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  • Cite this

    Roselli, E. A., Mezzadra, R., Frittoli, M. C., Maruggi, G., Biral, E., Mavilio, F., Mastropietro, F., Amato, A., Tonon, G., Refaldi, C., Cappellini, M. D., Andreani, M., Lucarelli, G., Roncarolo, M. G., Marktel, S., & Ferrari, G. (2010). Correction of β-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients. EMBO Molecular Medicine, 2(8), 315-328. https://doi.org/10.1002/emmm.201000083