Progress Toward the Genetic Treatment of the β-Thalassemias

Authors

  • MICHEL SADELAIN,

    Corresponding author
    1. Gene Transfer and Gene Expression Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
    2. Gene Transfer and Somatic Cell Engineering Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
      Address for correspondence: Michel Sadelain, M.D., Ph.D., Laboratory of Gene Transfer and Gene Expression, Memorial Sloan-Kettering Cancer Center, Box 182, 1275 York Ave., New York, NY 10021. Voice: 212-639-6190; fax: 917-432-2340. m-sadelain@ski.mskcc.org
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  • LESZEK LISOWSKI,

    1. Gene Transfer and Gene Expression Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
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  • SELDA SAMAKOGLU,

    1. Gene Transfer and Gene Expression Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
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  • STEFANO RIVELLA,

    1. Gene Transfer and Gene Expression Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
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  • CHAD MAY,

    1. Gene Transfer and Gene Expression Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
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  • ISABELLE RIVIERE

    1. Gene Transfer and Somatic Cell Engineering Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
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Address for correspondence: Michel Sadelain, M.D., Ph.D., Laboratory of Gene Transfer and Gene Expression, Memorial Sloan-Kettering Cancer Center, Box 182, 1275 York Ave., New York, NY 10021. Voice: 212-639-6190; fax: 917-432-2340. m-sadelain@ski.mskcc.org

Abstract

Abstract: The β-thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the β-globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated β-globin gene in autologous HSCs is a highly attractive alternative treatment. This strategy, which is simple in principle, raises major challenges in terms of controlling expression of the globin transgene, which ideally should be erythroid specific, differentiation- and stage-restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, May et al. demonstrated in 2000 that an optimized combination of proximal and distal transcriptional control elements permits lineage-specific and elevated β-globin expression, resulting in therapeutic hemoglobin production and correction of anemia in β-thalassemic mice. Several groups have by now replicated and extended these findings to various mouse models of severe hemoglobinopathies, thus fueling enthusiasm for a potential treatment of β-thalassemia based on globin gene transfer. Current investigation focuses on safety issues and the need for improved vector production methodologies. The safe implementation of stem cell-based gene therapy requires the prevention of the formation of replication-competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non-tissue-specific vectors, by virtue of their late-stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell-based gene therapy.

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