Globin gene transfer for treatment of the β-thalassemias and sickle cell disease Journal Article


Authors: Sadelain, M.; Rivella, S.; Lisowski, L.; Samakoglu, S.; Riviere, I.
Article Title: Globin gene transfer for treatment of the β-thalassemias and sickle cell disease
Abstract: The β-thalassemias and sickle cell disease are severe congenital anemias that are caused by mutations that alter the production of the β chain of hemoglobin. Allogeneic hematopoietic stem cell (HSC) transplantation is curative, but this therapeutic option is not available to the majority of patients. The transfer of a functional globin gene in autologous HCSs thus represents a highly attractive alternative treatment. This strategy, simple in principle, raises major challenges in terms of controlling the expression of the globin transgene, which ideally should be erythroid specific, differentiation-stage restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, we have demonstrated that an optimised combination of proximal and distal transcriptional control elements permits lineage-specific, elevated expression of the β-globin gene, resulting in therapeutic hemoglobin production and correction of anemia in β-thalassemic mice. Several groups have now confirmed and extended these findings in various mouse models of severe hemoglobinopathies, thus generating enthusiasm for a genetic treatment based on globin gene transfer. Furthermore, globin vectors represent a general paradigm for the regulation of transgene function and the improvement of vector safety by restricting transgene expression to the differentiated progeny within a single lineage, thereby reducing the risk of activating oncogenes in hematopoietic progenitors. Here we review the principles underlying the genesis of regulated vectors for stem cell therapy. © 2004 Elsevier Ltd. All rights reserved.
Keywords: hydroxyurea; review; drug efficacy; drug safety; nonhuman; animals; mice; gene expression; gene locus; gene function; hemoglobin; allogenic bone marrow transplantation; genetic transcription; carcinogenesis; gene transfer; viral gene delivery system; stem cell; disease model; oncogene; gene activation; disease severity; gene therapy; globin; lentivirus vector; retrovirus vector; beta thalassemia; blood transfusion; graft versus host reaction; beta-thalassemia; gene control; graft rejection; disease models, animal; autologous hematopoietic stem cell transplantation; gene structure; globins; nonviral gene delivery system; beta globin; gene regulation; hemoglobinopathy; sickle cell anemia; gamma globin; anemia, sickle cell; hemoglobinopathies; regulator gene; alpha globin; humans; human; priority journal; centiviral vector; insertional oncogenesis
Journal Title: Best Practice and Research: Clinical Haematology
Volume: 17
Issue: 3
ISSN: 1521-6926
Publisher: Elsevier Inc.  
Date Published: 2004-09-01
Start Page: 517
End Page: 534
Language: English
DOI: 10.1016/j.beha.2004.08.002
PROVIDER: scopus
PUBMED: 15498721
DOI/URL:
Notes: Best Pract. Res. Clin. Haematol. -- Cited By (since 1996):16 -- Export Date: 16 June 2014 -- CODEN: BPRCA -- Source: Scopus
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MSK Authors
  1. Stefano Rivella
    16 Rivella
  2. Michel W J Sadelain
    514 Sadelain
  3. Isabelle C Riviere
    206 Riviere