Globin gene transfer: A paradigm for transgene regulation and vector safety Journal Article


Authors: Rivella, S.; Lisowski, L.; Sadelain, M.
Article Title: Globin gene transfer: A paradigm for transgene regulation and vector safety
Abstract: The β-thalassemias and sickle cell disease are severe congenital anemias that are caused by the defective synthesis 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 regulated β-globin gene in autologous HCSs thus represents a highly attractive alternative treatment. This strategy, simple in principle, raises major challenges in terms of controlling transgene expression, which ideally should be erythroid-specific, differentiation stage-restricted, elevated, position-independent, and sustained over time. Using lentiviral vectors, we recently demonstrated that an optimized combination of proximal and distal transcriptional control elements permits lineage-specific and 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 provide a paradigm for improving 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.
Keywords: review; nonhuman; mouse; gene expression; animal experiment; animal model; hemoglobin; cell differentiation; cell lineage; gene transfer; animalia; oncogene; transcription regulation; lentivirus; thalassemia; globin; lentivirus vector; beta thalassemia; erythroid cell; stem cell gene therapy; transgene; allogeneic hematopoietic stem cell transplantation; safety; gene insertion; mouse models; mutagenesis; lentiviral vectors; sickle cell disease; hemoglobinopathy; sickle cell anemia; hemoglobinopathies; insertional mutagenesis; hemoglobin synthesis; human; insertion sequences
Journal Title: Gene Therapy and Regulation
Volume: 2
Issue: 2
ISSN: 1388-9532
Publisher: Koninklijke Brill NV  
Date Published: 2003-01-01
Start Page: 149
End Page: 175
Language: English
DOI: 10.1163/156855803322664637
PROVIDER: scopus
DOI/URL:
Notes: Gene Ther. Regul. -- Cited By (since 1996):8 -- Export Date: 16 June 2014 -- CODEN: GTREB -- Source: Scopus
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  1. Stefano Rivella
    16 Rivella
  2. Michel W J Sadelain
    514 Sadelain