Progress toward the genetic treatment of the β-thalassemias Conference Paper


Authors: Sadelain, M.; Lisowski, L.; Samakoglu, S.; Rivella, S.; May, C.; Riviere, I.
Title: Progress toward the genetic treatment of the β-thalassemias
Conference Title: 8th Cooley's Anemia Symposium
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 afflogeneic 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. © 2005 New York Academy of Sciences.
Keywords: gene mutation; dna-binding proteins; drug safety; nonhuman; conference paper; animals; mice; anemia; mice, mutant strains; hemoglobin; hematopoietic stem cell transplantation; cell differentiation; mice, inbred c57bl; risk assessment; carcinogenesis; cell lineage; cell specificity; gene transfer; genetic vectors; mice, transgenic; oncogenes; gene expression regulation; oncogene; gene activation; transcription regulation; gene therapy; lentivirus; thalassemia; lentivirus vector; beta thalassemia; erythroid cell; stem cell gene therapy; transgene; beta-thalassemia; allogeneic hematopoietic stem cell transplantation; hematopoietic stem cell; gene silencing; disease models, animal; virus genome; severe combined immunodeficiency; transgenes; retroviridae; mutagenesis, insertional; hiv-1; globins; gene transfer techniques; gene expression regulation, viral; beta globin; β-globin; hemoglobinopathy; gamma globin; lentiviral vector; metalloproteins; locus control region; leukemia, lymphocytic; terminal repeat sequences
Journal Title Annals of the New York Academy of Sciences
Volume: 1054
Conference Dates: 2005 Mar 17-19
Conference Location: Orlando, FL
ISBN: 0077-8923
Publisher: John Wiley & Sons  
Date Published: 2005-01-01
Start Page: 78
End Page: 91
Language: English
DOI: 10.1196/annals.1345.010
PUBMED: 16339654
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 17" - "Export Date: 24 October 2012" - "CODEN: ANYAA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Chad May
    21 May
  2. Stefano Rivella
    16 Rivella
  3. Michel W J Sadelain
    451 Sadelain
  4. Isabelle C Riviere
    161 Riviere