Locus control region elements HS1 and HS4 enhance the therapeutic efficacy of globin gene transfer in β-thalassemic mice Journal Article


Authors: Lisowski, L.; Sadelain, M.
Article Title: Locus control region elements HS1 and HS4 enhance the therapeutic efficacy of globin gene transfer in β-thalassemic mice
Abstract: Globin gene transfer in autologous hematopoietic stem cells is a promising therapeutic option for subjects with β-thalassemia major. In this approach, high level, erythroid-specific globin transgene expression should correct ineffective erythropoiesis and hemolytic anemia following the delivery of only 1 to 2 vector copies per cell. The generation of vectors that provide high-level globin expression and require low vector copy (VC) integration is therefore essential for both safety and efficacy. We show here the major roles played by 2 lesser-known locus control region elements, termed HS1 and HS4. Partial deletions within HS4 markedly reduce in vivo globin expression requiring multiple VC per cell to correct the anemia. Most strikingly, addition of HS1 to HS2-3-4 increases globin expression by 52%, yielding 9 g Hb/VC in β-thalassemic mice. Thus, while vectors encoding HS2-3-4 provide curative levels of hemoglobin at 1 to 2 copies per cell, adding HS1 is a promising alternative strategy if upcoming clinical trials prove higher levels of expression to be necessary. © 2007 by The American Society of Hematology.
Keywords: controlled study; protein expression; gene deletion; genetics; sequence deletion; nonhuman; methodology; animal cell; mouse; animal; animals; mice; gene expression; anemia; animal experiment; animal model; gene locus; hemoglobin; gene transfer; gene vector; genetic vectors; gene therapy; globin; beta thalassemia; globin gene; transgene; beta-thalassemia; hemoglobins; autologous hematopoietic stem cell transplantation; globins; gene transfer techniques; regulator gene; cell based gene therapy; locus control region
Journal Title: Blood
Volume: 110
Issue: 13
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2007-12-15
Start Page: 4175
End Page: 4178
Language: English
DOI: 10.1182/blood-2007-08-108647
PUBMED: 17921347
PROVIDER: scopus
PMCID: PMC2234778
DOI/URL:
Notes: --- - "Cited By (since 1996): 7" - "Export Date: 17 November 2011" - "CODEN: BLOOA" - "Source: Scopus"
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  1. Michel W J Sadelain
    511 Sadelain