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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4175-4178.
Prepublished online as a Blood First Edition Paper on October 5, 2007; DOI 10.1182/blood-2007-08-108647.

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GENE THERAPY

Brief Report

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

Leszek Lisowski1,2, and Michel Sadelain1

1 Center for Cell Engineering, Gene Transfer and Somatic Cell Engineering Laboratory, Department of Medicine, and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY; and 2 Cell Biology and Genetics Graduate Program, Weill Graduate School of Medical Sciences, Cornell University, New York, NY

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.


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P. Moi and M. Sadelain
Towards the genetic treatment of {beta}-thalassemia: new disease models, new vectors, new cells
Haematologica, March 1, 2008; 93(3): 325 - 330.
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