Publication Date:
2007-11-16
Description:
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 transgene expression is needed to correct ineffective erythropoiesis and hemolytic anemia following the delivery of few copies of therapeutic vector per cell. Several groups have successfully treated mouse models of severe hemoglobinopathies utilizing lentiviral vectors encoding β- or γ-globin genes placed under the transcriptional control of the human β-globin promoter and the HS2, HS3 and HS4 elements of the β-globin locus control region. The HS2 and HS3 elements are the most powerful and the best characterized single elements within the LCR. The relative importance of HS1 and HS4 is less well defined. We show here the major roles played by HS1 and HS4, which although not seen in MEL cells, are striking in β-thalassemic mice. The effect of HS1 element was tested in vectors, derived from the previously published TNS9 vector, that harbor different globin promoters (either 265, 615 or 1555bp in length). Addition of HS1 to vectors containing the 615bp or 1555bp promoters had no effect on average transgene expression per vector copy (VC) and even decreased average transgene expression from 38±3% (n=32 MEL cell pools) to 26±2% (n=23) of endogenous β-globin levels (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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