Comparative analysis of FV vectors with human alpha- or beta-globin gene regulatory elements for the correction of beta-thalassemia

Abstract

beta-Globin locus control region (LCR) sequences have been widely used for the regulated expression of the human beta-globin gene in therapeutic viral vectors. In this study, we compare the expression of the human beta-globin gene from either the HS2/HS3 beta-globin LCR or the HS40 regulatory element from the alpha-globin locus in the context of foamy virus (FV) vectors for the genetic correction of beta-thalassemia. Both regulatory elements expressed comparable levels of human beta-globin in a murine erythroleukemic line, whereas in murine hematopoietic stem cells the HS40.beta vector proved more efficient in beta-globin expression and correction of the beta-thalassemia phenotype. Following transplantation in the Hbb(th3/+) mouse model, the expression efficiency by the two vectors was similar, whereas the HS40.beta vector achieved relatively more stable transgene expression. In addition, in an ex vivo assay using CD34+ cells from thalassemic patients, both vectors achieved significant human beta-globin expression and restoration of the thalassemic phenotype as evidenced by enhanced erythropoiesis and decreased apoptosis. Our data suggest that FV vectors with the alpha-globin HS40 element can be used as alternative but equally efficient vehicles for human beta-globin gene expression for the genetic correction of beta-thalassemia. Gene Therapy (2012) 19, 303-311; doi:10.1038/gt.2011.98; published online 7 July 2011