title: Comparative analysis of FV vectors with human α- or β-globin gene regulatory elements for the correction of β-thalassemia.
abstract: β-Globin locus control region (LCR) sequences have been widely used for the regulated expression of the human β-globin gene in therapeutic viral vectors. In this study, we compare the expression of the human β-globin gene from either the HS2/HS3 β-globin LCR or the HS40 regulatory element from the α-globin locus in the context of foamy virus (FV) vectors for the genetic correction of β-thalassemia. Both regulatory elements expressed comparable levels of human β-globin in a murine erythroleukemic line, whereas in murine hematopoietic stem cells the HS40.β vector proved more efficient in β-globin expression and correction of the β-thalassemia phenotype. Following transplantation in the Hbb(th3/+) mouse model, the expression efficiency by the two vectors was similar, whereas the HS40.β 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 β-globin expression and restoration of the thalassemic phenotype as evidenced by enhanced erythropoiesis and decreased apoptosis. Our data suggest that FV vectors with the α-globin HS40 element can be used as alternative but equally efficient vehicles for human β-globin gene expression for the genetic correction of β-thalassemia.
authors: Division of Genetics and Gene Therapy, Basic Research II, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors: I
authors: I
authors: Morianos
authors: E K
authors: EK
authors: Siapati
authors: G
authors: G
authors: Pongas
authors: G
authors: G
authors: Vassilopoulos
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D019901:Locus Control Region; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016092:Spumavirus / Q000235:genetics*; D014161:Transduction, Genetic; D055542:alpha-Globins / Q000235:genetics*; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics* / Q000628:therapy*
chemical_list: D055542:alpha-Globins; D055544:beta-Globins