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

I. Morianos; E. K. Siapati; G. Pongas; G. Vassilopoulos

doi:10.1038/gt.2011.98

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

I. Morianos, E. K. Siapati, G. Pongas, G. Vassilopoulos

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Pages (from-to)	303-311
Number of pages	9
Journal	Gene therapy
Volume	19
Issue number	3
DOIs	https://doi.org/10.1038/gt.2011.98
State	Published - Mar 2012
Externally published	Yes

Bibliographical note

Funding Information:
We thank Dr G Stamatoyannopoulos, Q Li and D Emery from the University of Washington (Seattle, WA) for the HS40 plasmid; Dr N Anagnou for providing the Hbbth3/+ mice; and Drs E Gouseti, S Grafako and A Kattamis (Children’s Hospital, Agia Sofia, Athens, Greece) for providing b-thalassemia patient samples. The work was supported from an EU grant (CONSERT LSHB-CT-2004-005242) and a grant from the Greek GSRT (PENED 603).

Keywords

HS40
foamy virus
thalassemia
β-globin

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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.",

keywords = "HS40, foamy virus, thalassemia, β-globin",

author = "I. Morianos and Siapati, {E. K.} and G. Pongas and G. Vassilopoulos",

note = "Funding Information: We thank Dr G Stamatoyannopoulos, Q Li and D Emery from the University of Washington (Seattle, WA) for the HS40 plasmid; Dr N Anagnou for providing the Hbbth3/+ mice; and Drs E Gouseti, S Grafako and A Kattamis (Children{\textquoteright}s Hospital, Agia Sofia, Athens, Greece) for providing b-thalassemia patient samples. The work was supported from an EU grant (CONSERT LSHB-CT-2004-005242) and a grant from the Greek GSRT (PENED 603).",

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AU - Vassilopoulos, G.

N1 - Funding Information: We thank Dr G Stamatoyannopoulos, Q Li and D Emery from the University of Washington (Seattle, WA) for the HS40 plasmid; Dr N Anagnou for providing the Hbbth3/+ mice; and Drs E Gouseti, S Grafako and A Kattamis (Children’s Hospital, Agia Sofia, Athens, Greece) for providing b-thalassemia patient samples. The work was supported from an EU grant (CONSERT LSHB-CT-2004-005242) and a grant from the Greek GSRT (PENED 603).

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N2 - 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.

AB - 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.

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

Abstract

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