Toward Gene Therapy in Haemophilia A: Retrovirus-Mediated Transfer of a Factor VIII Gene into Murine Haematopoietic Progenitor Cells

R C Hoeben; M P W Einerhand; E Briët; H van Ormondt; D Valerio; A J van der Eb

doi:10.1055/s-0038-1648444

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1992; 67(03): 341-345
DOI: 10.1055/s-0038-1648444

Original Articles

Schattauer GmbH Stuttgart

Toward Gene Therapy in Haemophilia A: Retrovirus-Mediated Transfer of a Factor VIII Gene into Murine Haematopoietic Progenitor Cells

Authors

R C Hoeben

¹The Laboratory of Molecular Carcinogenesis, Department of Medical Biochemistry, University of Leiden, Rijswijk, The Netherlands
M P W Einerhand

²The Department of Gene Therapy, Institute for Applied Radiobiology and Immunology-TNO, Rijswijk, The Netherlands
E Briët

³The Department of Haematology, University of Leiden, Leiden, The Netherlands
H van Ormondt

¹The Laboratory of Molecular Carcinogenesis, Department of Medical Biochemistry, University of Leiden, Rijswijk, The Netherlands
D Valerio

²The Department of Gene Therapy, Institute for Applied Radiobiology and Immunology-TNO, Rijswijk, The Netherlands
A J van der Eb

¹The Laboratory of Molecular Carcinogenesis, Department of Medical Biochemistry, University of Leiden, Rijswijk, The Netherlands

Abstract

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Summary

To study and evaluate the potential of the haematopoietic system as a target for gene therapy in haemophilia A, we have infected murine bone-marrow cells with a recombinant retrovirus encoding blood-coagulation factor VIII and the bacterial enzyme neomycin-phosphotransferase. After transplantation of the infected bone marrow into lethally irradiated mice, the presence of intact vector could be demonstrated in DNA isolated from individual haematopoietic progenitor-cell-derived spleen colonies. About 8% of the spleen colonies were shown to contain the intact vector. Selection for resistance to the neomycin analogue G418 prior to transplantation specifically killed the uninfected bone-marrow cells and, as a result, over 90% of the spleen colonies contained the factor VIII vector. However, expression of factor VIII in vivo, either at the RNA or at the protein level could not be demonstrated. From these data we conclude that: 1) retroviral vectors can be used to transfer factor-VIII cDNA into haematopoietic progenitor cells; 2) the vector sequences are expressed immediately after integration; and 3) transcription of the vector is repressed in the progenitor-cell-derived cells.

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References

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