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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4728-4736. Prepublished online as a Blood First Edition Paper on February 14, 2006; DOI 10.1182/blood-2005-09-3605.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Phenotypic correction of von Willebrand disease type 3 blood-derived endothelial cells with lentiviral vectors expressing von Willebrand factorFrom the Laboratory for Thrombosis Research, Catholic University of Leuven Campus Kortrijk, Kortrijk, Belgium; the Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, Belgium; and the Vascular Biology Center and Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis.
Von Willebrand disease (VWD) is an inherited bleeding disorder, caused by quantitative (type 1 and 3) or qualitative (type 2) defects in von Willebrand factor (VWF). Gene therapy is an appealing strategy for treatment of VWD because it is caused by a single gene defect and because VWF is secreted into the circulation, obviating the need for targeting specific organs or tissues. However, development of gene therapy for VWD has been hampered by the considerable length of the VWF cDNA (8.4 kb [kilobase]) and the inherent complexity of the VWF protein that requires extensive posttranslational processing. In this study, a gene-based approach for VWD was developed using lentiviral transduction of blood-outgrowth endothelial cells (BOECs) to express functional VWF. A lentiviral vector encoding complete human VWF was used to transduce BOECs isolated from type 3 VWD dogs resulting in high-transduction efficiencies (95.6% ± 2.2%). Transduced VWD BOECs efficiently expressed functional vector-encoded VWF (4.6 ± 0.4 U/24 hour per 106 cells), with normal binding to GPIb
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
and collagen and synthesis of a broad range of multimers resulting in phenotypic correction of these cells. These results indicate for the first time that gene therapy of type 3 VWD is feasible and that BOECs are attractive target cells for this purpose. 