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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.
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Submitted September 7, 2005
Accepted January 31, 2006
Phenotypic correction of von Willebrand disease type 3 blood-derived endothelial cells with lentiviral vectors expressing von Willebrand factor
Simon F De Meyer, Karen Vanhoorelbeke, Marinee K Chuah, Inge Pareyn, Veerle Gillijns, Robert P Hebbel, Desire Collen, Hans Deckmyn, and Thierry VandenDriessche*
Laboratory for Thrombosis Research, K.U. Leuven Campus Kortrijk, Kortrijk, Belgium
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, Leuven, Belgium
Vascular Biology Center and Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
* Corresponding author; email: thierry.vandendriessche{at}med.kuleuven.be.
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 since it is caused by a single gene defect and since 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 (8.4kb) and the inherent complexity of the VWF protein which requires extensive post-translational 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/24hr/106 cells), with normal binding to GPIb 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.
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