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- Title
483. Phenotypic Correction of Von Willebrand Disease Type 3 Blood-Derived Endothelial Cells with Lentiviral Vectors Expressing Von Willebrand Factor.
- Authors
DeMeyer, Simon F.; Van hoorelbeke, Karen; Chuah, Marinee K.; Pareyn, Inge; Gilijns, Veerle; Hebbel, Robert P.; Collen, Désiré; Vandendriessche, Thierry
- Abstract
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 that 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 constructed and used to transduce BOECs isolated from type 3 VWD dogs, which are completely deficient in VWF synthesis due to a point mutation in the VWF gene. High transduction efficiencies were obtained (95.6±2.2%) and transduced VWD BOECs efficiently expressed functional vector-encoded VWF (4.6±0.4 U/24 hr/106 cells), with normal binding to factor VIII, GPIbα 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.Molecular Therapy (2006) 13, S187–S187; doi: 10.1016/j.ymthe.2006.08.552
- Subjects
VON Willebrand disease; VON Willebrand factor; CELLS; GENE therapy; GENETIC transduction
- Publication
Molecular Therapy, 2006, Vol 13, pS187
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1016/j.ymthe.2006.08.552