on June 12, 2008
Published online before print June 12, 2008, doi: 10.1161/ATVBAHA.108.168369
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Submitted on November 27, 2007
Accepted on June 2, 2008
Restoration of Plasma von Willebrand Factor Deficiency Is Sufficient to Correct Thrombus Formation After Gene Therapy for Severe von Willebrand Disease
Simon F. De Meyer ;
From the Laboratory for Thrombosis Research (S.F.D.M., N.V., I. Pareyn, H.D., K.V.), K.U. Leuven Campus Kortrijk, Belgium; the Center for Transgene Technology and Gene Therapy (I. Petrus, M.K.L.C., T.V.), Flanders Institute for Biotechnology (VIB), University of Leuven, Belgium; and the Laboratory for Thrombosis and Haemostasis (P.J.L.), Department of Clinical Chemistry & Haematology, University Medical Center Utrecht, The Netherlands.
* To whom correspondence should be addressed. E-mail: Karen.Vanhoorelbeke{at}kuleuven-kortrijk.be.
Objective—Gene therapy for severe von Willebrand disease (vWD) seems an interesting treatment alternative with long-term therapeutic potential. We investigated the feasibility of targeting the liver for ectopic expression of physiologically active von Willebrand factor (vWF).
Methods and Results—The capacity of transgene-encoded murine vWF to restore vWF function was studied in a mouse model of severe vWD after liver-specific gene transfer by hydrodynamic injection. By using a hepatocyte-specific 
1 antitrypsin promoter, a considerably higher and longer-lasting vWF expression was obtained when compared with a cytomegalovirus promoter, reaching maximum vWF plasma levels that are 10±1 times higher than the wild-type level. Liver-expressed vWF showed the full range of multimers, including the high molecular weight multimers, and restored factor VIII plasma levels, consistent with correction of the bleeding time 3 but not 7 days after gene transfer. Importantly, transgene encoded plasma vWF restored proper platelet adhesion and aggregation in a FeCl3 induced thrombosis model.
Conclusions—High ectopic expression of transgene encoded plasma vWF can be obtained after gene transfer to the liver. Liver-expressed vWF was fully multimerized and able to restore proper platelet plug formation in severe vWD. The liver therefore seems an attractive target for gene therapy for severe vWD.
Key words: gene therapy • von Willebrand factor • von Willebrand disease • liver • hemostasis
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