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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1621.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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; Nele Vandeputte; Inge Pareyn; Inge Petrus; Peter J. Lenting; Marinee K.L. Chuah; Thierry VandenDriessche; Hans Deckmyn; Karen Vanhoorelbeke

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.

Correspondence to Karen Vanhoorelbeke, Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, E. Sabbelaan 53, 8500 Kortrijk, Tel: 32-(0)56-246422, Fax: 32-(0)56-246997, 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.

To investigate the feasibility of ectopic vWF expression by targeting the liver, vWF liver gene transfer was established in vWD mice. Multimerized vWF was expressed that could restore proper platelet plug formation in severe vWD, suggesting that the liver is 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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