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Blood, 1 August 2006, Vol. 108, No. 3, pp. 862-869. Prepublished online as a Blood First Edition Paper on April 25, 2006; DOI 10.1182/blood-2005-06-2330. This Article Full Text (PDF) All Versions of this Article: 2005-06-2330v1 108/3/862    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pergolizzi, R. G Articles by Crystal, R. G Search for Related Content PubMed PubMed Citation Articles by Pergolizzi, R. G Articles by Crystal, R. G Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 20, 2005 Accepted January 30, 2006 Correction of a murine model of von Willebrand disease by gene transfer Robert G Pergolizzi, Guangchun Jin, Diane Chan, Lorraine Pierre, James Bussell, Barbara Ferris, Philip L Leopold, and Ronald G Crystal* Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY, USA Department of Pediatrics, Weill Medical College of Cornell University, New York, NY, USA * Corresponding author; email: geneticmedicine{at}med.cornell.edu. Von Willebrand disease (VWD), the most common inherited bleeding disorder of the U.S. population, is caused by defects in expression and processing of von Willebrand factor (VWF), a blood glycoprotein required for normal hemostasis that mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet glycoproteins and to constituents of exposed connective tissue. To assess whether VWF deficiency can be corrected by gene transfer, a plasmid expressing the intact 8.4 kb murine VWF coding sequence directed by the cytomegalovirus immediate/early promoter/enhancer was delivered via hydrodynamic tail vein injection to VWF knockout mice (VWF-/-) that exhibit defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events closely mimicking severe human VWD. VWF antigen levels in plasma from animals receiving VWF cDNA, but not controls, revealed normalized levels of circulating VWF that persists for at least 1wk after injection. Western analysis of plasma from animals receiving VWF cDNA, but not controls, revealed high-molecular weight multimers similar to the pattern observed in wild-type mice. RT-PCR on RNA isolated from liver of animals receiving VWF cDNA, but not controls, demonstrated expression of VWF is occurring in the liver, and immuohistochemical analysis of liver from treated VWF-/- mice revealed VWF-specific staining throughout the liver parenchyma, but not in endothelial cells. Plasma from treated VWF-/- mice, but not control VWF -/- mice, supported aggregation of murine platelets in the presence of botrocetin. While circulating factor VIII levels in untreated VWF -/- mice were <10% of that in wild-type mice, the VWF -/- animals treated with the VWF cDNA, but not controls, had normalized factor VIII levels to wild-type values, indicating restoration of factor VIII carrier function for VWF in the treated mice which persisted for at least 1 wk at higher doses of VWF cDNA.. Most importantly, bleeding time was normalized by 48 hr after delivery of VWF cDNA, but not by the control plasmid. These data suggest that using gene transfer of the VWF cDNA, VWF protein can be expressed, processed and secreted in a physiologically active form, and, thus, it may be possible to correct VWD using gene transfer. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M.-C. Chen, C.-F. Lin, H.-Y. Lei, S.-C. Lin, H.-S. Liu, T.-M. Yeh, R. Anderson, and Y.-S. Lin Deletion of the C-Terminal Region of Dengue Virus Nonstructural Protein 1 (NS1) Abolishes Anti-NS1-Mediated Platelet Dysfunction and Bleeding Tendency J. Immunol., August 1, 2009; 183(3): 1797 - 1803. [Abstract] [Full Text] [PDF] S. F. De Meyer, H. Deckmyn, and K. Vanhoorelbeke von Willebrand factor to the rescue Blood, May 21, 2009; 113(21): 5049 - 5057. [Abstract] [Full Text] [PDF] S. F. De Meyer, N. Vandeputte, I. Pareyn, I. Petrus, P. J. Lenting, M. K.L. Chuah, T. VandenDriessche, H. Deckmyn, and K. Vanhoorelbeke Restoration of Plasma von Willebrand Factor Deficiency Is Sufficient to Correct Thrombus Formation After Gene Therapy for Severe von Willebrand Disease Arterioscler Thromb Vasc Biol, September 1, 2008; 28(9): 1621 - 1626. [Abstract] [Full Text] [PDF] I. Marx, P. J. Lenting, T. Adler, R. Pendu, O. D. Christophe, and C. V. Denis Correction of Bleeding Symptoms in von Willebrand Factor-Deficient Mice by Liver-Expressed von Willebrand Factor Mutants Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 419 - 424. [Abstract] [Full Text] [PDF] P. J. Lenting, P. G. de Groot, S. F. De Meyer, K. Vanhoorelbeke, C. Pruss, D. Lillicrap, I. Marx, and C. V. Denis Correction of the bleeding time in von Willebrand factor (VWF)-deficient mice using murine VWF Blood, March 1, 2007; 109(5): 2267 - 2268. [Full Text] [PDF]

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