Restoration of plasma von Willebrand factor deficiency is sufficient to correct thrombus formation after gene therapy for severe von Willebrand disease.

Abstract

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 alpha1 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 FeCl(3) 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.

• Authors: Simon F De Meyer, Nele Vandeputte, Inge Pareyn, Inge Petrus, Peter J Lenting, Marinee K L Chuah, Thierry VandenDriessche, Hans Deckmyn, Karen Vanhoorelbeke
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 28 Issue 9 Pg. 1621-6 (Sep 2008) ISSN: 1524-4636 [Electronic] United States
• PMID: 18556568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chlorides
• Ferric Compounds
• SERPINA1 protein, human
• alpha 1-Antitrypsin
• von Willebrand Factor
• Factor VIII
• ferric chloride

Topics

• Animals
• Bleeding Time
• Chlorides
• Cytomegalovirus (genetics)
• Disease Models, Animal
• Factor VIII (metabolism)
• Feasibility Studies
• Ferric Compounds
• Gene Transfer Techniques
• Genetic Therapy (methods)
• Humans
• Liver (metabolism)
• Mice
• Mice, Knockout
• Platelet Adhesiveness
• Platelet Aggregation
• Promoter Regions, Genetic
• Severity of Illness Index
• Thrombosis (blood, chemically induced, genetics, therapy)
• Time Factors
• alpha 1-Antitrypsin (genetics)
• von Willebrand Diseases (blood, genetics, therapy)
• von Willebrand Factor (genetics, metabolism)