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


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.
Laboratory for Thrombosis Research, K.U. Leuven Campus Kortrijk, Belgium.
Simon F
SF
De Meyer
Nele
N
Vandeputte
Inge
I
Pareyn
Inge
I
Petrus
Peter J
PJ
Lenting
Marinee K L
MK
Chuah
Thierry
T
VandenDriessche
Hans
H
Deckmyn
Karen
K
Vanhoorelbeke
D000818:Animals; D001760:Bleeding Time; D002712:Chlorides; D003587:Cytomegalovirus / Q000235:genetics; D004195:Disease Models, Animal; D005169:Factor VIII / Q000378:metabolism; D005240:Feasibility Studies; D005290:Ferric Compounds; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D011401:Promoter Regions, Genetic; D012720:Severity of Illness Index; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000235:genetics; D014842:von Willebrand Diseases / Q000097:blood / Q000235:genetics / Q000628:therapy*; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
D002712:Chlorides; D005290:Ferric Compounds; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D014841:von Willebrand Factor; D005169:Factor VIII; C024555:ferric chloride