Too Much Of A Good Thing: High Levels Of Factor VIIa Cause Problems In Mice
April 10, 2008
Individuals with hemophilia lack either factor VIII or factor IX, proteins crucial for the cascade of events that leads to blood clotting. Although individuals with hemophilia can be treated by intravenous infusion of the factor that they miss, over time, some individuals develop antibodies that prevent the infused factor from working. Intravenous infusion of an activated form of a factor that works earlier in the blood clotting cascade, factor VII (FVIIa), has been used for over a decade to treat individuals who develop antibodies that target factor VIII or factor IX. However, some researchers and clinicians hope that FVIIa gene therapy might provide a simplified way to provide FVIIa to individuals with hemophilia. In a new study, Katherine High and colleagues, at The Children’s Hospital of Philadelphia, have determined a safe and effective level of mouse FVIIa that can be continuously expressed in hemophilia B mice through gene therapy.
The authors observed that continuous expression for up to 16 months of up to 1.5 micrograms per milliliter of mouse FVIIa, either by engineering hemophilia B mice to express this factor throughout life or by treating hemophilia B mice with gene therapy, was safe and corrected the abnormal bleeding of the mice. By contrast, continuous expression of 2 micrograms per milliliter (or more) of mouse FVIIa was associated with early mortality and with heart and lung problems. These data should provide useful information for researchers and clinicians developing gene therapy approaches for the treatment of individuals with hemophilia.
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TITLE: Long-term expression of murine activated factor VII is safe, but elevated levels cause premature mortality
AUTHOR CONTACT:
Katherine A. High
The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
http://www.chop.edu
View the PDF of this article at: http://www.the-jci.org/article.php?id=32878
Source:
Karen Honey
Journal of Clinical Investigation
