Factor IX ectopically expressed in platelets can be stored in α-granules and corrects the phenotype of hemophilia B mice
- Guowei Zhang1,
- Qizhen Shi1,
- Scot A Fahs2,
- Erin L Kuether3,
- Christopher E Walsh4, and
- Robert R Montgomery1,*
- 1 Dept. of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States;
- 2 Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, United States;
- 3 Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, United States;
- 4 Mount Sinai School of Medicine, New York, NY, United States
- * Corresponding author; email: bob.montgomery{at}bcw.edu
Abstract
We developed 2bF9 transgenic mice in a hemophilia B mouse model with the expression of human factor IX (FIX) under control of the platelet-specific integrin αIIb promoter, to determine whether ectopically expressing FIX in megakaryocytes can enable the storage of FIX in platelet α-granules and corrects murine hemophilia B phenotype. FIX was detected in the platelets and plasma of 2bF9 transgenic mice by both antigen and activity assays. About 90% of total FIX in blood was stored in platelets, most of which is releasable upon activation of platelets. Immuno-staining demonstrated that FIX was expressed in platelets and megakaryocytes and stored in α-granules. All 2bF9 transgenic mice survived tail clipping, suggesting that platelet-derived FIX normalizes hemostasis in the hemophilia B mouse model. This protection can be transferred by bone marrow transplantation or platelet transfusion. However, unlike our experience with platelet FVIII, the efficacy of platelet-derived FIX was limited in the presence of anti-FIX inhibitory antibodies. These results demonstrate that releasable FIX can be expressed and stored in platelet α-granules, and that platelet-derived FIX can correct the bleeding phenotype in hemophilia B mice. Our studies suggest that targeting FIX expression to platelets could be a new gene therapy strategy for hemophilia B.
- Submitted November 24, 2009.
- Accepted April 24, 2010.
- Copyright © 2005 American Society of Hematology
