Faculty Collaboration Database

Factor IX ectopically expressed in platelets can be stored in alpha-granules and corrects the phenotype of hemophilia B mice. Blood 2010 Aug 26;116(8):1235-43

Date

05/07/2010

Pubmed ID

20445020

Pubmed Central ID

PMC2938234

DOI

10.1182/blood-2009-11-255612

Scopus ID

2-s2.0-77955921912 (requires institutional sign-in at Scopus site)   44 Citations

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 alphaIIb promoter, to determine whether ectopically expressing FIX in megakaryocytes can enable the storage of FIX in platelet alpha-granules and corrects the murine hemophilia B phenotype. FIX was detected in the platelets and plasma of 2bF9 transgenic mice by both antigen and activity assays. Approximately 90% of total FIX in blood was stored in platelets, most of which is releasable on activation of platelets. Immunostaining demonstrated that FIX was expressed in platelets and megakaryocytes and stored in alpha-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 alpha-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.

Author List

Zhang G, Shi Q, Fahs SA, Kuether EL, Walsh CE, Montgomery RR

Authors

Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Coagulation
Blood Platelets
Blotting, Western
Bone Marrow Transplantation
Cytoplasmic Granules
Factor IX
Factor VIII
Female
Genetic Therapy
Hemophilia B
Humans
Immunization
Male
Megakaryocytes
Mice
Mice, Inbred C57BL
Mice, Transgenic
Phenotype
Platelet Count
Platelet Membrane Glycoprotein IIb
Promoter Regions, Genetic