Factor IX ectopically expressed in platelets can be stored in α-granules and corrects the phenotype of hemophilia B mice
| Autor: | Christopher E. Walsh, Qizhen Shi, Erin L. Kuether, Guowei Zhang, Scot A. Fahs, Robert R. Montgomery |
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| Rok vydání: | 2010 |
| Předmět: |
Blood Platelets
Male Platelet Membrane Glycoprotein IIb Genetically modified mouse medicine.medical_specialty Transgene Blotting Western Immunology Mice Transgenic Biology Cytoplasmic Granules Hemophilia B Biochemistry Factor IX Mice Internal medicine Coagulopathy medicine Animals Humans Platelet Promoter Regions Genetic Blood Coagulation Bone Marrow Transplantation Factor VIII Hematology Platelet Count Gene Therapy Genetic Therapy Cell Biology medicine.disease Molecular biology Mice Inbred C57BL Phenotype Platelet transfusion Hemostasis Female Immunization Megakaryocytes medicine.drug |
| Zdroj: | Blood. 116:1235-1243 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2009-11-255612 |
| Popis: | 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 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 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. |
| Databáze: | OpenAIRE |
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