Abstract | BACKGROUND: Previous studies from our laboratory have demonstrated that lineage-targeted synthesis of factor VIII (FVIII) under the direction of the platelet-specific integrin alphaIIb gene promoter (2bF8) can correct the murine haemophilia A phenotype even in the presence of high titer inhibitory antibodies in a transgenic mouse model. OBJECTIVE: In this study, we assessed the efficacy of using a genetic therapy approach to correct haemophilia A in FVIII-deficient (FVIII(null)) mice by transplantation of bone marrow (BM) transduced with a lentivirus (LV)-based gene transfer cassette encoding 2bF8. RESULTS: Functional FVIII activity (FVIII:C) was detected in platelet lysates from treated mice and the levels were similar to 2bF8 heterozygous transgenic mice. Mice transplanted with 2bF8 LV-transduced BM survived tail clipping and we did not detected inhibitory or non-inhibitory FVIII antibodies over the period of this study (11 months). Furthermore, BM transferred from the primary transplant recipients into FVIII(null) secondary recipients demonstrated sustained platelet-FVIII expression leading to correction of the haemophilia A phenotype showing that gene transfer occurred within long-term repopulating haematopoietic stem cells. CONCLUSIONS: These results demonstrate that ectopic expression of FVIII in platelets by lentivirus-mediated bone marrow transduction/ transplantation may be a promising strategy for gene therapy of haemophilia A in humans.
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Authors | Q Shi, D A Wilcox, S A Fahs, J Fang, B D Johnson, L M DU, D Desai, R R Montgomery |
Journal | Journal of thrombosis and haemostasis : JTH
(J Thromb Haemost)
Vol. 5
Issue 2
Pg. 352-61
(Feb 2007)
ISSN: 1538-7933 [Print] England |
PMID | 17269937
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
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Topics |
- Animals
- Antibodies
- Blood Platelets
- Bone Marrow
(metabolism)
- Bone Marrow Transplantation
- Cell Lineage
- Factor VIII
(administration & dosage)
- Genetic Therapy
(methods)
- Hemophilia A
(immunology, therapy)
- Lentivirus
(genetics)
- Mice
- Mice, Transgenic
- Transduction, Genetic
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