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Lentivirus‐mediated platelet‐derived factor VIII gene therapy in murine haemophilia A
Author(s) -
SHI Q.,
WILCOX D. A.,
FAHS S. A.,
FANG J.,
JOHNSON B. D.,
DU L. M.,
DESAI D.,
MONTGOMERY R. R.
Publication year - 2007
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2007.02346.x
Subject(s) - genetic enhancement , haemophilia a , haematopoiesis , haemophilia , transgene , bone marrow , immunology , transplantation , microbiology and biotechnology , cancer research , biology , stem cell , medicine , gene , genetics
Summary. Background: Previous studies from our laboratory have demonstrated that lineage‐targeted synthesis of factor VIII (FVIII) under the direction of the platelet‐specific integrin α IIb 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.