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Lentivirus-mediated platelet-derived factor VIII gene therapy in murine haemophilia A. J Thromb Haemost 2007 Feb;5(2):352-61



Pubmed ID




Scopus ID

2-s2.0-33846453333   83 Citations


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.

Author List

Shi Q, Wilcox DA, Fahs SA, Fang J, Johnson BD, DU LM, Desai D, Montgomery RR


Bryon D. Johnson PhD Professor in the Medicine department at Medical College of Wisconsin
Robert R. Montgomery MD Clinical Professor in the Pediatrics department at Medical College of Wisconsin
Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
David A. Wilcox PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

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

Blood Platelets
Bone Marrow
Bone Marrow Transplantation
Cell Lineage
Factor VIII
Genetic Therapy
Hemophilia A
Mice, Transgenic
Transduction, Genetic
jenkins-FCD Prod-398 336d56a365602aa89dcc112f077233607d6a5abc