Lentivirus-mediated platelet-derived factor VIII gene therapy in murine haemophilia A.

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.

• 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)

Chemical References

• Antibodies
• Factor VIII

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