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

J Thromb Haemost. 2007 Feb;5(2):352-61. doi: 10.1111/j.1538-7836.2007.02346.x.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies
  • Blood Platelets*
  • Bone Marrow / metabolism
  • Bone Marrow Transplantation
  • Cell Lineage
  • Factor VIII / administration & dosage*
  • Genetic Therapy / methods*
  • Hemophilia A / immunology
  • Hemophilia A / therapy*
  • Lentivirus / genetics*
  • Mice
  • Mice, Transgenic
  • Transduction, Genetic

Substances

  • Antibodies
  • Factor VIII