Lentivirus-mediated platelet-derived factor VIII gene therapy in murine haemophilia A.
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.
Shi
Q
Q
Department of Pediatrics, Medical College of Wisconsin Milwaukee, WI 53226, USA. qizhen.shi@bcw.edu
Wilcox
D A
DA
Fahs
S A
SA
Fang
J
J
Johnson
B D
BD
DU
L M
LM
Desai
D
D
Montgomery
R R
RR
D000818:Animals; D000906:Antibodies; D001792:Blood Platelets; D001853:Bone Marrow / Q000378:metabolism; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D005169:Factor VIII / Q000008:administration & dosage*; D015316:Genetic Therapy / Q000379:methods*; D006467:Hemophilia A / Q000276:immunology / Q000628:therapy*; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D014161:Transduction, Genetic
D000906:Antibodies; D005169:Factor VIII