S. Connelly et al., Evaluation of an adenoviral vector encoding full-length human factor VIII in hemophiliac mice, THROMB HAEM, 81(2), 1999, pp. 234-239
Adenoviral vectors provide a promising gene therapy system for the treatmen
t of hemophilia A. Potent vectors encoding a human factor VIII (FVIII) cDNA
were developed that mediated sustained FVIII expression in normal and hemo
philiac mice and complete phenotypic correction of the bleeding disorder in
hemophiliac mice and dogs (Connelly and Kaleko, Haemophilia 1998; 4: 380-8
). However, these studies utilized vectors encoding a truncated version of
the human FVIII cDNA lacking the B-domain (BDD FVIII). In this work, an ade
noviral vector encoding the human full-length (FL) FVIII cDNA was generated
and characterized. While functional FL FVIII was secreted in vitro, expres
sion of the FL protein was not detected in the plasma of vector-treated hem
ophiliac mice. Unexpectedly, the FL FVIII vector-treated animals demonstrat
ed phenotypic correction of the bleeding defect as measured by a rail-clip
survival study. FL FVIII protein was visualized in the mouse livers using h
uman FVIII-specific immunohistochemical analyses. These data demonstrate th
at adenoviral vector-mediated in vivo expression of BDD FVIII is more effic
ient than that of the FL protein and that phenotypic correction can occur i
n the absence of detectable levels of FVIII.