Evaluation of an adenoviral vector encoding full-length human factor VIII in hemophiliac mice

Citation
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
Citations number
36
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
THROMBOSIS AND HAEMOSTASIS
ISSN journal
03406245 → ACNP
Volume
81
Issue
2
Year of publication
1999
Pages
234 - 239
Database
ISI
SICI code
0340-6245(199902)81:2<234:EOAAVE>2.0.ZU;2-0
Abstract
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.