Submitted January 31, 2003
Accepted May 15, 2003
A gene deleted adenoviral vector results in phenotypic correction of canine hemophilia B without liver toxicity or thrombocytopenia
Anja Ehrhardt, Hui Xu, Aaron M Dillow, Dwight A Bellinger, Timothy C Nichols, and Mark A Kay*
Pediatrics and Genetics, Stanford University, Palo Alto, CA, USA
Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
* Corresponding author; email: markay{at}stanford.edu.
Many approaches for treating hemophilia via gene transfer have been attempted in large animal models but all have potential drawbacks. Recombinant adenoviral vectors offer high efficiency transfer of an episomal vector but has been plagued by the cytotoxicity/immunogenicity of early generation vectors that contain viral genes. In our current study, we have used a non-integrating helper dependent (HD) adenoviral vector for liver directed gene transfer to achieve hemostatic correction in a hemophilia B dog. We measured plasma canine factor IX (cFIX) concentrations at a therapeutic range for up to 2.5 months, and normalization of the whole blood clotting time (WBCT) for about a month. This was followed by a decrease, and stabilized partial correction for 4.5 months. Hepatic gene transfer of a slightly lower dose of the HD vector, resulted in WBCTs that were close to normal for two weeks suggesting a dose threshold effect in dogs. In sharp contrast to other studies using first or second generation adenoviral vectors, we observed no vector-related elevation of liver enzymes, no fall in platelet counts, and normal liver histology. Taken together, this study demonstrates that injection of an adenoviral HD vector results in complete but transient phenotypic correction of factor IX deficiency in canine models with no detectable toxicity.
