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Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-05-1426.
Submitted May 14, 2003
Accepted August 19, 2003
Helper-dependent adenoviral vectors mediate therapeutic factor VIII expression for several months with minimal accompanying toxicity in a canine model of severe hemophilia A
Brian D Brown, Chang Xin Shi, Sandra Powell, David Hurlbut, Frank L Graham, and David Lillicrap*
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
Departments of Biology and Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
* Corresponding author; email: lillicrap{at}cliff.path.queensu.ca.
Two Helper-dependent adenoviral (HD) vectors encoding a canine Factor VIII B-domain deleted transgene (cFVIII) were constructed and evaluated in 4 hemophilia A dogs. One vector was regulated by the cytomegalovirus (CMV) promoter (HD-CMV-cFVIII), while the other vector contained a tissue-restricted promoter comprised of the human FVIII proximal promoter with an upstream concatemer of 5 Hepatocyte Nuclear Factor 1 binding sites (HD-HNF-cFVIII). We detected no toxicity at low dose (5x1011vp/kg), but at higher vector doses (>1x1012vp/kg) transient hepatotoxicity and thrombocytopenia were observed. Low level increases in FVIII activity were detected in all three HD-HNF-cFVIII treated dogs which corresponded with decreased whole blood clotting times. None of the animals receiving the HD-HNF-cFVIII vector developed FVIII inhibitors, and in 1 of the 3 animals, FVIII activity was sustained for over 6 months post-treatment. One animal, which received the HD-CMV-cFVIII vector, achieved peak levels of FVIII above 19000 mU/mL, but FVIII activity disappeared within one week, coincident with the development of a potent anti-canine FVIII antibody response. This study supports previous demonstrations of improved safety using HD gene transfer and suggests that these vectors can provide transient FVIII expression with minimal, acute toxicity in the absence of inhibitor formation.
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