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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-03-0823.
Submitted March 15, 2002
Accepted October 8, 2002
Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of hemophilia A following gene therapy with high-capacity adenoviral vectors
Marinee K L Chuah, Gudrun Schiedner, Lieven Thorrez, Brian Brown, Marion Johnston, Veerle Gillijns, Sabine Hertel, Nico Van Rooijen, David Lillicrap, Desire Collen, Thierry VandenDriessche*, and Stefan Kochanek
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology - University of Leuven, Leuven, Belgium
Center for Molecular Medicine, University of Cologne, Cologne, Germany
Department of Pathology, Queen's University, Kingston, ON, Canada
Department of Cell Biology & Immunology, Vrije Universiteit, Amsterdam, The Netherlands
* Corresponding author; email: thierry.vandendriessche{at}med.kuleuven.ac.be.
High-capacity adenoviral (HC-Ad) vectors expressing B-domain deleted human or canine factor VIII from different liver-specific promoters were evaluated for gene therapy of hemophilia A. Intravenous administration of these vectors into hemophilic FVIII-deficient immunodeficient SCID mice (FVIIIKO-SCID) at a dose of 5x109 i.u. resulted in efficient hepatic gene delivery and long-term expression of supra-physiologic FVIII levels (exceeding 15,000 mU/ml), correcting the bleeding diathesis. Injection of only 5x107 i.u. still resulted in therapeutic FVIII levels. In immunocompetent hemophilic FVIII-deficient mice (FVIIIKO), FVIII expression levels peaked at 75,000 mU/ml but declined thereafter due to neutralizing anti-FVIII antibodies and a cellular immune response. Vector administration did not result in thrombocytopenia, anemia or elevation of the pro-inflammatory cytokine IL-6 and caused no or only transient elevations in serum transaminases. Following transient in vivo depletion of macrophages prior to gene transfer, significantly higher and stable FVIII expression levels were observed. Injection of only 5x106 HC-Ad vectors after macrophage depletion resulted in long-term therapeutic FVIII levels in the FVIIIKO and FVIIIKO-SCID mice. Intravenous injection of an HC-Ad vector into a hemophilia A dog at a dose of 4.3x109 i.u./kg led to transient therapeutic canine FVIII levels that partially corrected the whole blood clotting time. Inhibitory antibodies to canine FVIII could not be detected and there were no signs of hepatotoxicity nor hematologic abnormalities. These results contribute to a better understanding of the safety and efficacy of HC-Ad vectors and suggest that the therapeutic window of HC-Ad vectors could be improved by minimizing the interaction between HC-Ad vectors and the innate immune system.
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