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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-03-0823.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1734-1743
GENE THERAPY
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,
Désiré Collen,
Thierry VandenDriessche, and
Stefan Kochanek
From the Center for Transgene Technology and Gene
Therapy, Flanders Interuniversity Institute for Biotechnology,
University of Leuven, Belgium; Center for Molecular
Medicine, University of Cologne, Germany; Department of
Pathology, Queen's University, Kingston, ON, Canada; and
Department of Cell Biology and Immunology, Vrije Universiteit,
Amsterdam, The Netherlands.
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
5 × 109 infectious units (IU) resulted in efficient
hepatic gene delivery and long-term expression of supraphysiologic
FVIII levels (exceeding 15 000 mU/mL), correcting the bleeding
diathesis. Injection of only 5 × 107 IU 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 because of neutralizing anti-FVIII antibodies and a cellular immune response. Vector
administration did not result in thrombocytopenia, anemia, or elevation
of the proinflammatory cytokine interleukin-6 (IL-6) and caused no or only transient elevations in serum transaminases. Following transient in vivo depletion of macrophages before gene transfer, significantly higher and stable FVIII expression levels were observed. Injection of
only 5 × 106 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 4.3 × 109 IU/kg led to
transient therapeutic canine FVIII levels that partially corrected
whole-blood clotting time. Inhibitory antibodies to canine FVIII could
not be detected, and there were no signs of hepatotoxicity or of
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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