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Blood, 1 January 2004, Vol. 103, No. 1, pp. 85-92.
Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-05-1446.
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GENE THERAPY
Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1
Valder R. Arruda,
Joerg Schuettrumpf,
Roland W. Herzog,
Timothy C. Nichols,
Nancy Robinson,
Yasmin Lotfi,
Federico Mingozzi,
Weidong Xiao,
Linda B. Couto, and
Katherine A. High
From the Department of Pediatrics, University of Pennsylvania Medical Center and The Children's Hospital of Philadelphia, PA; the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill; Avigen Inc, Alameda, CA; and the Howard Hughes Medical Institute, Philadelphia, PA.
Adeno-associated viral (AAV) vectors (serotype 2) efficiently transduce skeletal muscle, and have been used as gene delivery vehicles for hemophilia B and for muscular dystrophies in experimental animals and humans. Recent reports suggest that AAV vectors based on serotypes 1, 5, and 7 transduce murine skeletal muscle much more efficiently than AAV-2, with reported increases in expression ranging from 2-fold to 1000-fold. We sought to determine whether this increased efficacy could be observed in species other than mice. In immunodeficient mice we saw 10- to 20-fold higher levels of human factor IX (hF.IX) expression at a range of doses, and in hemophilic dogs we observed approximately 50-fold higher levels of expression. The increase in transgene expression was due partly to higher gene copy number and a larger number of cells transduced at each injection site. In all immunocompetent animals injected with AAV-1, inhibitory antibodies to F.IX developed, but in immunocompetent mice treated with high doses of vector, inhibitory antibodies eventually disappeared. These studies emphasize that the increased efficacy of AAV-1 vectors carries a risk of inhibitor formation, and that further studies will be required to define doses and treatment regimens that result in tolerance rather than immunity to F.IX.
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