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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3458-3464.
Prepublished online as a Blood First Edition Paper on October 12, 2004; DOI 10.1182/blood-2004-07-2908.
 Previous Article | Table of Contents | Next Article 
GENE THERAPY
Regional intravascular delivery of AAV-2-F.IX to skeletal muscle achieves long-term correction of hemophilia B in a large animal model
Valder R. Arruda,
Hansell H. Stedman,
Timothy C. Nichols,
Mark E. Haskins,
Matthew Nicholson,
Roland W. Herzog,
Linda B. Couto, and
Katherine A. High
From the Hematology Division, Department of Pediatrics, and the Howard Hughes Medical Institute, Children's Hospital of Philadelphia, PA; the Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA; the Francis Owen Blood Research Laboratory, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill; the School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA; andAvigen, Inc,Alameda, CA.
In earlier work, we showed that adeno-associated virus–mediated delivery of a Factor IX gene to skeletal muscle by direct intramuscular injection resulted in therapeutic levels of circulating Factor IX in mice. However, achievement of target doses in humans proved impractical because of the large number of injections required. We used a novel intravascular delivery technique to achieve successful transduction of extensive areas of skeletal muscle in a large animal with hemophilia. We provide here the first report of long-term (> 3 years, with observation ongoing), robust Factor IX expression (circulating levels of 4%-14%) by muscle-directed gene transfer in a large animal, resulting in essentially complete correction of the bleeding disorder in hemophilic dogs. The results of this translational study establish an experimental basis for clinical studies of this delivery method in humans with hemophilia B. These findings also have immediate relevance for gene transfer in patients with muscular dystrophy.
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