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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 | Next Article 
Submitted July 27, 2004
Accepted September 13, 2004
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, Mattew Nicholson, Roland W Herzog, Linda B Couto, and Katherine A High*
Hematology Division, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Francis Owen Blood Research Laboratory, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
Avigen, Inc., Alameda, CA, USA
Hematology Division, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Howard Hughes Medical Institute, Children's Hospital of Philadelphia, Philadelphia, PA, USA
* Corresponding author; email: high{at}email.chop.edu.
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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