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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-10-3296.
Submitted October 30, 2002
Accepted December 3, 2002
AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B
Catherine S Manno*, Amy J Chew, Sylvia Hutchison, Peter J Larson, Roland W Herzog, Valder R Arruda, Shing Jen Tai, Margaret V Ragni, Arthur Thompson, Margareth Ozelo, Linda B Couto, Debra G B Leonard, Frederick A Johnson, Alan McClelland, Ciaran Scallan, Erik Skarsgard, Alan W Flake, Mark A Kay, Katherine A High, and Bertil Glader
Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA
Department of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
Avigen, Inc., Alameda, CA, USA
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
Biological Products Division, Bayer Corporation, Research Triangle Park, NC, USA
Hemophilia Center of PA, University of Pittsburgh, Pittsburgh, PA, USA
Puget Sound Blood Center, Seattle, WA, USA
Hematology-Hemotherapy Center, State University of Campinas, Campinas, SP, Brazil
Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA
Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
* Corresponding author; email: manno{at}email.chop.edu.
Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (F.IX). Previously, we established an experimental basis for gene transfer as a method of treating the disease in mice and hemophilic dogs through intramuscular injection of a recombinant AAV vector expressing F.IX. In this study we investigated the safety of this approach in patients with hemophilia B. In an open-label dose escalation study, adult males with severe hemophilia B (F.IX <1%) due to a missense mutation were injected at multiple intramuscular sites with a recombinant AAV vector. At doses ranging from 2 x 1011 vector genomes (vg)/kg to 1.8 x 1012 vg/kg, there was no evidence of local or systemic toxicity up to 40 months post-injection. Muscle biopsies of injection sites performed 2 to 10 months after vector administration confirmed gene transfer as evidenced by Southern blot, and transgene expression as evidenced by immunohistochemical staining. Pre-existing high titer antibodies to AAV did not prevent gene transfer or expression. Despite strong evidence for gene transfer and expression, circulating levels of F.IX were in all cases <2% and most were <1%. Although more extensive transduction of muscle fibers will be required to develop a therapy that reliably raises circulating levels to >1% in all subjects, these results of the first parenteral administration of rAAV demonstrate that administration of AAV vector by the IM route is safe at the doses tested, and effects gene transfer and expression in humans in a manner similar to that seen in animals.
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