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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2316-2323. Prepublished online as a Blood First Edition Paper on November 18, 2004; DOI 10.1182/blood-2004-08-2990. This Article Full Text (PDF) All Versions of this Article: 2004-08-2990v1 105/6/2316    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Schuettrumpf, J. Articles by Arruda, V. R Search for Related Content PubMed PubMed Citation Articles by Schuettrumpf, J. Articles by Arruda, V. R Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 3, 2004 Accepted November 16, 2004 Factor IX variants improve gene therapy efficacy for hemophilia B Joerg Schuettrumpf, Roland W Herzog, Alexander Schlachterman, Antje Kaufhold, Darrel W Stafford, and Valder R Arruda* The Children's Hospital of Philadelphia, Philadelphia, PA, USA The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania Medical Center, Philadelphia, PA, USA Department of Biology, University of North Carolina, Chapel Hill, NC, USA * Corresponding author; email: arruda{at}email.chop.edu. Intramuscular (IM) injection of adeno-associated viral (AAV) vector to skeletal muscle of humans with hemophilia B is safe but higher doses are required to achieve therapeutic factor IX (F.IX) levels. The efficacy of this approach is hampered by the retention of F.IX in muscle extracellular spaces and by the limiting capacity of muscle to synthesize fully active F.IX at high expression rates. To overcome these limitations we constructed AAV vectors encoding F.IX variants for muscle- or liver-directed expression in hemophilia B mice. Circulating F.IX levels following IM injection of AAV-F.IX-K5A/V10K, a variant with low-affinity to extracellular matrix, were 2-5 fold higher compared to wild-type (WT) F.IX, while the protein specific activities remained similar. Expression of F.IX-R338A generated a protein with 2- or 6-fold higher specific activity than F.IX-WT following vector delivery to skeletal muscle or liver, respectively. F.IX-WT and variant forms provide effective hemostasis in vivo upon challenge by tail-clipping assay. Importantly, IM injection of AAV-F.IX variants did not trigger antibody formation to F.IX in mice tolerant to F.IX-WT. These studies demonstrate that F.IX variants provide a promising strategy to improve the efficacy for a variety of gene-based therapies for hemophilia B. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Gain-of-function proteins for gene transfer in hemophilia Francesco Bernardi Blood 2005 105: 2243. [Full Text] [PDF] This article has been cited by other articles: P. Simioni, D. Tormene, G. Tognin, S. Gavasso, C. Bulato, N. P. Iacobelli, J. D. Finn, L. Spiezia, C. Radu, and V. R. Arruda X-Linked Thrombophilia with a Mutant Factor IX (Factor IX Padua) N. Engl. J. Med., October 22, 2009; 361(17): 1671 - 1675. [Abstract] [Full Text] [PDF]

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