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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3391. This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Johnson, P. R. Search for Related Content PubMed Articles by Johnson, P. R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Comment on Arruda et al, page 3458 Hemophilia and gene transfer: this dog might hunt Philip R. Johnson THE CHILDREN'S HOSPITAL OF PHILADELPHIA The authors have shown sustained correction of bleeding in hemophiliac dogs using a new method of viral vector–mediated gene transfer to skeletal muscle. The blight of hemophilia is well documented, dating back to ancient times. Two distinct forms of the disease (A and B) were recognized over 50 years ago. Hemophilia A (factor VIII deficiency; "classic" hemophilia) affects 1 in 10 000 live male births, whereas hemophilia B (factor IX deficiency; Christmas disease) is less common, affecting about 1 in 35 000 male births. Even though modern approaches using recombinant DNA technologies to produce clotting factors have greatly enhanced the quality and length of life, such therapies remain expensive and cumbersome. Given that both hemophilias are single-gene defects, the lure of gene transfer as a permanent cure has been like the Siren's song. Early results in large animal models had suggested that hemophilia B might be easily treated using gene transfer,1 but these preclinical results could not be reproduced in human subjects in early phase 1 trials.2,3 The issue appeared to be that an effective dose of vector could not be practically delivered to skeletal muscle in humans. In this issue of Blood, Arruda and colleagues report a new technique that ostensibly overcomes the hurdle of dose delivery. Using the canine model of hemophilia B, the authors showed that extensive regions of skeletal muscle could be transduced using recombinant adeno-associated virus (rAAV) vectors carrying the canine factor IX gene. They borrowed a technique previously tested in rodents wherein the limb vasculature is isolated, clamped, and infused with papaverine followed by a mixture of vector and histamine.4 The hemophiliac dogs so treated were found to have a rise in circulating factor IX levels from less than 1% of normal to 4% to 14%. Importantly, these levels have remained undiminished for over 3 years. Clinically, the treated dogs have had one tenth the bleeding episodes of untreated animals over the same period, thereby shifting the disease phenotype from severe to mild. At the cellular level, factor IX synthesized in the muscle was biologically active as demonstrated by the high correlation between antigen and activity. Inhibitor formation, a potential show-stopping side effect, was blocked by transient immunosuppression with cyclophosphamide at the time of vector delivery. These data have implications beyond the clotting world. Any disorder that requires large-scale transduction of skeletal muscle is fair game. For example, gene transfer for certain muscular dystrophies could be carried out in this same fashion. Also, delivery of therapeutic molecules for a variety of disease states is worthy of consideration. There are at least 2 potential drawbacks to this approach. First, the technique is highly invasive and requires a certain level of expertise. Second, even with isolation of the limb vasculature, vasoactive drugs must be given during the procedure to achieve efficient vector delivery. Less invasive alternatives can and should be sought and tested in the same dog model. However, this general approach has great merit and is likely to be successful when transferred to human subjects. Indeed, this dog might hunt. View larger version (105K): [in this window] [in a new window]   Histology of normal dog muscle 8 weeks after intravascular vector delivery by isolated limb perfusion. Immunofluorescence staining for canine F.IX, showing extensive positive staining. See the related figure in the article beginning on page 3458.   References Herzog R, Yang E, Couto L, et al. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat Med. 1999;5: 56-63.[CrossRef][Medline] [Order article via Infotrieve] Kay MA, Manno CS, Ragni MV, et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet. 2000;24: 257-261.[CrossRef][Medline] [Order article via Infotrieve] Manno CS, Chew AJ, Hutchison S, et al. AAV mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood. 2003;101: 2963-2972.[Abstract/Free Full Text] Greelish J, Su L, Lankford E, et al. Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector. Nat Med. 1999;5: 439-443.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: 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 Blood 2005 105: 3458-3464. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Johnson, P. R. Search for Related Content PubMed Articles by Johnson, P. R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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