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Blood, 1 April 2005, Vol. 105, No. 7, pp. 2620. 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 Ponder, K. P. Search for Related Content PubMed Articles by Ponder, K. P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Comment on Ohlfest et al, page 2691 An ounce of prevention potentiates a pound of cure for hemophilia A Katherine Parker Ponder WASHINGTON UNIVERSITY SCHOOL OF MEDICINE Ohlfest and colleagues demonstrate that injection of human factor VIII (hFVIII) protein into hemophilia A mice shortly after birth induces long-lasting tolerance to hFVIII and allows gene therapy to be performed during adulthood with a Sleeping Beauty transposon without inhibitor formation. Hemophilia A has an incidence of 1 in 5000 males and is due to deficiency of hFVIII. The mainstay of treatment is intravenous injection of hFVIII protein prophylactically or during bleeding, which is expensive and inconvenient. Identification of alternative treatments would be a very important advance. Gene therapy for hemophilia A involves transfer of a FVIII gene into cells that can secrete functional FVIII into the blood. Gene therapy has been successful with retroviral, adenoviral, adeno-associated viral (AAV), and plasmid-based vectors after delivery to the liver or other organs.1 However, inhibitory antibodies that block the coagulation function of hFVIII have developed.2 Identifying a way to prevent inhibitor formation would be an important advance for gene therapy for hemophilia. It was reported previously that injection of hFVIII protein shortly after birth into hemophilia A mice induced tolerance to subsequent infusion of hFVIII protein during adulthood.3 Ohlfest and colleagues extend these studies here by showing that injection of hFVIII protein shortly after birth induces tolerance to subsequent gene therapy in 82% of adults that had the Sleeping Beauty transposase system delivered to their livers, allowing them to achieve stable expression at 16% of normal hFVIII levels. In contrast, all mice that received the same gene therapy procedure without neonatal tolerization developed inhibitors and lost expression in plasma. There are 2 major implications of this study. First, neonatal tolerance might be used to prepare a patient for gene or protein therapy at an older age. Indeed, 58% of hemophilia B dogs that began to receive human factor IX (hFIX) treatment shortly after birth were tolerant to infusion of hFIX at an older age, whereas 0% of those that initiated hFIX treatment at an older age were tolerant.4 However, is not clear if neonatal tolerance will be effective in humans, as their immune system is much more mature at birth than that of mice.5 Trials in which humans who are at high risk for inhibitor formation are initiated on immune tolerance induction shortly after birth might be indicated. The second important finding of this study is that therapeutic levels of hFVIII were achieved in plasma in mice after rapid high-pressure intravenous injection of the Sleeping Beauty transposon system to the liver. However, a method for delivering plasmids that does not involve a rapid highpressure injection, and demonstration that the risk of cancer is very low with this vector that integrates randomly into the chromosome, will be necessary before this approach should be considered for the use in humans with hemophilia A. References Lozier J. Gene therapy of the hemophilias. Semin Hematol. 2004;41: 287-296.[CrossRef][Medline] [Order article via Infotrieve] Key NS. Inhibitors in congenital coagulation disorders. Br J Haematol. 2004;127: 379-391.[CrossRef][Medline] [Order article via Infotrieve] Madoiwa S, Yamauchi T, Hakamata Y, et al. Induction of immune tolerance by neonatal intravenous injection of human factor VIII in murine hemophilia A. J Thromb Haemost. 2004;2: 754-762.[CrossRef][Medline] [Order article via Infotrieve] Russell KE, Olsen EH, Raymer RA, et al. Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs. Blood. 2003;102: 4393-4398.[Abstract/Free Full Text] West LJ. Developmental aspects of immunomodulation: exploiting the immature immune system for organ transplantation. Transpl Immunol. 2002;9: 149-153.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Phenotypic correction and long-term expression of factor VIII in hemophilic mice by immunotolerization and nonviral gene transfer using the Sleeping Beauty transposon system John R. Ohlfest, Joel L. Frandsen, Sabine Fritz, Paul D. Lobitz, Scott G. Perkinson, Karl J. Clark, Gary Nelsestuen, Nigel S. Key, R. Scott McIvor, Perry B. Hackett, and David A. Largaespada Blood 2005 105: 2691-2698. [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 Ponder, K. P. Search for Related Content PubMed Articles by Ponder, K. P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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