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Blood, 15 October 2007, Vol. 110, No. 8, pp. 2855-2863. Prepublished online as a Blood First Edition Paper on June 25, 2007; DOI 10.1182/blood-2007-04-082602. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-04-082602v1 blood-2007-04-082602v2 110/8/2855    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Ide, L. M. Articles by Spencer, H. T. Search for Related Content PubMed PubMed Citation Articles by Ide, L. M. Articles by Spencer, H. T. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Stem Cells in Hematology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Hematopoietic stem-cell gene therapy of hemophilia A incorporating a porcine factor VIII transgene and nonmyeloablative conditioning regimens Lucienne M. Ide1,2, Bagirath Gangadharan1, Kuang-Yueh Chiang1, Christopher B. Doering1, and H. Trent Spencer1,2 1 Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Emory University and Children's Healthcare of Atlanta, GA; 2 Graduate Program in Molecular and System Pharmacology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA Insufficient expression of factor VIII (fVIII) is a major hurdle in the development of successful nucleic acid treatments for hemophilia. However, we recently showed that under myeloablative and reduced-intensity total body irradiation (TBI) conditioning, transplantation of hematopoietic stem cells (HSCs) transduced with recombinant retroviruses containing B domain–deleted porcine fVIII (BDDpfVIII) sequences provides curative fVIII levels in a hemophilia A mouse model. In the current study, we tested BDDpfVIII activity after nonmyeloablative conditioning with busulfan, cyclophosphamide, or fludarabine and immunosuppressive agents CTLA4-Ig + anti-CD40L or anti-(murine)thymocyte serum (ATS). ATS is similar in action to anti-(human)thymocyte globulin (ATG), which is used clinically with busulfan in bone marrow transplantations to increase donor cell engraftment. Mice conditioned with busulfan + ATS and that received a transplant of BDDpfVIII-transduced stem-cell antigen 1-positive cells exhibited moderate levels of donor cell chimerism (between 20% and 60%) and achieved sustained fVIII levels more than 1 U/mL. Similar results were observed in mice preimmunized with human fVIII and conditioned with 5 Gy TBI + ATS or busulfan + ATS. These data demonstrate that it is possible to achieve sufficient fVIII expression after transplantation of BDDpfVIII-transduced HSCs following low-toxicity pretransplantation conditioning with targeted immunosuppression, potentially even in the context of preexisting inhibitors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: I. B. Enquist, E. Nilsson, J.-E. Mansson, M. Ehinger, J. Richter, and S. Karlsson Successful Low-Risk Hematopoietic Cell Therapy in a Mouse Model of Type 1 Gaucher Disease Stem Cells, March 1, 2009; 27(3): 744 - 752. [Abstract] [Full Text] [PDF] A. W. Nienhuis Development of gene therapy for blood disorders Blood, May 1, 2008; 111(9): 4431 - 4444. [Abstract] [Full Text] [PDF]

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