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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 14, 2007June 25, 2007; DOI 10.1182/blood-2007-04-082602. This Article 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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 2, 2007 Accepted June 12, 2007 Hematopoietic stem cell gene therapy of hemophilia A incorporating a porcine factor VIII transgene and nonmyeloablative conditioning regimens Lucienne M. Ide, Bagirath Gangadharan, K.Y. Chiang, Christopher B Doering, and H. Trent Spencer* Dept of Pediatrics, Aflac Cancer Center & Blood Disorders Service, Emory University & Children's Healthcare of Atlanta, Atlanta, GA, United States Graduate Program in Molecular & System Pharmacology, Graduate Division of Biological & Biomedical Sciences, Emory University, Atlanta, GA, United States * Corresponding author; email: hspence{at}emory.edu. 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 (BDDp)fVIII sequences provides curative fVIII levels in a hemophilia A mouse model. In the current study, we test 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 transplanted with BDDpfVIII-transduced stem cell antigen 1-positive cells exhibited moderate levels of donor cell chimerism (between 20 and 60%) and achieved sustained fVIII levels >1 U/mL. Similar results were observed in mice pre-immunized 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 pre-transplantation conditioning with targeted immunosuppression, potentially even in the context of pre-existing inhibitors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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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