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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.
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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.
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