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 Blood, 15 May 2006, Vol. 107, No. 10, pp. 3859-3864.
Prepublished online as a Blood First Edition Paper on January 31, 2006; DOI 10.1182/blood-2005-12-4961.

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GENE THERAPY

High-level expression of porcine factor VIII from genetically modified bone marrow–derived stem cells

Bagirath Gangadharan, Ernest T. Parker, Lucienne M. Ide, H. Trent Spencer, and Christopher B. Doering

From the Division of Hematology/Oncology/BMT, Department of Pediatrics, Emory University, Atlanta, GA; the Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, GA; and the Program in Molecular and Systems Pharmacology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA.

Clinical success for gene therapy of hemophilia A will be judged by achievement of sustained, therapeutic levels of coagulation factor VIII (fVIII). Previous clinical trials have suffered from transient, subtherapeutic expression of human fVIII transgenes. Porcine fVIII contains sequence elements that enable more efficient biosynthesis than human fVIII due to enhanced posttranslational transit through the secretory pathway. In this study, we evaluated ex vivo retroviral gene transfer of a high-expression porcine fVIII transgene into bone marrow–derived stromal and hematopoietic stem/progenitor cells (MSCs and HSCs, respectively) and transplantation into genetically immunocompetent hemophilia A mice. Both MSCs and HSCs demonstrated high-level expression of porcine fVIII in vivo. However, following transplantation of gene-modified MSCs, fVIII activity levels rapidly returned to baseline due to the formation of anti–porcine fVIII–neutralizing antibodies. Alternatively, transplantation of HSCs into myeloablated and nonmyeloablated hemophilia A mice resulted in high-level fVIII expression despite low-level hematopoietic reconstitution by gene-modified cells. FVIII expression was sustained beyond 10 months, indicating that immunologic tolerance to porcine fVIII was achieved. Furthermore, transplantation of bone marrow from primary recipients into naive secondary recipients resulted in sustained, high-level fVIII expression demonstrating successful genetic modification and engraftment of HSCs.


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