1. ¹Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Emory University, Atlanta, Georgia, USA
2. ²Cooperative Education and Undergraduate Professional Internship Program, Georgia Institute of Technology, Atlanta, Georgia, USA

Correspondence: Christopher B. Doering, 2015 Uppergate Drive, Aflac Cancer Center and Blood Disorders Service, Emory Children's Center, Room 418, Emory University, Atlanta, Georgia 30322, USA. E-mail: cdoerin@emory.edu

Received 31 August 2006; Accepted 29 January 2007; Published online 27 March 2007.

Abstract

The development of inhibitory antibodies directed against factor VIII (fVIII) remains the most significant clinical complication associated with the treatment of hemophilia A. Recently, we demonstrated that transplantation of genetically modified hematopoietic stem cells containing a high-expression porcine fVIII transgene promoted sustained high-level fVIII expression in naïve hemophilia A mice. In the current study, a similar gene transfer strategy was tested in hemophilia A mice harboring clinically significant anti–human factor VIII (anti-hfVIII) inhibitory antibody titers. Although the majority of mice contained circulating antibodies that cross-reacted with and inhibited porcine fVIII activity, transplantation of genetically modified hematopoietic stem cells containing a porcine fVIII transgene into myeloablated hemophilia A mice induced high-level fVIII activity. Furthermore, anti-hfVIII antibody titers steadily declined throughout the course of the study. However, non-myeloablative transplantation conditioning resulted in only partial success. No correlation between pre-transplantation antibody titers and post-transplantation fVIII activity levels or donor cell engraftment was observed. These data suggest that hematopoietic stem cell transplantation–based gene therapy incorporating a high-expression porcine fVIII transgene can be utilized successfully to treat hemophilia A patients harboring anti-hfVIII inhibitors.