|
|
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.
 Previous Article | Next Article 
Submitted December 16, 2005
Accepted January 12, 2006
High-level expression of porcine factor VII from genetically-modified bone marrow-derived stem cells
Bagirath Gangadharan, Ernest T Parker, Lucienne M Ide, H. Trent Spencer, and Christopher B Doering*
Division of Hematology, Oncology, BMT, Department of Pediatrics, Emory University, Atlanta, Georgia, USA; Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
Division of Hematology, Oncology, BMT, Department of Pediatrics, Emory University, Atlanta, Georgia, USA; Program in Molecular and Systems Pharmacology, Graduate Division of Biological and Biomedical Sciences, Emory Universityrogram in Molecular and Systems Pharmacology, Atlanta, Georgia, USA
* Corresponding author; email: cdoerin{at}emory.edu.
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, sub-therapeutic expression of human fVIII transgenes. Porcine fVIII contains sequence elements that enable more efficient biosynthesis than human fVIII due to enhanced post-translational 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 hematopoetic 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 non-myeloablated 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 immunological 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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Bringing home the bacon for hemophilia
- Katherine P. Ponder
Blood 2006 107: 3817.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
A. Ramezani and R. G. Hawley
Correction of murine hemophilia A following nonmyeloablative transplantation of hematopoietic stem cells engineered to encode an enhanced human factor VIII variant using a safety-augmented retroviral vector
Blood,
July 16, 2009;
114(3):
526 - 534.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Ide, B. Gangadharan, K.-Y. Chiang, C. B. Doering, and H. T. Spencer
Hematopoietic stem-cell gene therapy of hemophilia A incorporating a porcine factor VIII transgene and nonmyeloablative conditioning regimens
Blood,
October 15, 2007;
110(8):
2855 - 2863.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. B. Doering, B. Gangadharan, and H. T. Spencer
Marrow-Derived Stromal Cells as Gene Transfer Vehicles in a Murine Model of Hemophilia A.
Blood (ASH Annual Meeting Abstracts),
November 16, 2006;
108(11):
5489 - 5489.
[Abstract]
[PDF]
|
|
|
|
|
