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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2713-2721. Prepublished online as a Blood First Edition Paper on May 21, 2008; DOI 10.1182/blood-2008-02-138214. This Article Full Text (PDF) All Versions of this Article: blood-2008-02-138214v1 112/7/2713    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 Shi, Q. Articles by Montgomery, R. R Search for Related Content PubMed PubMed Citation Articles by Shi, Q. Articles by Montgomery, R. R Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 13, 2008 Accepted April 13, 2008 Syngeneic transplantation of hematopoietic stem cells (HSC) that are genetically modified to express factor VIII (FVIII) in platelets restores hemostasis to hemophilia A mice with pre-existing FVIII immunity Qizhen Shi*, Scot A Fahs, David A Wilcox, Erin L Kuether, Patricia A Morateck, Nicole Mareno, Hartmut Weiler, and Robert R Montgomery Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, United States Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI, United States * Corresponding author; email: qizhen.shi{at}bcw.edu. While genetic induction of FVIII expression in platelets can restore hemostasis in hemophilia A mice, this approach has not been studied in the clinical setting of pre-existing FVIII inhibitory antibodies to determine whether such antibodies would affect therapeutic engraftment. We generated a line of transgenic mice (2bF8) that express FVIII only in platelets using the platelet-specific IIb promoter and bred this 2bF8 transgene into a FVIIInull background. Bone marrow (BM) from heterozygous 2bF8 transgenic (2bF8tg+/-) mice was transplanted into immunized FVIIInull mice following lethal or sub-lethal irradiation. Following BM reconstitution, 85% of recipients survived tail clipping when 1100 cGy (myeloablative) regimen was employed, 85.7% of recipients survived when 660 cGy (non-myeloablative) regimens were employed, and 60% of recipients survived when the recipients were conditioned with 440 cGy. Our further studies showed that transplantation with 1 to 5% 2bF8tg+/- BM cells still improved hemostasis in hemophilia A mice with inhibitors. These results demonstrate that the presence of FVIII-specific immunity in recipients does not negate engraftment of 2bF8 genetically modified HSC and transplantation of these HSC can efficiently restore hemostasis to hemophilic mice with pre-existing inhibitory antibodies under either myeloablative or non-myeloablative regimens. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Killing 2 birds with 1 stone Edward G. D. Tuddenham Blood 2008 112: 2595. [Full Text] [PDF] This article has been cited by other articles: S. F. De Meyer, H. Deckmyn, and K. Vanhoorelbeke von Willebrand factor to the rescue Blood, May 21, 2009; 113(21): 5049 - 5057. [Abstract] [Full Text] [PDF] J. H. McVey FVIIa gene delivery: potential treatment for hemophilia? Blood, April 16, 2009; 113(16): 3649 - 3650. [Full Text] [PDF] P. Laje, D. Shang, W. Cao, M. Niiya, M. Endo, A. Radu, N. DeRogatis, F. Scheiflinger, P. W. Zoltick, A. W. Flake, et al. Correction of murine ADAMTS13 deficiency by hematopoietic progenitor cell-mediated gene therapy Blood, March 5, 2009; 113(10): 2172 - 2180. [Abstract] [Full Text] [PDF]

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