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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 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 Citation Map 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 Hemostasis, Thrombosis, and Vascular Biology Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Syngeneic transplantation of hematopoietic stem cells that are genetically modified to express factor VIII in platelets restores hemostasis to hemophilia A mice with preexisting FVIII immunity Qizhen Shi13, Scot A. Fahs2, David A. Wilcox13, Erin L. Kuether13, Patricia A. Morateck2, Nicole Mareno2, Hartmut Weiler2, and Robert R. Montgomery13 1 Department of Pediatrics, Medical College of Wisconsin, Milwaukee; 2 Blood Research Institute, BloodCenter of Wisconsin, Milwaukee; and 3 Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee Although genetic induction of factor VIII (FVIII) expression in platelets can restore hemostasis in hemophilia A mice, this approach has not been studied in the clinical setting of preexisting 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 after lethal or sublethal irradiation. After BM reconstitution, 85% of recipients survived tail clipping when the 1100-cGy (myeloablative) regimen was used, 85.7% of recipients survived when 660-cGy (nonmyeloablative) regimens were used, 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 hematopoietic stem cells, and transplantation of these hematopoietic stem cells can efficiently restore hemostasis to hemophilic mice with preexisting inhibitory antibodies under either myeloablative or nonmyeloablative 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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