Faculty Collaboration Database

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. Blood 2008 Oct 01;112(7):2713-21

Date

05/23/2008

Pubmed ID

18495954

Pubmed Central ID

PMC2556608

DOI

10.1182/blood-2008-02-138214

Scopus ID

2-s2.0-53449090226 (requires institutional sign-in at Scopus site)   86 Citations

Abstract

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 alphaIIb promoter and bred this 2bF8 transgene into a FVIII(null) background. Bone marrow (BM) from heterozygous 2bF8 transgenic (2bF8(tg+/-)) mice was transplanted into immunized FVIII(null) 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% 2bF8(tg+/-) 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.

Author List

Shi Q, Fahs SA, Wilcox DA, Kuether EL, Morateck PA, Mareno N, Weiler H, Montgomery RR

Authors

Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin
David A. Wilcox PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Biological Assay
Blood Platelets
Factor VIII
Genetic Therapy
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Hemophilia A
Hemostasis
Immunity
Immunization
Mice
Myeloablative Agonists
Phenotype
Reverse Transcriptase Polymerase Chain Reaction
Time Factors
Transformation, Genetic
Transgenes
Transplantation Conditioning
Transplantation, Isogeneic