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The impact of GPIbα on platelet-targeted FVIII gene therapy in hemophilia A mice with pre-existing anti-FVIII immunity. J Thromb Haemost 2019 Mar;17(3):449-459

Date

01/05/2019

Pubmed ID

30609275

Pubmed Central ID

PMC6397061

DOI

10.1111/jth.14379

Scopus ID

2-s2.0-85061041842 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

Essentials Platelet-specific FVIII gene therapy is effective in hemophilia A mice even with inhibitors. The impact of platelet adherence via VWF/GPIbα binding on platelet gene therapy was investigated. GPIbα does not significantly affect platelet gene therapy of hemophilia A with inhibitors. Platelet gene therapy induces immune tolerance in hemophilia A mice with pre-existing immunity. SUMMARY: Background We have previously demonstrated that von Willebrand factor (VWF) is essential in platelet-specific FVIII (2bF8) gene therapy of hemophilia A (HA) with inhibitory antibodies (inhibitors). At the site of injury, platelet adherence is initiated by VWF binding to the platelet GPIb complex. Objective To investigate the impact of GPIbα on platelet gene therapy of HA with inhibitors. Methods Platelet-FVIII expression was introduced by 2bF8 lentivirus (2bF8LV) transduction of hematopoietic stem cells (HSCs) from GPIbαnull (Ibnull ) mice or rhF8-primed FVIIInull (F8null ) mice followed by transplantation into lethally irradiated rhF8-primed F8null recipients. Animals were analyzed by flow cytometry, FVIII assays and the tail bleeding test. Results After transplantation, 99% of platelets were derived from donors. The macrothrombocytopenia phenotype was maintained in F8null mice that received 2bF8LV-transduced Ibnull HSCs (2bF8-Ibnull /F8null ). The platelet-FVIII expression level in 2bF8-Ibnull /F8null recipients was similar to that obtained from F8null mice that received 2bF8LV-transduced F8null HSCs (2bF8-F8null /F8null ). The tail bleeding test showed that the remaining hemoglobin level in the 2bF8-Ibnull /F8null group was significantly higher than in the F8null control group, but there was no significant difference between the 2bF8-Ibnull /F8null and 2bF8-F8null /F8null groups. The half-life of inhibitor disappearance time was comparable between the 2bF8-Ibnull /F8null and 2bF8-F8null /F8null groups. The rhF8 re-challenge did not elicit a memory immune response once inhibitor titers dropped to undetectable levels after 2bF8 gene therapy. Conclusion GPIbα does not significantly impact platelet gene therapy of HA with inhibitors. 2bF8 gene therapy restores hemostasis and promotes immune tolerance in HA mice with pre-existing immunity.

Author List

Chen J, Schroeder JA, Luo X, Montgomery RR, Shi Q

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




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

Animals
Antibodies
Blood Platelets
Disease Models, Animal
Factor VIII
Genetic Therapy
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Hemophilia A
Hemostasis
Immune Tolerance
Mice, Knockout
Platelet Adhesiveness
Platelet Glycoprotein GPIb-IX Complex
Transduction, Genetic
von Willebrand Factor