The impact of GPIbα on platelet‐targeted FVIII gene therapy in hemophilia A mice with pre‐existing anti‐FVIII immunity
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. Platele...
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Veröffentlicht in: | Journal of thrombosis and haemostasis 2019-03, Vol.17 (3), p.449-459 |
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Zusammenfassung: | 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. |
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ISSN: | 1538-7933 1538-7836 1538-7836 |
DOI: | 10.1111/jth.14379 |