Abstract Number: PB0654
Meeting: ISTH 2021 Congress
Background: We have demonstrated that platelet-FVIII gene therapy restores hemostasis in Hemophilia A (HA) mice with anti-FVIII inhibitors under total body irradiation (TBI) preconditioning. Currently, Fludarabine along with busulfan (FB) as preconditioning has been shown to be highly effective for hematopoietic stem cell transplantation (HSCT) in the clinic.
Aims: To evaluate if FB works as a preconditioning approach for platelet gene therapy of HA with inhibitors.
Methods: Fludarabine was administered on days -7 through -4, and busulfan was given on days -2 and -1 into rhF8-primed HA mice. A TBI regimen was used as a parallel control. Platelet FVIII expression was introduced by transplantation of 2bF8 lentivirus (2bF8LV)-transduced HSCs. Animals were analyzed by FACS, quantitative PCR, FVIII assays, and tail bleeding test.
Results: All recipients achieved more than 55% donor-derived leukocytes at 20 weeks after HSCT with not significantly difference between the two groups. The copy number of the 2bF8 cassette and the platelet-FVIII in the FB group were not significantly different compared to the TBI group (0.93±0.17 vs 0.79±0.11 copy/cell and 4.44±1.14 and 5.16±3.19 mU/108 platelets, respectively). The bleeding phenotype was rescued in 2bF8LV-transduced recipients. Notably, anti-FVIII antibody titers declined with time under both preconditioning. The half-life of inhibitor was no significant difference between the two groups. When the titer dropped to undetectable, recipients were challenged with rhF8. There were no detectable anti-FVIII inhibitors in the transduced recipients from either the FB or TBI group. In contrast, all the untransduced control mice produced inhibitors. These data demonstrated that immune tolerance was established in 2bF8LV-transduced primed-HA mice.
Conclusions: FB preconditioning successfully introduced therapeutic levels of platelet FVIII expression, leading to phenotypic correction and immune tolerance induction in rhF8-primed HA mice. Our data suggest that this approach may be a promising clinically translatable strategy for gene therapy of hemophilia A with inhibitors.
To cite this abstract in AMA style:Chen Y, Schroeder J, Li J, Jing W, Hu J, Shi Q. Clinical Translatable Preconditioning for Platelet Gene Therapy in Murine Hemophilia A with Inhibitors [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/clinical-translatable-preconditioning-for-platelet-gene-therapy-in-murine-hemophilia-a-with-inhibitors/. Accessed November 29, 2023.
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