Enhancing therapeutic efficacy of in vivo platelet-targeted gene therapy in hemophilia A mice.

Blood Advances
Xuefeng WangCarol H Miao

Abstract

Our previous studies demonstrated that intraosseous (IO) infusion of lentiviral vectors (LVs) carrying a modified B domain-deleted factor VIII (FVIII) transgene driven by a megakaryocyte-specific promoter (GP1Bα promoter; G-F8/N6-LV) successfully transduced hematopoietic stem cells (HSCs) to produce FVIII stored in the platelet α-granules. Platelet FVIII corrected the bleeding phenotype with limited efficacy in hemophilia A (HemA) mice with and without preexisting anti-FVIII inhibitors. The present study sought to further enhance the therapeutic efficacy of this treatment protocol by increasing both the efficiency of LV transduction and the functional activity of platelet FVIII. A combined drug regimen of dexamethasone and anti-CD8α monoclonal antibody enhanced the percentage of transduced bone marrow and HSCs over time. In G-F8/N6-LV-treated HemA mice, significant improvement in phenotypic correction was observed on day 84. To improve platelet FVIII functionality, genes encoding FVIII variant F8X10K12 with increased expression or F8N6K12RH with increased functional activity compared with F8/N6 were incorporated into LVs. Treatment with G-F8X10K12-LV in HemA mice produced a higher level of platelet FVIII but induced anti-FVIII ...Continue Reading

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