constructs) is costly, inconvenient, and incompletely effective. In addition, approximately 25 % of treated patients\ndevelop anti-factor VIII immune responses. Gene therapy that can achieve long-term phenotypic correction without\nthe complication of anti-factor VIII antibody formation is highly desired. Lentiviral vector (LV)-mediated gene transfer\ninto hematopoietic stem cells (HSCs) results in stable integration of FVIII gene into the host genome, leading\nto persistent therapeutic effect. However, ex vivo HSC gene therapy requires pre-conditioning which is highly\nundesirable for hemophilia patients. The recently developed novel methodology of direct intraosseous (IO)\ndelivery of LVs can efficiently transduce bone marrow cells, generating high levels of transgene expression in\nHSCs. IO delivery of E-F8-LV utilizing a ubiquitous EF1�± promoter generated initially therapeutic levels of FVIII,\nhowever, robust anti-FVIII antibody responses ensued neutralized functional FVIII activity in the circulation. In\ncontrast, a single IO delivery of G-FVIII-LV utilizing a megakaryocytic-specific GP1b�± promoter achieved platelet-specific\nFVIII expression, leading to persistent, partial correction of HemA in treated animals. Most interestingly, comparable\ntherapeutic benefit with G-F8-LV was obtained in HemA mice with pre-existing anti-FVIII inhibitors. Platelets is an ideal\nIO delivery vehicle since FVIII stored in �±-granules of platelets is protected from high-titer anti-FVIII antibodies; and that\neven relatively small numbers of activated platelets that locally excrete FVIII may be sufficient to promote efficient clot\nformation during bleeding. Additionally, combination of pharmacological agents improved transduction of LVs and\npersistence of transduced cells and transgene expression. Overall, a single IO infusion of G-F8-LV can generate\nlong-term stable expression of hFVIII in platelets and correct hemophilia phenotype for long term. This approach has\nhigh potential to permanently treat FVIII deficiency with and without pre-existing anti-FVIII antibodies.
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