Core Clinical Centers for the Blood and Marrow Transplant Clinical Trials Network

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Project Summary: The MCW hematopoietic cell transplant and cell therapy (HCT CT) program proposes to contribute as a BMT CTN Core Center based on our expertise in HCT, novel cell therapies, prior accrual history, quality data submission, clinical trial design and novelty of scientific idea. We seek to advance the key scientific area of gene therapy for Hemophilia A using the multi-site BMT CTN platform for a phase I-II study in patients with Hemophilia A and refractory FVIII inhibitors. Over the past decade, our basic science group has advanced the idea of curing severe Hemophilia A (HA) using patient’s own platelets to ectopically express and store FVIII for release at sites of vascular injury where it can be available for clot formation. This approach has been extensively tested in preclinical syngeneic and xenograft mouse models, canine models, human primary cells and cell lines with great success. The proposed idea is a phase I-II, first in human, gene therapy study using reduced intensity conditioning HCT to engraft a gene modified autologous graft capable of producing platelets that express and store FVIII. The gene modified autologous graft is produced by CD34 cell selection of an autologous apheresis product, followed by transduction with a lentiviral vector carrying the B domain deleted form of FVIII under the control of an ITGA2B promoter. We hypothesize that following engraftment of the gene modified graft, lineage specific expression of FVIII gene in the megakaryocyte lineage will lead to a proportion of circulating platelets synthesizing and storing FVIII. Platelets  granules containing FVIII (an immune privileged site) will provide FVIII at the sites of vascular injury where platelet aggregation and activation occurs. This approach limits the immunogenicity of FVIII without limiting availability, can induce tolerance and restore hemostasis in subjects with inhibitors without the need for FVIII bypassing agents or tolerizing FVIII infusions. This early phase trial is limited to those with refractory inhibitors to FVIII, a subgroup with no effective therapy and area of significant unmet need. In preclinical tests, platelet FVIII expression was highly effective at producing hemostasis even in those with high titer inhibitors, was not associated with thrombosis or mutagenesis and was able to lower inhibitor titers. We believe the use of lower intensity conditioning will be safe rendering this a major innovation in the field and with potential future application to FVIII gene in HA patients without inhibitors, severe von Willebrand’s disease and other transgenes in platelet receptor disorders.