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

项目总结： MCW造血细胞移植和细胞治疗(HCT CT)计划建议作为 BMT CTN核心中心基于我们在HCT、新型细胞疗法、既往累积病史、质量方面的专业知识 数据提交、临床试验设计和科学理念的新颖性。我们寻求推进关键的科学研究 年利用多点骨髓移植CTN平台进行I-II期研究的血友病A基因治疗领域 血友病A患者和难治性FVIII抑制剂。在过去的十年里，我们的基础科学小组 提出了使用患者自己的血小板异位移植治疗重度血友病A(HA)的想法 表达和储存FVIII，以便在血管损伤部位释放，在那里它可以用于凝块形成。 这种方法已经在临床前同基因和异种移植小鼠模型、犬身上进行了广泛的测试 模型，人类原代细胞和细胞系取得了巨大的成功。提议的想法是第一阶段-第二阶段，首先是 降低强度条件下HCT植入基因修饰的人的基因治疗研究 能够产生表达和储存FVIII的血小板的自体移植物。修改后的基因 自体移植物是通过CD34细胞选择自体分离产品产生的，随后 携带B结构域缺失形式FVIII的慢病毒载体在An控制下的转导 ITGA2B启动子。我们假设，在植入基因修饰的移植物后，具有谱系特异性 巨核细胞系中FVIII基因的表达将导致一定比例的循环血小板 FVIII的合成和储存。含有FVIII(免疫特权部位)的血小板颗粒将 在发生血小板聚集和激活的血管损伤部位提供FVIII。这种方法 限制FVIII的免疫原性而不限制可获得性，可诱导耐受并恢复止血 在有抑制剂的受试者中，不需要FVIII旁路药物或耐受FVIII输注。这 早期试验仅限于具有FVIII难治性抑制剂的患者，FVIII是一个亚组，没有有效的 治疗和重大未得到满足的需求领域。在临床前试验中，血小板FVIII的表达很高 即使在那些具有高效价抑制剂的患者中也能有效止血，与 血栓形成或突变，并能够降低抑制物效价。我们认为使用较低强度的 空调将是安全的，这将是该领域的一项重大创新，具有潜在的未来 FVIII基因在无抑制剂、重型血管性血友病等HA患者中的应用 血小板受体紊乱中的转基因。

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.