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

血液和骨髓移植临床试验网络核心临床中心

• 批准号: 10657476
• 负责人: Nirav Shah
• 金额: $ 18.48万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-27 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657476
• 关键词: Address; Adult; Alpha Granule; Area; Autologous; Autologous Transplantation; Basic Science; Blood; Blood Coagulation Disorders; Blood Component Removal; Blood Platelets; Bone Marrow Transplantation; Bypass; CD34 gene; Canis familiaris; Cell Line; Cell Therapy; Cells; Clinical; Clinical Sciences; Clinical Trials; Clinical Trials Design; Clinical Trials Network; Coagulation Process; Collaborations; Cytoplasmic Granules; Data Coordinating Center; Disease; Engraftment; Enrollment; Event; Factor VIII; Freedom; Future; Gene Modified; Gene Transduction Agent; Gene Transfer; Gene therapy trial; Genes; Goals; Hematological Disease; Hematologist; Hematology; Hematopoietic; Hemoglobinopathies; Hemophilia A; Hemorrhage; Hemostatic function; Human; Immune; Immune system; Information Dissemination; Infusion procedures; Insertional Mutagenesis; Lentivirus Vector; Malignant - descriptor; Megakaryocytes; Melphalan; Multi-Institutional Clinical Trial; Multicenter Trials; Mus; Mutagenesis; Non-Malignant; Patients; Phase; Platelet Activation; Platelet aggregation; Preclinical Testing; Recording of previous events; Refractory; Research Proposals; Risk Reduction; Safety; Scientific Advances and Accomplishments; Site; Subgroup; Testing; Therapeutic; Thrombosis; Toxic effect; Transgenes; Wisconsin; Work; Xenograft Model; Xenograft procedure; canine model; cellular transduction; chemotherapy; clinical center; conditioning; data submission; design; early phase trial; effective therapy; first-in-human; flexibility; fludarabine; gene therapy; hematopoietic cell transplantation; immunogenicity; improved outcome; inhibitor; innovation; medical schools; mouse model; multi-site trial; network models; novel; novel therapeutics; pre-clinical; programs; promoter; protocol development; receptor; response; safety and feasibility; safety assessment; success; transplantation therapy; vascular injury; vector; von Willebrand Disease

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.

项目概要： MCW造血细胞移植和细胞治疗（HCT CT）计划建议作为一个 BMT CTN核心中心基于我们在HCT、新型细胞疗法、既往招募史、质量 数据提交、临床试验设计和科学思想的新奇。我们寻求推进关键的科学 使用多位点BMT CTN平台进行血友病A基因治疗领域的I-II期研究， 血友病A和难治性FVIII抑制物患者。在过去的十年里，我们的基础科学小组 提出了利用患者自身血小板异位移植治疗重症血友病A（HA）的想法， 表达和储存FVIII以在血管损伤部位释放，在那里它可用于凝块形成。 这种方法已经在临床前同基因和异种移植小鼠模型、犬模型和小鼠模型中进行了广泛的测试。 模型，人类原代细胞和细胞系取得了巨大成功。拟议的想法是一个阶段I-II，首先在 使用降低强度调节HCT植入经修饰的基因的人类基因治疗研究 能够产生表达和储存FVIII的血小板的自体移植物。基因修饰 自体移植物通过自体单采产物的CD 34细胞选择产生，随后 用携带FVIII的B结构域缺失形式的慢病毒载体转导， ITGA 2B启动子。我们假设，在基因修饰的移植物植入后， 巨核细胞系中FVIII基因的表达将导致循环血小板的比例增加， 合成和储存FVIII。含有FVIII（免疫豁免部位）的血小板颗粒将 在发生血小板聚集和活化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用性，可诱导耐受性并恢复止血 在有抑制剂的受试者中，不需要FVIII旁路药物或耐受性FVIII输注。这 早期试验仅限于FVIII难治性抑制剂患者，这是一个没有有效治疗的亚组。 治疗和重大未满足需求的领域。在临床前试验中，血小板FVIII表达高度 即使在那些具有高滴度抑制剂的患者中也能有效止血， 血栓形成或诱变，并且能够降低抑制剂滴度。我们认为使用低强度 调节将是安全的，使其成为该领域的重大创新，并具有潜在的未来 在无抑制剂的HA患者、严重血管性血友病和其他 转基因在血小板受体疾病中的作用