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: 9384841
• 负责人: Parameswaran N Hari
• 金额: $ 17.56万
• 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/9384841
• 关键词: Address; Adult; Alpha Granule; Area; Autologous; Autologous Transplantation; Basic Science; Blood; Blood Coagulation Disorders; Blood Component Removal; Blood Platelets; Blood Vessels; Bone Marrow Transplantation; Bypass; CD34 gene; Canis familiaris; Cell Line; Cell Therapy; Cell Transplants; Cells; Clinical; Clinical Sciences; Clinical Trials; Clinical Trials Design; Clinical Trials Network; Coagulation Process; Collaborations; Data Coordinating Center; Data Quality; Disease; Engraftment; Enrollment; Event; F8 gene; Factor VIII; Freedom; Future; Gene Targeting; Gene Transduction Agent; Gene Transfer; Gene therapy trial; Gene-Modified; Genes; Goals; Hematological Disease; Hematologist; Hematology; Hematopoietic; Hemoglobinopathies; Hemophilia A; Hemorrhage; Hemostatic function; Human; Immune; Immune system; Information Dissemination; Infusion procedures; Injury; Lead; Lentivirus Vector; Malignant - descriptor; Marrow; Megakaryocytes; Melphalan; Modeling; 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; Safety; Scientific Advances and Accomplishments; Site; Subgroup; Testing; Therapeutic; Thrombosis; Time; Toxic effect; Transgenes; Transplantation; Wisconsin; Work; Xenograft Model; Xenograft procedure; base; cellular transduction; chemotherapy; conditioning; design; effective therapy; flexibility; fludarabine; gene therapy; hematopoietic cell transplantation; immunogenicity; improved outcome; inhibitor/antagonist; innovation; medical schools; mouse model; multi-site trial; network models; novel; novel therapeutics; pre-clinical; programs; promoter; protocol development; receptor; response; safety and feasibility; success; 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.

项目摘要： MCW造血细胞移植和细胞疗法（HCT CT）计划提案作为一个提案 BMT CTN核心中心基于我们在HCT，新颖的细胞疗法，先前的历史，质量方面的专业知识 数据提交，临床试验设计和科学思想的新颖性。我们试图推进关键科学 血友病A的基因治疗区域使用多站点BMT CTN平台进行I-II期研究 血友病A和难治性FVIII抑制剂患者。在过去的十年中，我们的基础科学小组 已经提出了使用患者自己的血小板来治疗严重的血友病A（HA）的想法 表达并存储FVIII以在血管损伤部位释放，可以在其中可用于凝块形成。 该方法已在临床前和异种移植小鼠模型，犬类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I-II期，首先 人类，基因治疗研究使用降低强度调节HCT以植入基因修饰的基因 自体移植物能够产生表达和存储FVIII的血小板。基因修饰 自体移植是由自体寄作产物的CD34细胞选择产生的，其次是 在A的控制下，用带有B结构域删除的FVIII的慢病毒载体转导的转导 itga2b启动子。我们假设在植入基因修饰的移植物之后，谱系特异性 FVIII基因在巨核细胞谱系中的表达将导致一定比例的循环血小板 合成和存储FVIII。血小板含有FVIII的颗粒（一个免疫特权地点）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的免疫原性而无需限制可用性，可以诱导耐受性并恢复止血 在具有抑制剂的受试者中，不需要FVIII绕过药物或容忍FVIII输注。这 早期试验仅限于对FVIII难治性抑制剂的试验，该子组无效 治疗和大量未满足的领域。在临床前测试中，血小板FVIII表达高度 即使在具有高滴度抑制剂的患者中，有效产生止血，也无关 血栓形成或诱变，能够降低抑制剂滴度。我们相信使用较低的强度 条件将是安全的，使这是该领域的主要创新，并具有潜在的未来 在没有抑制剂的HA患者中应用FVIII基因，严重的von Willebrand病和其他 血小板受体障碍中的转基因。