MSC Therapy & Immune Response in Children with Osteogenesis Imperfecta

间充质干细胞治疗

• 批准号: 8047859
• 负责人: Edwin M Horwitz
• 金额: $ 421.52万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047859
• 关键词: Address; Adverse event; Allogenic; Antibodies; Appearance; Area; Bacterial Proteins; Basic Science; Biological Assay; Blood Platelets; Bone Diseases; Bone Growth; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Therapy; Cells; Characteristics; Chemistry; Child; Childhood; Chondrocytes; Clinical; Clinical Trials; Common Terminology Criteria for Adverse Events; Complete Blood Count; Data; Development; Disease; Effector Cell; Epiphysial cartilage; Flow Cytometry; Foundations; Future; Gene Expression; Genes; Goals; Growth; HLA-DR Antigens; Hereditary Disease; Human; Immune; Immune response; Immune system; Immunologics; Immunosuppressive Agents; Infusion procedures; Intravenous infusion procedures; Laboratories; Marrow; Measurement; Mediating; Mesenchymal; Mesenchymal Stem Cells; Metabolic Pathway; Modeling; Molecular Profiling; Mus; Neomycin resistance gene; Only Child; Osteogenesis Imperfecta; Osteoporosis; Outcome; Patients; Peripheral; Phase; Physical Examination; Physiologic calcification; Property; Proteins; Quality of life; Readiness; Regenerative Medicine; Reporting; Research; Research Ethics Committees; Research Personnel; Safety; Secure; Serum; Serum Proteins; Stromal Cells; Testing; Therapeutic; Tissues; Toxic effect; Translating; Translational Research; United States National Institutes of Health; Urine; X-Ray Computed Tomography; base; body system; bone; cell growth; cell mediated immune response; conditioning; effective therapy; enzyme linked immunospot assay; fetal bovine serum; graft vs host disease; growth promoting activity; immunogenicity; impression; monocyte; next generation; novel; public health relevance; response; safety testing; stem

DESCRIPTION (provided by applicant): Mesenchymal stromal cells (MSCs), designated mesenchymal stem cells by some investigators, hold promise for the future therapy of diseases in nearly all tissues in the body. This application addresses Thematic Area 2, "Translating Basic Science Discoveries into New and Better Treatments," by building on three critical observations in our MSC research. (i) We previously demonstrated that the intravenous infusion of ex vivo- expanded MSCs unequivocally (but transiently) stimulates growth in children with severe osteogenesis imperfecta (OI), a genetic disorder of bone in which the characteristic growth deficiency has no proven effective therapy. (ii) In contrast to the much current opinion that MSCs are immune privileged, our clinical trial data suggest that MSCs may be recognized by host immune effector cells. (iii) We recently showed in a murine model that a soluble protein released by ex vivo-expanded MSCs mediates the growth-promoting activity of these primitive stromal cells. Thus, we hypothesize that repeated infusions of MSCs, by providing constant stimulation of growth-promoting activity, could maintain normal or near-normal growth rates in children with OI. In this application, we propose to test our hypothesis by conducting a clinical trial, approved by both the FDA and our IRB, in which we will intravenously infuse allogeneic MSCs into children with severe OI every 4 months for 2 years. In Aim 1, we will assess the clinical safety of repeated infusions of MSCs, while Aim 2 addresses the critical question of allogeneic MSC immunogenicity by undertaking a complete analysis of humoral and cell-mediated immune responses in fully immune competent patients receiving repeated infusions of MSCs without prior bone marrow transplantation. Demonstration of allo-reactivity in this phase of the trial would have broad implications for the continued use of allogeneic MSCs in regenerative medicine trials worldwide. Aim 3 will assess the clinical outcome of repeated infusions of MSCs in patients with severe OI, through measurements of linear growth, bone mineralization, developmental progress, and quality of life. The strengths of this proposal are the applicant's extensive track record of laboratory-based clinical trials of bone marrow cell therapy for OI, the secured regulatory approvals assuring feasibility and readiness for immediate implementation, the potential to demonstrate a novel therapy for a presently incurable pediatric disease, and the unique opportunity to prospectively evaluate the allo-immunogenicity of MSCs in immune competent patients. The data generated in this 3-year project will provide the foundation for the next generation of MSC clinical trials, not only for children with OI, but extending potentially to other disorders of bone, including osteoporosis, as well as any disorder targeted by MSC research. PUBLIC HEALTH RELEVANCE: The objective of the proposed clinical trial is to develop a novel mesenchymal stromal cell (MSC) therapy to stimulate a durable accelerated growth velocity in children with severe osteogenesis imperfecta (OI), a genetic disorder of bone in which marked growth deficiency is a cardinal manifestation. This therapeutic opportunity will enable us to prospectively evaluate the immunogenicity of allogeneic MSCs, which will not only directly benefit children with OI, but have broad ramifications for MSC research in all disorders. Thus, the outcome of this translational research will substantially impact the direction of the next generation of MSC clinical trials.

描述（由申请人提供）：间充质基质细胞（MSC），一些研究人员指定的间充质干细胞，有望在未来治疗身体几乎所有组织的疾病。该应用程序解决了主题领域2，“将基础科学发现转化为新的和更好的治疗方法”，通过建立在我们的MSC研究中的三个关键观察。(i)我们先前证明了离体扩增的MSC的静脉输注明确地（但短暂地）刺激患有严重成骨障碍（OI）的儿童的生长，所述成骨障碍是骨的遗传性疾病，其中特征性生长缺陷没有被证明有效的疗法。(ii)与目前认为MSC是免疫特权的观点相反，我们的临床试验数据表明MSC可能被宿主免疫效应细胞识别。(iii)我们最近在小鼠模型中发现，由体外扩增的MSC释放的可溶性蛋白介导这些原始基质细胞的促生长活性。因此，我们假设，通过持续刺激生长促进活性，反复输注MSC可以维持OI儿童正常或接近正常的生长速率。在本申请中，我们建议通过进行一项经FDA和IRB批准的临床试验来验证我们的假设，在该临床试验中，我们将每4个月向患有严重OI的儿童静脉输注同种异体MSC，持续2年。在目标1中，我们将评估重复输注间充质干细胞的临床安全性，而目标2通过对接受重复输注间充质干细胞而未进行骨髓移植的完全免疫功能正常的患者的体液和细胞介导的免疫应答进行全面分析，解决同种异体间充质干细胞免疫原性的关键问题。在试验的这个阶段中，同种异体反应性的证明将对在全球再生医学试验中继续使用同种异体MSC产生广泛的影响。目的3将通过测量线性生长、骨矿化、发育进展和生活质量来评估严重OI患者重复输注MSC的临床结果。该提案的优势在于申请人对骨髓细胞治疗OI的实验室临床试验的广泛跟踪记录，确保立即实施的可行性和准备就绪性的安全监管批准，证明目前无法治愈的儿科疾病的新疗法的潜力，以及前瞻性评估免疫功能正常患者中MSC的同种免疫原性的独特机会。在这个为期3年的项目中产生的数据将为下一代MSC临床试验提供基础，不仅适用于患有OI的儿童，而且可能扩展到其他骨骼疾病，包括骨质疏松症，以及MSC研究所针对的任何疾病。 公共卫生相关性：拟议的临床试验的目的是开发一种新的间充质基质细胞（MSC）疗法，以刺激患有严重成骨障碍（OI）的儿童的持久加速生长速度，OI是一种遗传性骨骼疾病，其中明显的生长缺陷是主要表现。这种治疗机会将使我们能够前瞻性地评估同种异体MSC的免疫原性，这不仅将直接使OI儿童受益，而且对所有疾病的MSC研究具有广泛的影响。因此，这项转化研究的结果将对下一代MSC临床试验的方向产生重大影响。