Genetically-engineered stem cells for self-regulating arthritis therapy

用于自我调节关节炎治疗的基因工程干细胞

• 批准号: 10630757
• 负责人: Farshid Guilak
• 金额: $ 11.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630757
• 关键词: Adverse event; Affect; Anatomy; Animal Model; Anti-Cytokine Therapy; Apoptosis; Autoimmune Diseases; Biological Response Modifier Therapy; Cartilage; Cell Therapy; Cells; Chronic; Clinical; Clinical Trials; Clinical assessments; Collagen Arthritis; Complex; Data; Degenerative polyarthritis; Development; Diagnosis; Disabled Persons; Disease; Early Diagnosis; Early treatment; Emission-Computed Tomography; Engineering; Enzymes; Flare; Future; Genetic; Genetic Engineering; Goals; Gold; Health Promotion; Histologic; Image; Imaging technology; Implant; In Vitro; Inflammation; Inflammatory; Inflammatory Arthritis; Interleukin-1; Interleukin-6; Intervention; Joints; K/BxN model; Laboratories; Light; Measurement; Measures; Mentorship; Metabolic; Methodology; Modeling; Molecular; Monitor; Mus; Musculoskeletal; Osteoclasts; Osteogenesis; Osteoporosis; Output; Pain Measurement; Patients; Pattern; Physical Examination; Population; Positron-Emission Tomography; Prediction of Response to Therapy; Prevention; Process; Production; Receptor Gene; Reporting; Research; Rheumatoid Arthritis; Safety; Series; Serum; Site; Synovial Membrane; System; TNF gene; Testing; Therapeutic Intervention; Time; Tissues; Tracer; Translating; X-Ray Computed Tomography; arthritis therapy; arthropathies; base; bone; bone erosion; bone metabolism; bone turnover; career development; clinical remission; collagen antibody induced arthritis; cytokine; design; engineered stem cells; fluorodeoxyglucose; imaging biomarker; imaging modality; in vivo; ineffective therapies; insight; joint inflammation; microCT; molecular imaging; mouse model; next generation; novel; outcome prediction; personalized medicine; preservation; radiological imaging; response; spatiotemporal; therapy resistant; translational goal; translational scientist; treatment response; uptake

PROJECT SUMMARY/ABSTRACT Rheumatoid arthritis (RA) is the most common chronic inflammatory and destructive joint disease, affecting 1% of the population worldwide. Perpetuation of inflammatory processes within the synovial tissue leads to local activation of tissue‐degrading enzymes and formation of bone‐resorbing osteoclasts, provoking progressive cartilage and bone destruction. Therefore, early diagnosis of inflammatory processes and prevention of bone and cartilage destruction are crucial to preserve function in RA. Currently, early assessment of RA disease activity and response to therapy mainly consists of physical examination, patient reports, and laboratory analyses. Thus, there is a clear need to develop precision-based therapy for patients with RA in tandem with non-invasive molecular imaging to predict therapeutic response, and limit adverse events and ineffective therapies. Conventional radiography remains the first choice for the assessment of structural bone and cartilage damage in RA patients. Novel imaging methods, such as combined positron emission tomography/computed tomography (PET/CT) provide insights into pathophysiological processes together with whole-body anatomical localization. 18F-FDG has been used to localize articular inflammatory processes in patients suffering from RA; showing not only increased uptake of 18F-FDG in inflamed joints, but also a strong correlation with disease activity. PET imaging with the bone tracer 18F-NaF has shown high bone turnover in RA, osteoarthritis, and osteoporosis. Our group has developed cell-based implants that can deliver multiplexed anti-cytokine therapies for treating rheumatoid arthritis (RA) or other autoimmune diseases in a self-regulating manner for extended durations. Our approach is to longitudinally characterize pattern and intensity of joint inflammation and bone erosion to identify changes that reflect sensitivity or resistance to the therapy administered. The overall translational goal is to leverage imaging methodologies with imaging biomarkers to assess the efficacy of next generation cell-based therapies using in vivo mouse models of RA. This approach will enable us to systematically test our central hypothesis: RA inflammation and bone erosion will be reversed after therapeutic intervention. To test this hypothesis in a site-specific manner, we will assess spatio-temporal metabolic changes in synovium and bone leveraging 18F-FDG and 18F-NaF PET/CT. Our comprehensive approach using molecular imaging biomarkers will better inform our assessment of different biologic therapies in mice. We expect this study to provide data that shifts our current understanding about RA therapies and intervention response. This research will influence the design of future studies and clinical trials aimed at identifying personalized therapies in rheumatic and other musculoskeletal inflammatory conditions. Under the mentorship of Drs. Guilak and Pham, this supplement will allow me to achieve my career development goal of becoming an independent translational scientist with research focused on promoting the health of patients by developing imaging biomarkers to diagnose, monitor, and predict outcomes of cell-based therapies in inflammatory arthritis.

项目摘要/摘要 类风湿关节炎（RA）是最常见的慢性炎症性和破坏性关节疾病，影响1％ 全球人口。滑膜组织内炎症过程的延续导致局部 组织降解酶的激活和骨呈现骨细胞的形成，引起渐进性 软骨和骨骼破坏。因此，炎症过程的早期诊断和预防骨骼 软骨破坏对于保留RA的功能至关重要。目前，对RA病的早期评估 活动和对治疗的反应主要包括体格检查，患者报告和实验室 分析。这很明显需要针对RA患者与 非侵入性分子成像以预测治疗反应，并限制广告事件和无效 疗法。常规X线摄影仍然是评估结构骨和软骨的首选 RA患者的损害。新颖的成像方法，例如正电子发射断层扫描/计算 断层扫描（PET/CT）提供了对病理生理过程的见解以及全身解剖学 本土化。 18F-FDG已被用来定位患有RA患者的关节炎症过程； 不仅显示出发炎的关节中18f-fdg的摄取增加，而且与疾病有很强的相关性 活动。用骨示踪剂18F-NAF进行宠物成像，在RA，骨关节炎和 骨质疏松症。我们的小组开发了基于细胞的Imprans，可以提供多路复用的抗循环疗法 用于治疗类风湿关节炎（RA）或其他自身免疫性疾病以自我调节方式扩展 持续时间。我们的方法是纵向表征关节注射和骨骼的模式和强度 侵蚀以识别反映对治疗敏感性或抵抗力的变化。总体 翻译目标是利用成像生物标志物的成像方法来评估下一个的效率 使用RA的体内小鼠模型基于生成细胞的疗法。这种方法将使我们能够系统地 测试我们的中心假设：治疗干预后，RA炎症和骨侵蚀将被逆转。到 以特定地点的方式检验该假设，我们将评估滑膜的时空代谢变化和 利用18F-FDG和18F-NAF PET/CT的骨骼。我们使用分子成像的全面方法 生物标志物将更好地告知我们对小鼠不同生物疗法的评估。我们希望这项研究能够 提供可以改变我们当前对RA疗法和干预反应的数据。这项研究 将影响旨在识别个性化疗法的未来研究和临床试验的设计 风湿性和其他肌肉骨骼炎症条件。在Drs的精神状态下。 Guilak和Pham， 这种补充剂将使我实现成为独立翻译的职业发展目标 研究的科学家专注于通过开发成像生物标志物来促进患者的健康 诊断，监测和预测炎症性关节炎中基于细胞的疗法的结果。