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.

项目概要/摘要 类风湿性关节炎 (RA) 是最常见的慢性炎症和破坏性关节疾病，影响 1% 全世界人口的滑膜组织内炎症过程的持续存在会导致局部炎症。 组织降解酶的激活和骨吸收破骨细胞的形成，引发渐进性 因此，早期诊断炎症过程并预防骨质疏松。 和软骨破坏对于维持 RA 的功能至关重要。目前，RA 疾病的早期评估。 活动和对治疗的反应主要包括体检、患者报告和实验室 因此，显然需要为 RA 患者开发基于精准的治疗方法。 非侵入性分子成像可预测治疗反应，并限制不良事件和无效事件 传统放射线照相仍然是评估结构性骨和软骨的首选。 RA 患者的损伤。新的成像方法，例如组合正电子发射断层扫描/计算机 断层扫描 (PET/CT) 可以深入了解病理生理过程以及全身解剖学 18F-FDG 已用于定位 RA 患者的关节炎症过程； 不仅显示发炎关节中 18F-FDG 的摄取增加，而且与疾病有很强的相关性 使用骨示踪剂 18F-NaF 进行 PET 成像显示 RA、骨关节炎和骨关节炎患者骨转换率较高。 我们的团队开发了基于细胞的植入物，可以提供多重抗细胞因子疗法。 用于以自我调节方式长期治疗类风湿性关节炎（RA）或其他自身免疫性疾病 我们的方法是纵向描述关节炎症和骨骼的模式和强度。 侵蚀以识别反映对所施用治疗的敏感性或抵抗性的变化。 转化目标是利用成像方法和成像生物标志物来评估下一步的疗效 这种方法将使我们能够系统地使用 RA 小鼠模型来产生基于细胞的疗法。 检验我们的中心假设：治疗干预后，RA 炎症和骨质侵蚀将会逆转。 以特定地点的方式检验这一假设，我们将评估滑膜的时空代谢变化和 骨利用 18F-FDG 和 18F-NaF PET/CT 我们使用分子成像的综合方法。 生物标志物将更好地为我们评估小鼠的不同生物疗法提供信息，我们希望这项研究能够实现。 这项研究提供的数据改变了我们目前对 RA 治疗和干预反应的理解。 将影响未来研究和临床试验的设计，旨在确定个性化疗法 在 Guilak 和 Pham 博士的指导下，治疗风湿病和其他肌肉骨骼炎症。 该补充将使我能够实现成为独立翻译人员的职业发展目标 科学家的研究重点是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细胞疗法的结果。