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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘