Genetically-engineered stem cells for self-regulating arthritis therapy

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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.