One of the focuses of the Pham lab is to develop novel approaches to deliver therapeutics that will halt or reverse joint inflammation and degeneration in preclinical models of rheumatoid arthritis and osteoarthritis, with the ultimate goal of translating these findings to the clinic. These projects represent a team-science, interdisciplinary approach to arthritis research, combining the Pham lab expertise in basic mechanisms underpinning these rheumatic conditions with innovative bioengineering advances in nanomedicine and regenerative medicine pioneered by outstanding collaborators in the Departments of Orthopaedics and Bioengineering.
We collaborated with Drs. Linda Sandell, Farooq Rai, Farshid Guilak, and Sam Wickline (currently at University of South Florida) to deliver a peptide-siRNA nanocomplex targeting the NF-kB pathway to mitigate inflammation in murine models of rheumatoid arthritis and post-traumatic osteoarthritis. We have shown that peptide- NF-kB p65 siRNA nanocomplex suppresses experimental rheumatoid arthritis. We also leveraged the expertise and support of the Musculoskeletal Research Center, specifically the Structure and Strength Core and the Musculoskeletal Histology and Morphometry Core to conduct a murine model of controlled knee joint impact injury to test the hypothesis that delivery of peptide- NF-kB p65 siRNA nanocomplex in the immediate aftermath of joint injury will prevent cartilage degeneration and the eventual development of post-traumatic osteoarthritis. We showed that peptide-siRNA nanocomplex suppresses NF-kB activation (Figure 1) and mitigates several important early events post injury, including chondrocyte apoptosis, thus reducing the extent of cartilage injury and reactive synovitis. In addition to structural changes, we have now shown that treatment with peptide-siRNA nanocomplex is associated with improvement in pain sensitivity post injury. These findings may lead to the development of a first-in-class disease-modifying nanotherapeutic approach to prevent post-traumatic osteoarthritis.
More recently we have also collaborated with Dr. Guilak and Drs. Yun-Rak Choi and Kelsey Collins (postdoctoral scholars in the Guilak lab) to test the ability of a tissue-engineered stem cell-based system with autoregulated cytokine antagonist delivery to mitigate inflammation in a robust murine model of rheumatoid arthritis. The system employs genome-engineered pre-differentiated iPSCs to deliver anti-cytokine therapeutics, the production of which is driven by endogenous levels of inflammatory cytokines. Our data suggest that this “SMART” cell-based delivery of IL-1 receptor antagonist suppresses inflammation, prevents bone erosions and mitigates pain induced by inflammatory arthritis.
In addition to work in pre-clinical models of diseases, our lab is also actively involved in several translational projects. Our translational work is partially supported by the Washington University Rheumatic Diseases Research Resource-based Center (WU-RDRRC), a NIAMS-funded mechanism. WU-RDRRC’s mission is to promote cross-disciplinary collaborations and to stimulate the development of new initiatives that will advance the pace of discovery, with the goal of disseminating and implementing research findings into the practice of personalized medicine.
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