? This proposal seeks to apply magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) in vivo imaging techniques to demonstrate therapeutic efficacy using a novel treatment in a rat model of rheumatoid arthritis (RA). The proposed novel treatment is an intra-articular injection of SLPI-loaded thermo-reversible (TR) gel. After intra-articular injection, the TR gel delivery system will enable local slow release of SLPI, a protease inhibitor which plays a protective role in the normal joint by accumulating in cartilage. It is hypothesized that an SLPI treatment will be effective in neutralizing excess protease activity in the rheumatoid arthritic joint, which, in turn, could inhibit the erosion and destruction of the joint. In the proposed preclinical trial, a streptococcal cell wall-induced (SCW) rat model of rheumatoid arthritis will be used. The SCW-induced disease resembles human arthritis in its clinical course and distribution, and in its radiological and histological features. MRI and micro-CT imaging modalities will initially be validated in the rat SCW RA model, to demonstrate the ability to quantify bone and cartilage modifications with disease progression, including bone erosions, synovial fluid loss and changes in bone mass density. A preclinical trial will then be implemented to measure theraputic efficacy of the intra-articular SLPI-loaded TR gel system, compared with untreated controls, controls treated with direct SLPI injection (both local and systemic injection), and a positive control treated using the current drug of choice for RA treatment, methotrexate. An additional group will be treated with intra-articular SLPI-loaded TR gel, 4 weeks after the onset of chronic disease. Having successfully demonstrated efficacy in Phase I, MIR will further optimize the therapy in Phase II, also seeking to incorporate standard agents for sustained local delivery by the TR gel system, conducting further preclinical trials with a view towards implementing initial clinical trials by the end of Phase II. The goals of this work are (1) to demonstrate complete inhibition of RA disease progression using the SLPI-loaded TR gel system, addressing the current lack of efficacious therapies for RA, and (2) to validate MRI and micro-CT imaging methods for following RA disease biomarkers in this preclinical model. ? ?
