Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by the loss of joint structure and function, resulting in significant pain and morbidity. In this proposal, we plan to investigate a new therapeutic strategy for the treatment of RA. In normal joints, the cartilage matrix turnover is maintained due to a balance between the activities of proteases and protease inhibitors. This balance is lost in arthritic joints, resulting in a greater protease activity, leading to cartilage and bone degeneration. Secretory leukocyte protease inhibitor (SLPI) has been identified as an endogenous potent protease inhibitor that maintains the critical balance against the proteases in the joint. Since SLPI is not produced by the joint tissue and the arthritic joints loose their ability to sequester SLP1 from the blood, it is hypothesized that intra articular administration of SLPI in a sustained release formulation would be effective in reinstating the balance between the proteases and protease inhibitors, and in inhibiting the progression of the disease. SLPI is also considered to be involved in protecting the cartilage growth factor (Link N) in the joint from protease-mediated degradation. The link N promotes the synthesis of proteoglycan and collagen, which are required for maintaining normal cartilage composition in the joint. Therefore, localized SLPI therapy could also lead to regeneration of the cartilage matrix and restoration of joint functions. Therefore, the objective of the proposed studies is to determine the efficacy of sustained intra articular delivery of SLPI using an injectable thermo reversible (TR) gel system in RA.
The specific aims of the research program are: (1) To formulate a sustained release TR gel system for SLP1 using biodegradable and biocompatible Polyethylene oxide-Poly (L-Lactide)-Polyethylene oxide copolymer, and to evaluate the gel for sustained protein release properties, (2) To investigate the kinetics of intra articularly injected SLPI-gel system to provide localized and sustained delivery of the protein, and to determine the therapeutic efficacy of the gel to inhibit the progression of the disease in a rat streptococcal. cell wall-induced model of inflammatory erosive arthritis.
