In the first funding cycle, Project 2 was successful in elucidating the nature of OA changes in mice carryinggenetic mutations for key fibrillar collagens, including types IX and XI collagen. In the absence of type IXcollagen, we learned that complete erosion of joint cartilage occurs with concomitant changes in animalbehavior, cartilage biomechanics and chemistry. For Project 2, we take the finding of pro-inflammatorycytokines in the serum of OA patients, as well as our mouse models of OA, and turn towards developing atargeted intervention appropriate for OA based on delivering anti-inflammatory compounds to the joint. Antiinflammatorydrugs that attenuate IL-1 and TNFa activity have therapeutic potential for OA but require highprotein doses and cause significant side effects when administered via intravenous or subcutaneousinjection for inflammatory disease. Strategies that utilize low protein doses and provide for sustained releasehave great potential to achieve value in the clinic as a treatment for OA. In Project 2, we propose to developand evaluate the utility of an in situ forming, intra-articular 'drug 'depot' that can provide for local andsustained delivery of anti-inflammatory protein drugs for the treatment of OA. We have previouslyconstructed thermally responsive drug depots the drugs, IL-1 receptor antagonist (IL1Ra) or soluble TNFreceptor (sTNFRII), conjugated to a thermally responsive peptide. We have shown that these thermallyresponsive peptide 'tags', composed from elastin sequences called ELPs, spontaneously form a depot uponinjection into the joint space that provide for a 25-fold increase in the half-life of the administered protein and75% reduction in peak serum exposure.
In Aim 1, we propose studies to evaluate the following for bothELP-IL1Ra and ELP-sTNFRII: (a) in vitro bioactivity against cytokines in primary synoviocytes; (b) in vivobiodistribution following delivery to the rat knee joint; (c) in vitro immunotoxicity; and (d) in vivo efficacy inmediating inflammatory joint disease caused by overexpression of IL-1 and/or LPS injection in the jointspace.
In Aim 2, we propose to evaluate the disease-modifying effects of ELP-IL1 Ra and ELP-sTNFRII in ajoint instability model of OA with the following measures: (a) gross and histological joint appearances; (b)synovial fluid and serum biomarkers (through Core B); and (c) parameters of gait and pain perception. Wehypothesize that thermally responsive ELPs conjugated to these anti-inflammatory drugs will contribute tolong drug half-lives in the joint space while retaining bioactivity, reducing serum drug exposure and modifyingdisease in these pre-clinical models of OA. The results of this 5-year project are expected to advance anovel drug depot strategy to easily deliver drugs to the joint, advancing the application of disease-modifyingdrugs with significant systemic side effects for the treatment of OA.
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