Research Projects

Osteoarthritis (OA) is a complex joint disorder that affects over 500 million people worldwide and poses a significant socio-economic burden. Current treatments such as pharmacotherapeutics only alleviate symptoms without modifying the disease condition and surgeries are associated with secondary complications. Hence, there is an urgent need to develop disease-modifying approaches for OA treatment. The current research strategies have limitations in the clinical setting due to targeting single molecular factors and reduced bioavailability of drugs within the cartilage. OA is characterized by multiple hallmarks such as senescence, matrix degradation, inflammation, hypertrophy of chondrocytes, etc. To inhibit these, a less-invasive and disease-modifying pharmacotherapy is required. As OA is an age-related disease, we anticipated that the elimination of senescent cells may partially ameliorate OA by downregulating senescence. We identified KAT-7, a protein that helps the survival of senescent cells in Werner Syndrome, as a potential target. Since OA also manifests senescence, we hypothesized that KAT-7 might be present in OA cartilage. Intriguingly, our preliminary experiments using human OA cartilage and goat ex vivo OA model demonstrated overexpression of KAT-7. Therefore, to inhibit KAT-7, a specific inhibitor (WM-3835) will be used to downregulate senescence in the goat OA model and human OA cartilage. In addition to senescence, HIF2α regulates multiple OA hallmarks including matrix degradation, pain, inflammation, and hypertrophy. Therefore, we identified a HIF2α specific inhibitor (PT-2385) to downregulate the other OA hallmarks. However, as evidenced by the clinical failure of individual candidate drugs, simultaneous targeting of multiple hallmarks is essential. Hence, the combinatorial efficacy of the inhibitors (as potential DMOADs) will be studied in a goat ex vivo OA model and human OA cartilage explants to demonstrate enhanced OA mitigation. It is anticipated that the combination will show synergistic effect on the downregulation of multiple hallmarks in comparison to single targeting. To increase the bioavailability of the DMOADs in the joint, PAMAM dendrimer of 5 nm size will be PEGylated to increase stealth and can penetrate through the cartilage ECM pores (15 nm) via electrostatic interaction. To allow its retention within the dynamic cartilage, the dendrimers will be modified with an active cartilage targeting peptide against collagen XII, which has been recently identified to be abundant in human OA. The DMOADs will be loaded in the modified dendrimer and the efficacy will be evaluated in ex vivo OA systems (goat and human) followed by in vivo validation in rat ACLT model to evaluate their therapeutic efficacy and translational potential. Implementation of the proposal would lead to a paradigm shift in OA disease modification impacting lives of millions of OA-affected individuals.