DescriptionOsteoporosis generates 27% of the nation's disability at an annual cost of $3.4billion. As our population ages this cost may triple by 2040. Osteoporosis results from a failure of the critical balance between bone formation and resorption, controlled by the interaction between osteoblasts and osteoclasts respectively. Pathological resorption by osteoclasts is common, resulting in osteoporosis and other osteolytic conditions such as rheumatoid arthritis (RA), and orthopaedic implant loosening, Conversely, a failure of bone resorption can be fatal in childhood as vital marrow spaces are obliterated in Malignant Infantile Osteopetrosis (MIOP). Our research has been pivotal in the discovery of the mechanisms underlying these bone diseases and new therapeutics.
We have found that a novel mutation of SNX10 mediates bone resorption in MIOP and in RA. Using bimolecular fluorescence complementation (BIFC) to screen for putative SNX10-interacting partners, we have identified that SNX10 interacts with other novel molecules, and co-localizes in the autophagosome pathways. We have screened a library of several million compounds at the selected site of the target. By using two separate screening assays [1. In vitro, Differential Scanning Fluorimetry (DSF); 2. in vivo, using real time BRET assay (live cell based)], we aim to determine optimal hit compounds for further med chem optimization and development of a lead compound for the treatment of osteolytic diseases. We have also explored new treatment for the fatal condition of MIOP using overexpression of AVV2-Snx10 and application of AAV2-based CRISPR/CAS9 nuclease sgRNA genome editing technology. These strategies will pave the way for a new resolution to address this unmet medical need.
|16 Mar 2022
|Australia-China Centre for Tissue Engineering and Regenerative Medicine ACCTERM, Australia
|Degree of Recognition