Drug repurposing for genetic bone diseases

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are rare genetic bone diseases (GSDs) that result in disproportionate short stature and early onset osteoarthritis. There are currently no therapies and they result in poor quality of life and high health care costs. We have unequivocally demonstrated over the last 20 years that in a defined group of GSDs (including PSACH-MED), endoplasmic reticulum (ER) stress, caused by the intracellular accumulation of mutant cartilage structural proteins, is the underlying disease mechanism. ER-stress is an attractive and readily targeted therapeutic approach. Drug repurposing has recently become a powerful approach to deliver rapid and cost-effective therapies for this unmet medical need; rare diseases. Recently, curcumin has been shown to reduce ER-stress in a cell model of MATN3-MED and CurQ+ (a next generation formulation of curcumin) in a mouse model PSACH. In this context we propose to determine the efficacy of CurQ+ to reduce ER-stress in a mouse model of MATN3-MED and further validate its effectiveness in our mouse model of PSACH. To achieve these aims we will use our previously validated mouse models of PSACH-MED and following treatment with CurQ+ we will study the bones and cartilage of treated and untreated mice using our well-established and sensitive quantitative and qualitative assays. In addition, we will also examine the mechanistic pathways of curcumin/CurQ+ activity using an allelic series of PSACH-MED cell models. Finally, to understand the protective properties of CurQ+ we will treat wild type and mutant mice prior to inducing cartilage degradation and osteoarthritis using our well-established destabilisation of the medial meniscus (DMM) procedure.