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Journal of Drugs and Ecotoxicology

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New therapies in genetic skeletal diseases achieved through drug repurposing

Author(s): Michael Darren Briggs

 Genetic skeletal diseases (GSDs) are an extremely diverse and complex group of diseases that development and homeostasis of the skeleton. There are more than 450 unique and well-characterised phenotypes that range in severity from relatively mild to severe and lethal forms and although individually rare, as a group of related orphan diseases, GSDs have an overall prevalence of at least 1 per 4,000 children, which represents a large unmet medical need. Our studies have focussed on a group of clinically-related GSDs that present with disproportionate short stature and early onset OA and result from dominant-negative mutations in a range of cartilage structural proteins including cartilage oligomeric matrix protein (COMP), matrilin-3, aggrecan and types II, IX and X collagens. We have unequivocally established that endoplasmic reticulum (ER) stress, induced in chondrocytes as a result of accumulated misfolded mutant proteins, is the primary cause of growth plate dysplasia and reduced bone growth in a broad group of GSDs. Moreover, we have recently demonstrated that reducing ER-stress, through the administration of a repurposed anti-epileptic drug carbamazepine (cbz), in both cell and mouse models, restores cell homeostasis and bone growth in metaphyseal chondrodysplasia, type Schmid (MCDS) resulting from collagen X mutations