A clinical trial-in-a-dish using iPSC-derived cartilage and bone organoids

Summary We have developed new protocols to differentiate induced pluripotent stem cells into cartilage and bone cells so that we can model inherited skeletal disorders. This project focusses on a disorder called metaphyseal chondrodysplasia, type Schmid (MCDS) which is an autosomal dominant genetic skeletal disease caused by mutations in COL10A1, the gene for the hypertrophic cartilage structural protein collagen X. It is a serious chronic medical condition. We have shown that MCDS mice treated with carbamazepine (CBZ), a drug that relieves ER stress by stimulating intracellular protein degradation, have improved long bone growth and decreased hip dysplasia. Based on this, an EU funded world-wide clinical trial is underway to test if CBZ, an FDA approved drug, can be repurposed to treat MCDS. Most MCDS patients have private mutations and the precise cellular pathology will vary between mutation types and affect therapeutic outcomes.

Project Details

We have developed new protocols to differentiate induced pluripotent stem cells into cartilage and bone cells so that we can model inherited skeletal disorders. This project focusses on a disorder called metaphyseal chondrodysplasia, type Schmid (MCDS) which is an autosomal dominant genetic skeletal disease caused by mutations in COL10A1, the gene for the hypertrophic cartilage structural protein collagen X. It is a serious chronic medical condition. We have shown that MCDS mice treated with carbamazepine (CBZ), a drug that relieves ER stress by stimulating intracellular protein degradation, have improved long bone growth and decreased hip dysplasia. Based on this, an EU funded world-wide clinical trial is underway to test if CBZ, an FDA approved drug, can be repurposed to treat MCDS. Most MCDS patients have private mutations and the precise cellular pathology will vary between mutation types and affect therapeutic outcomes.

This project, running alongside the clinical trial, will use induced pluripotent stem cell (iPSC) lines with COL10A1 mutations identified in the clinical trial patients. The lines will be differentiated in vitro to produce collagen X expressing hypertrophic chondrocytes and then osteoblasts. Transcriptomics (RNAseq) will determine the gene expression networks and signalling pathways downstream of the patient mutations to highlight differences between mutation types and how the in vitro disease models respond to CBZ treatment. This in vitro data can then be correlated with the patient outcomes in the clinical trial. This work will validate using iPSC-derived cartilage/bone disease models for screening and testing drug therapies for genetic skeletal disorders.