Gene therapy for Osteogenesis imperfecta

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Osteogenesis Imperfecta (OI) is a group of rare heritable connective tissue disorders, affecting 1 in 15,000 live births. 85-90% of OI cases are due to pathogenic variants in genes encoding Collagen I (COL1A1/A2). The fragility and deformation of bones are the most prominent features of OI, resulting in reduced mobility and impeding the life quality in OI patients. Current therapeutic approaches for OI are focused on managing symptoms rather than treating the underlying genetic aetiology. Whilst present treatments such as antiresorptive medication, orthopaedic surgery and physiotherapy can help alleviate some symptoms, there is no definitive cure. Gene therapy has been proposed as a promising approach for treating OI, but proof-of-concept studies are required to show the feasibility of this strategy. In our previous work, we have established a panel of induced pluripotent stem cell (iPSC) lines from OI patients with COL1A1 mutations. iPSCs can be differentiated to specialised cell types, including bone cells that are most affected by the disease and used to test potential therapies. In this project, we will build upon this valuable human iPSC bioresource to develop and test a gene therapy approach for OI. The techniques that will be used in the project include genetic engineering of cells (e.g. using CRISPR/Cas9), differentiation of iPSCs and in-depth biochemical and phenotypic assaying of cells.