Gene therapy for Osteogenesis imperfecta

成骨不全(OI)是一组罕见的遗传性结缔组织疾病，每15,000名活产儿中就有1名患病。85-90%的OI病例是由于编码I型胶原基因(COL1A1/A2)的致病变异所致。骨骼的脆性和变形是OI最突出的特征，导致OI患者活动能力降低，阻碍了患者的生活质量。目前OI的治疗方法侧重于管理症状，而不是治疗潜在的遗传病因。虽然目前的治疗方法，如抗吸收药物、矫形外科手术和物理疗法可以帮助缓解一些症状，但没有确定的治疗方法。基因治疗已被认为是治疗OI的一种有前景的方法，但需要概念验证研究来证明这一策略的可行性。在我们之前的工作中，我们已经建立了一组来自COL1A1突变的OI患者的诱导多能干细胞(IPSC)系。IPSCs可以分化为特殊的细胞类型，包括受疾病影响最大的骨细胞，用于测试潜在的治疗方法。在这个项目中，我们将以这一宝贵的人类IPSC生物资源为基础，开发和测试OI的基因治疗方法。该项目将使用的技术包括细胞基因工程(例如使用CRISPR/Cas9)、IPSCs的分化以及对细胞进行深入的生化和表型分析。

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.