Dr Claire E L Smith

Ciliopathies are a heterogeneous collection of individually rare diseases that are collectively common. They include Bardel-Biedl syndrome, Joubert syndrome, nephronophthisis, retinitis pigmentosa and polycystic kidney disease (PCKD). A major symptom of many ciliopathies is the development of a cystic kidney phenotype, which can result in the need for regular dialysis or a kidney transplant. This greatly impacts on quality of life and is costly to treat. Currently only one drug, Tolvaptan, a vasopressin V2 receptor antagonist, is licensed for the treatment of cystic kidney disease, however the drug is not always effective and is poorly tolerated. Therefore there is a great clinical need for new and effective drug treatments.

My research focuses on identifying compounds with the ability to restore the incidence and efficient function of primary cilia in ciliopathy disease models. Two large chemical libraries (totalling 2,160 compounds) have been screened using a high throughput, high content imaging platform utilising siRNA knockdown of ciliopathy gene expression. One main hit chemical has been identified. Interestingly, an independent, parallel whole genome siRNA screen for negative regulators of ciliogenesis identified the drug’s target molecule as its biggest hit, strengthening the evidence for the potential efficacy of this drug in treating ciliopathies.

Having already tested this chemical in CRISPR-Cas9 edited immortalised cell lines, I have now CRISPR-Cas9 edited induced pluripotent stem (iPS) cells by introducing relevant mutations in ciliopathy genes. Kidney organoids provide an ideal model system for testing drugs for ciliopathies, since kidney cysts are a common phenotype of many ciliopathies that can be easily assayed. In addition, kidney organoids can be fully differentiated from iPS cells in as little as 25 days. I will use these kidney organoid models as a starting point for pre-clinical testing of the hit compound, to provide proof of concept and to prompt the development of a hit series of compounds, in collaboration with the Faculty of Chemistry, for further testing.