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Abstract: TH-PO561

Discovery of Novel Treatments for Ciliopathies and Cystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases


  • Molinari, Elisa, University of Newcastle, Newcastle upon Tyne, United Kingdom
  • Bond, Jacquelyn, University of Leeds, Leeds, United Kingdom
  • Higgins, Julie, University of Leeds, Leeds, United Kingdom
  • Srivastava, Shalabh, University of Newcastle, Newcastle upon Tyne, United Kingdom
  • Ramsbottom, Simon, University of Newcastle, Newcastle upon Tyne, United Kingdom
  • Johnson, Colin A., University of Leeds, Leeds, United Kingdom
  • Sayer, John, University of Newcastle, Newcastle upon Tyne, United Kingdom

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that represents one of the most frequent genetic causes of end-stage kidney disease during childhood and adolescence. NPHP is a genetically heterogeneous disorder with 20 identified causative genes all encoding for proteins with a function in the primary cilium. NPHP is part of a spectrum of disease phenotypes associated with ciliopathies.
We have previously generated a Cep290LacZ/LacZ viable mouse model for NPHP. These animals exhibit renal cysts that originate from collecting duct epithelium from which we derived an immortalised cell culture. In recent work, we have shown that the Hedgehog (Hh) agonist Purmorphamine can rescue the cellular and ciliary phenotype in these cells, indicating that ciliopathies are both reversible and treatable. However, the carcinogenic effects of Hh agonism make it unsuitable as a means of treatment, especially of paediatric patients. We set forth to identify existing compounds which can be repurposed for the treatment of NPHP.


A PerkinElmer “Operetta” High Content Imager, with an “Harmony’ and “Columbus” analysis and data storage system, was used to test 1120 biologically active compounds from the Tocriscreen Mini drug library on ciliated monolayers of immortalised murine Cep290LacZ/LacZ collecting duct epithelial cells. Measured parameters were cell number, cilia incidence and cell junction integrity.


Through a high-throughput screening approach, we have tested 1120 existing drugs for their efficacy in ameliorating the cellular and ciliary defect of NPHP cells and we identified 33 hits in a primary screen. A secondary screen validated the efficacy of 5 compounds.


Our high-throughput screening revealed that the ciliary phenotype of NPHP cells can be rescued by treatment with selected drugs. Positive hits from our high-throughput screening will be further validated on murine and human NPHP 2D and 3D cell models.


  • Private Foundation Support