Smith, C.E.L., Streets, A.J. orcid.org/0000-0002-4328-044X, Lake, A.V.R. orcid.org/0000-0002-6341-8661 et al. (14 more authors) (2025) Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies. Communications Medicine, 5. 129. ISSN 2730-664X
Abstract
Background Primary cilia mediate vertebrate development and growth factor signalling. Defects in primary cilia cause inherited developmental conditions termed ciliopathies. Ciliopathies often present with cystic kidney disease, a major cause of early renal failure. Currently, only one drug, Tolvaptan, is licensed to slow the decline of renal function for the ciliopathy polycystic kidney disease. Novel therapeutic interventions are needed.
Methods We screened clinical development compounds to identify those that reversed cilia loss due to siRNA knockdown. In parallel, we undertook a whole genome siRNA-based reverse genetics phenotypic screen to identify positive modulators of cilia formation.
Results Using a clinical development compound screen, we identify fasudil hydrochloride. Fasudil is a generic, off-patent drug that is a potent, broadly selective Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor. In parallel, the siRNA screen identifies ROCK2 and we demonstrate that ROCK2 is a key mediator of cilium formation and function through its possible effects on actin cytoskeleton remodelling.
Conclusions Our results indicate that specific ROCK2 inhibitors (e.g. belumosudil) could be repurposed for cystic kidney disease treatment. We propose that ROCK2 inhibition represents a novel, disease-modifying therapeutic approach for heterogeneous ciliopathies.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2025 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | High-throughput screening; Polycystic kidney disease; RNAi |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Funding Information: | Funder Grant number KIDNEY RESEARCH UK PKD_RP_005_20211124 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 24 Apr 2025 08:41 |
Last Modified: | 24 Apr 2025 08:41 |
Published Version: | https://doi.org/10.1038/s43856-025-00847-1 |
Status: | Published |
Publisher: | Springer Science and Business Media LLC |
Refereed: | Yes |
Identification Number: | 10.1038/s43856-025-00847-1 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:225720 |