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Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies
Claire E L Smith1, Andrew J Streets2, Alice V R Lake1
1Division of Molecular Medicine, Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
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.
Insights
Fasudil hydrochloride, a Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, was identified to reverse cilia loss. ROCK2 inhibition may offer a novel therapeutic strategy for treating cystic kidney disease in ciliopathies.
Area of Science:
- Cell Biology
- Developmental Biology
- Pharmacology
Background:
- Primary cilia are crucial for vertebrate development and signaling.
- Cilia defects lead to ciliopathies, often causing cystic kidney disease and renal failure.
- Current treatments for polycystic kidney disease, a ciliopathy, are limited.
Purpose of the Study:
- Identify compounds that can restore primary cilia function.
- Discover novel therapeutic targets for ciliopathies, specifically cystic kidney disease.
Main Methods:
- Screened clinical development compounds for their ability to reverse cilia loss.
- Conducted a whole-genome siRNA screen to find positive regulators of cilia formation.
- Investigated the role of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) in cilia biology.
Main Results:
- Identified fasudil hydrochloride, a potent Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, as effective in reversing cilia loss.
- The siRNA screen identified ROCK2 as a key mediator of cilia formation and function.
- Demonstrated ROCK2's involvement in cilia regulation, potentially through actin cytoskeleton remodeling.
Conclusions:
- Specific ROCK2 inhibitors, such as belumosudil, show potential for repurposing in treating cystic kidney disease.
- ROCK2 inhibition represents a promising, disease-modifying therapeutic approach for various ciliopathies.
