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Background <p>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.</p> Methods <p>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.</p> Results <p>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 <i>ROCK2</i> and we demonstrate that ROCK2 is a key mediator of cilium formation and function through its possible effects on actin cytoskeleton remodelling.</p> Conclusions <p>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.</p>

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Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月19日

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  • Claire E. L. Smith,
  • Andrew J. Streets,
  • Alice V. R. Lake,
  • Subaashini Natarajan,
  • Sunayna K. Best,
  • Katarzyna Szymanska,
  • Magdalena Karwatka,
  • Thomas Stevenson,
  • Rachel Trowbridge,
  • Gary Grant,
  • Sushma N. Grellscheid,
  • Richard Foster,
  • Ciaran G. Morrison,
  • Georgia Mavria,
  • Jacquelyn Bond,
  • Albert C. M. Ong,
  • Colin A. Johnson

摘要

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.