Topical CAY-10746, a Novel ROCK Inhibitor, Reduces Intraocular Pressure and Modulates the Trabecular Meshwork in Normotensive Rats.

BACKGROUND

Elevated intraocular pressure (IOP) is the primary modifiable risk factor for glaucoma. Rho-associated kinase (ROCK) inhibitors lower IOP by targeting the trabecular meshwork (TM) to increase conventional aqueous humor outflow. This study evaluates the IOP-lowering efficacy of CAY-10746, a novel ROCK inhibitor, and investigates its effects on TM structure and gene expression in normotensive rats.

METHODS

Normotensive Sprague-Dawley rats received once-daily topical CAY-10746 (10 µM or 25 µM) or vehicle for 5 days. IOP was measured using rebound tonometry. The drug's effect on TM morphology was assessed with histological analysis, and changes in gene expression were profiled using RNA sequencing (RNA-Seq). Cytotoxicity was evaluated in vitro on human TM cells.

RESULTS

CAY-10746 was nontoxic to human TM cells at effective concentrations. Topical administration significantly lowered IOP in rats in a concentration-dependent manner. The 25 µM dose produced a robust IOP reduction for at least 8 h post-instillation (p < 0.001). Histological analysis revealed significantly increased porosity in the TM of treated eyes compared to controls (p < 0.05). RNA-Seq identified 762 differentially expressed genes (DEGs) in the TM. Pathway analysis showed significant enrichment of DEGs related to the extracellular matrix, focal adhesion, and the PI3K-Akt signaling pathway. Key glaucoma-related genes, including FN1, RHO, and CYP1B1, were among those modulated.

CONCLUSION

The novel ROCK inhibitor CAY-10746 effectively lowers IOP in normotensive rats. This effect is associated with structural changes (increased porosity) and modulation of gene expression pathways critical to TM function. These findings suggest CAY-10746 is a promising therapeutic candidate for glaucoma that warrants further investigation.