Targeting RhoA/ROCK Signaling to Modulate Extracellular Matrix Remodeling in Corneal Endothelial Dystrophies

Area of Science:

• Ophthalmology
• Corneal Disease Research
• Pharmacology

Background:

• Fuchs endothelial corneal dystrophy (FECD) is characterized by abnormal extracellular matrix (ECM) accumulation in Descemet's membrane.
• This pathological process leads to guttae formation, corneal endothelial dysfunction, and vision loss.
• Current treatments for FECD are primarily surgical, highlighting the need for alternative therapeutic strategies.

Purpose of the Study:

• To investigate the potential of Rho-associated protein kinase (ROCK) inhibition to mitigate fibrotic ECM remodeling in FECD.
• To explore ROCK inhibition as a therapeutic approach for FECD and related corneal endothelial disorders.
• To assess the efficacy of specific ROCK inhibitors, such as ripasudil, in ex vivo and in vitro models.

Main Methods:

• Ex vivo treatment of human corneal endothelial-Descemet membrane specimens (FECD, PBK, PEX-K, normal donors) with ROCK inhibitors (ripasudil, netarsudil, Y-27632).
• In vitro studies using human corneal endothelial cells.
• Analysis of ROCK activity, ECM expression, matrix metalloproteinase (MMP) activity, and TGF-β/Smad signaling via molecular and imaging techniques.

Main Results:

• FECD samples exhibited constitutive ROCK and TGF-β signaling activation compared to controls.
• Ripasudil significantly suppressed ROCK activity, downregulated fibrosis-associated ECM components, and promoted ECM turnover by modulating MMP/TIMP balance.
• Similar beneficial ECM-modulating effects were observed in PBK and PEX-K models, with ripasudil demonstrating the strongest impact.

Conclusions:

• Pharmacologic inhibition of ROCK, particularly with ripasudil, effectively reduces pathological ECM deposition and promotes ECM remodeling in FECD.
• ROCK inhibition normalizes ECM homeostasis by suppressing pro-fibrotic production and enhancing remodeling pathways.
• ROCK inhibition represents a promising non-surgical therapeutic avenue for FECD and associated corneal endothelial diseases, meriting further preclinical investigation.