Aniridia-associated keratopathy: Clinical and molecular mechanisms of disease progression and emerging therapeutic...

Congenital aniridia is a rare genetic disorder primarily caused by pathogenic variants of the PAX6 gene. It leads to various panocular anomalies, including aniridia-associated keratopathy (AAK). This review highlights recent insights into its pathogenesis, focusing on clinical staging, microstructural changes in the cornea and molecular dysregulation. We synthesized clinical and experimental findings from large European cohorts, integrating data on over 550 eyes. AAK severity correlates with iris malformation, secondary glaucoma and lens status. In vivo confocal microscopy reveals a reduction in subbasal nerve plexus density, altered keratocyte and endothelial morphology and an increase in Langerhans cell infiltration. RNA and miRNA microarrays, as well as RNA-seq studies, highlight dysregulated miRNAs (such as miR-204-5p and miR-138-5p) and altered expression of PAX6 and keratocyte markers. Limbal fibroblasts show enhanced inflammatory responses and vulnerability to oxidative stress. Advanced AAK is associated with a reduced quality of life. The progression of AAK involves intricate interactions between developmental deficits, inflammation and changes in the limbal microenvironment, suggesting molecular targets for future therapies.