Kaye, Abigail Eve; (2025) Understanding Aniridia-Related Keratopathy: From Cellular Mechanisms to Clinical Translation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Congenital aniridia is a rare developmental eye disorder caused by heterozygous PAX6 mutations, resulting in iris hypoplasia and a spectrum of ocular abnormalities, including aniridia-related keratopathy (ARK). ARK is a progressive and sightthreatening corneal disease with variable severity between individuals. This thesis investigates how PAX6 genotype influences ocular surface phenotype, with a particular focus on the corneal stroma and its role in disease progression. Clinical and imaging analyses using slit-lamp biomicroscopy, anterior segment optical coherence tomography, and in vivo confocal microscopy revealed that increased corneal thickness in ARK arises primarily from stromal expansion and that the anterior stroma may represent the principal site of pathology. A quantitative relationship between iris hypoplasia, asymmetry, and glaucoma was also demonstrated, providing new insight into phenotype variability and disease risk. Deep-learning analysis of IVCM images was applied for the first time in congenital aniridia, identifying microstructural alterations that correlate with disease severity and highlighting the potential of artificial intelligence for objective disease assessment. At the cellular level, this research established the first three-dimensional co-culture model combining aniridic stromal cells and limbal epithelial stem cells within a RAFT tissue equivalent (RAFT-TE). The model demonstrated that aniridic stromal environments can alter epithelial morphology and function, supporting a mechanistic role for epithelial–stromal crosstalk in ARK. Notably, cells carrying the same PAX6 variant displayed divergent behaviour, indicating that additional regulatory factors beyond genotype influence stromal phenotype. The translational impact of this work extends to the RAFT-OS clinical trial, the firstin-human transplantation of a regenerative RAFT-based therapy for ARK. Together, these findings bridge clinical and laboratory research, defining new structural, molecular, and functional aspects of aniridic corneal disease and laying the foundation for genotype-informed, personalised therapies for patients with congenital aniridia.

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