無虹彩症

A female in her early 20s with bilateral congenital aniridia-associated keratopathy (AAK) and progressive limbal stem cell deficiency (LSCD) presented with recurrent epithelial defects in the left eye for which she underwent cadaveric allogeneic simple limbal epithelial transplantation (allo-SLET) with lateral paramedian tarsorrhaphy. Postoperatively, topical and systemic immunosuppression with topical corticosteroids and oral cyclosporine was initiated. The ocular surface stabilised after surgery; however, an episode of epithelial rejection occurred at 4 months which resolved with intensified corticosteroid therapy and intravenous methylprednisolone. Subsequent cataract surgery was performed and the ocular surface remained stable. Best-corrected visual acuity improved from 20/600 to 20/160 and remained stable over a 2.5-year follow-up. This case highlights allo-SLET as an effective option for advanced bilateral AAK and the need for long term immunosuppression to prevent episodes of epithelial rejection and recurrence of LSCD.

This study aimed to measure mRNA and miRNA expression profile in corneal impression cytology (IC) samples from patients with congenital aniridia (CA) and healthy controls, and to elucidate the key genes and signaling pathways involved in aniridia-associated keratopathy (AAK). Corneal IC samples were collected from 14 patients with CA and 14 healthy controls. RNA sequencing was performed to identify differentially expressed genes (DEGs) and miRNAs. Correlations with age and AAK grade were analyzed, selected miRNAs were validated by RT-qPCR, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to characterize biological functions and pathways. A total of 695 DEGs and 19 differentially expressed miRNAs were identified. KRT24 expression was negatively associated with age, whereas LY6D expression positively correlated with AAK grade. Several miRNAs were linked to disease severity, including positive correlations for miR-224-5p, miR-224-3p, and miR-452-5p, and negative correlations for miR-204-3p, miR-181b-5p, and miR-181a-5p. RT-qPCR confirmed significant downregulation of miR-204-5p and miR-138-5p in aniridia samples. Functional enrichment analyses showed that DEGs were mainly involved in cell adhesion, extracellular matrix remodeling, inflammatory and immune responses, and neural-related processes. Target genes of dysregulated miRNAs were enriched in transcriptional regulation, cell proliferation, apoptosis, and migration, with significant involvement of PI3K-Akt, AGE-RAGE, and EGFR signaling pathways. Corneal epithelial cells from patients with CA exhibit coordinated mRNA and miRNA dysregulation associated with extracellular matrix disruption, inflammation, and altered signaling pathways. These findings improve understanding of AAK pathogenesis and identify potential biomarkers and therapeutic targets.

AIMS: This study aims to investigate the efficacy of drug repurposing using a corneal organoid model developed from patient-derived iPSCs and to elucidate the pathophysiology of Aniridia-Associated Keratopathy (AAK). MATERIALS AND METHODS: A 90-day stepwise differentiation protocol was used to generate corneal organoids from iPSC cell lines developed from aniridia patients and healthy control. The corneal organoids produced were characterized using histology, immunofluorescence, qPCR, western blot, and transcriptomics. Two known agents, Duloxetine and Ataluren, were tested for corneal organoids for the restoring PAX6 protein expression. KEY FINDINGS: Histological analyses showed that the corneal organoids had a similar architecture to the native corneal tissue. Corneal epithelial, stromal, and endothelial cell biomarker staining showed positive expressions. AAK corneal organoids exhibited features that indicate the AAK disease phenotype, such as thickening of the epithelial cell layers and decrease in expressions of PAX6, ΔNP63, and keratocan genes. An increase in PAX6 protein was observed in organoids produced from AAK1 after duloxetine treatment and in organoids produced from AAK2 following ataluren treatment. AAK3 did not respond to either agent, indicating that there was no mutation-specific drug activity. Transcriptomic analyses showed clear corneal differentiation and absence of retina or lens profile in organoids. SIGNIFICANCE: This study presents patient-specific organoid models for AAK using iPSCs and offers insight into mutation effects and PAX6 restoration following drug repurposing. The findings form the basis of personalized treatments for congenital aniridia.

Aniridia is a rare congenital vision-loss disorder caused primarily by loss-of-function variants of the paired box 6 (PAX6) gene. There is currently no cure. Augmentation gene therapy has emerged as a successful treatment for inherited ocular diseases. Here, we conducted the first pilot preclinical intrastromal augmentation gene therapy for aniridic cornea. It was undertaken in an aniridia mouse model, using adeno-associated virus 9 (AAV9), with a ubiquitous promoter driving PAX6, delivered by injection at 3 months, and harvest at 5 months post-injection (PI). The primary endpoint was histologically quantified epithelial thickness. The secondary endpoints were the slit lamp assessment of keratopathy and the RT-ddPCR measurement of four key signaling genes in the cornea. At 5 months PI, we demonstrated virally delivered PAX6 protein in the aniridic mouse corneal stroma. Critically, we found a statistically significant, albeit suggestive due to low n values, structural improvement in the corneal epithelial thickness. When the data were pooled, we also demonstrated a significant and complete transcription correction of four key genes-Notch1, Hes1, Wnt5a, and Mtor. We explore a variety of hypothesizes to explain these initial results, including that the virally delivered PAX6 is acting non-cell autonomously, moving from the non-dividing stroma into the epithelium, causing structural and molecular improvement.

WAGR syndrome is a rare congenital disorder, occurring in approximately 1 in 500,000 to 1,000,000 individuals, often presenting with ocular malformations such as aniridia. Glaucoma frequently develops when the iris and angle structures are affected, posing a significant risk of vision loss. We report a one-year and seven-month-old patient who presented with corneal opacity of the left eye. Examination revealed corneal opacity, aniridia, and markedly elevated intraocular pressure of 65 mmHg, while the fellow eye, also with aniridia, was normotensive. The patient underwent immediate combined trabeculectomy-trabeculotomy. Postoperative follow-up and timely management of complications allowed acceptable pressure control over one year, though visual prognosis remained guarded. This case highlights the challenges of managing glaucoma in WAGR syndrome, particularly in resource-limited settings. Medical therapy alone is often insufficient, making surgical intervention essential. Combined trabeculectomy-trabeculotomy proved effective in maintaining pressure control when glaucoma drainage devices were not feasible. Multiple interventions and close monitoring are frequently required due to the risk of scarring and postoperative complications. Our experience emphasizes the need for a multidisciplinary ophthalmology approach to optimize outcomes. Despite pressure control, visual outcomes often remain poor due to structural anomalies and the challenges inherent to pediatric patients with this rare syndrome.