Keratoconus is a degenerative thinning of the ECM of the cornea. The cornea is a specialized ECM-rich protective barrier tissue of the eye made up of collagens, glycoproteins, and proteoglycans, like lumican, keratocan, biglycan and decorin. In keratoconus the corneal ECM deteriorates, becomes thin and protrudes. Patients suffer from high astigmatism, scarring and progressive loss of vision. Keratoconus is managed by contact lens use and UV cross-linking of collagens (CXL) to temporarily strengthen the ECM connective tissue at the early stages. In advanced stages cornea-transplants are required, making keratoconus a leading cause for cornea-transplants worldwide. Although influenced by multiple environmental stressors, keratoconus has a strong genetic basis where multiple genetic variants individually or in combination are hypothesized to be causal.
We are using a multipronged approach to understand the genetic and pathogenic changes in keratoconus. 1) Whole exome and genomic sequences of DNA from blood samples of individual keratoconus patients and families are being analyzed to identify genetic variants that may lead to keratoconus. We identified several genes, some entirely unknown to the cornea, that may contribute to keratoconus. 2) We will use cell culture and iPSC-derived 3D cornea organoids with gene-editing approaches to understand functions of the newly identified genetic variants in keratoconus. 3) Our group is experienced in developing and using genetic mouse models. We will investigate the contributions of these variants to keratoconus, and explore therapeutic interventional approaches in mouse models. 4) We are conducting gene expression and proteomic studies on discarded keratoconus surgical corneal tissues to identify molecular pathways and biomarkers in keratoconus.