Development and utilisation of an ex vivo patient-derived cell model to investigate the aetiology of Fuchs endothelial corneal dystropy (FECD) and test potential therapies

The cornea is the transparent tissue situated at the front of the eye. It protects the eye from the external environment and focuses light onto the retina. The innermost part of this tissue is comprised of a specialised layer of corneal endothelial cells. These cells perform a pump-like mechanism removing water from the outer layers of the cornea, which, if left to accumulate, causes corneal swelling and clouding leading to loss of vision and/or blindness.
Fuchs endothelial corneal dystrophy (FECD), characterised by corneal endothelial cell death, is a common, age-related, disease estimated to affect more than 4% of individuals over 40 years of age. A genetic mistake, termed ‘mutation’, in a gene called TCF4 is the most common cause of FECD. We have recently discovered that approximately 75% of FECD patients in the UK have a mutation in the TCF4 gene.

Need for Research
Invasive corneal transplantation surgery is currently the only treatment option available to restore vision and prevent blindness for FECD patients. This treatment relies upon specialist facilities and is dependent on the availability of healthy donor material, of which there is currently a global shortage. Graft rejection and the need for systemic immunosuppression in some individuals, coupled with the global aging population, highlight the need for alternative and effective treatment strategies to be developed for FECD.

Aim of the Study
1. To further understand the relationship between mutations in the TCF4 gene and FECD.
2. To investigate the biological reasons for the disease, using a model system that we have developed using donated corneal endothelial cells removed from FECD patients as part of their planned surgery.
3. To use the cell model to test new therapies for FECD designed to target the common TCF4 mutation that causes disease.

Expected Outcomes
Cutting-edge technology will be used to develop a genetic test for FECD that will have the potential to accurately identify pre-symptomatic individuals so that we have a window of opportunity to prevent and treat the condition before sight loss. The cell model of FECD will be used to enhance our understanding of the biological reasons for disease, and enable us to test potential therapies that could be rapidly translated into clinical trials for this sight threatening condition.