Gene regulation, genetic mechanisms and development of potential therapies for corneal endothelial dystrophies

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Background and need for the research: The cornea is the transparent window situated at the front of the eye. It protects the eye from the external environment and focuses light onto the retina. The inner most 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, to ensure that the tissue is optimally hydrated, and regulate the movement of crucial nutrients into the rest of the cornea. The term 'corneal endothelial dystrophies (CEDs)' describes a group of diseases that lead to dysfunction of this specialised cellular layer. Patients with CEDs experience corneal swelling and clouding, due to endothelial cell dysfunction, leading to impaired vision. In some patients, glaucoma develops, that further increases the likelihood of visual impairment and/or blindness. Fuchs endothelial corneal dystrophy (FECD) is an age-related disease and by far the most common CED, affecting 4.5% of people >50 years of age. Other much rarer types of CEDs include a disorder called posterior polymorphous corneal dystrophy (PPCD). In recent years, there has been much progress in understanding the genetic causes of CEDs and we now know certain genetic faults, known as mutations, in several different genes are responsible for disease. However, we still do not fully understand the underlying biological basis of these diseases, and >20% of cases still remain genetically unexplained. Corneal transplantation is currently the only treatment option available for CED patients experiencing visual loss, but the long-term survival of grafts is poor. Surgery also relies upon specialist facilities and healthy donor corneas, of which there is a currently a global shortage. Only by understanding how the mutations alter the normal functioning of the corneal endothelium, can appropriate new therapeutic strategies be developed to address the urgent clinical need for alternative treatment options. Aim: This research program aims to 1) identify the genetic cause of disease in unsolved CED cases and 2) investigate how and why different CED-associated mutations cause endothelial cell dysfunction and 3) use this knowledge to develop new therapies. Methods: DNA samples from CED patients will be analysed using a range of genetic sequencing methods to identify genetic origins of disease. In parallel, using donated tissue removed during planned corneal transplant surgery, I will use techniques that I have established in the laboratory to grow and maintain the corneal endothelial cells, to enable investigation of how and why particular mutations cause cellular dysfunction and disease. This knowledge will be harnessed to design gene-directed treatment strategies. Endothelial cell cultures established from diseased patients tissue will act as the ideal model system to test the efficacy of different treatment strategies in a safe and disease relevant context. Expected outcomes of the study: This study will identify genetic causes of CEDs that will in the short term facilitate earlier pre-symptomatic detection of disease in affected families, inform genetic counselling and may alter the clinical management of disease. In parallel, cellular mechanisms of corneal disease will be investigated to enhance understanding of the biological reasons for disease to enable effective non-surgical treatments to be developed for these sight threatening conditions. Knowledge gained will also impact upon the areas of personalised medicine, age-related disease, and human genetics.