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

Lead Research Organisation: University College London
Department Name: Institute of Ophthalmology


Background: 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 the cornea is 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, while also regulating the movement of crucial nutrients into the rest of the cornea. Corneal endothelial dystrophies (CEDs) are a group of genetic diseases that result in dysfunction of this specialised cellular layer. They results in corneal swelling, clouding and consequently visual impairment, and in some instances, blindness. Fuchs Endothelial Corneal Dystrophy (FECD) is an age-related disease and the most common CED by far, affecting 4.5% of people >50 years of age. Up to 80% of cases have the same genetic cause, termed a mutation, that affects a repetitive part of the human genome. Other much rarer types of CEDs include a disorder called Posterior Polymorphous Corneal Dystrophy. In recent years, we and others have identified multiple mutations in numerous genes that cause rarer CEDs. However, we still do not know the cause of approximately 25% of total CED cases, and for the cases in which we know the mutations responsible, we still do not fully understand how these mutations cause disease.

Clinical Need: Corneal transplantation is currently the only treatment option available for CED patients experiencing visual loss, but the long-term survival of grafts is poor, and there is a global shortage of donor tissues. Coupled with the age-related nature of FECD, this means that in our globally aging society there is an urgent clinical need for alternative and ideally preventative, or disease-delaying, therapies to be developed.

Aim: This research program aims to 1) discover genetic causes and risk factors that predispose individuals to developing CEDs, 2) define how these genetic risk factors and/or causes lead to impaired corneal function, and 3) use this knowledge to develop innovative new therapies.

Methods: DNA samples from CED patients will be analysed using a range of genetic methods to identify genetic causes and modifiers of disease. In parallel, using donated tissues removed during corneal transplant surgery, we will establish and implement a range of specialist methods to grow the cornea cells and tissue in a dish to investigate how particular mutations cause cell dysfunction and disease. This knowledge, in combination with the optimised cellular disease models, will be harnessed to pioneer the pre-clinical development of gene-directed treatment strategies in a safe and disease-relevant context.

Expected outcomes of the study: This study will identify genetic causes and modifiers 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 the longer-term insight gained will enable clinicians to better recognise individuals at risk of developing CEDs eligible for preventatives therapies. In parallel, knowledge gained from studying molecular disease mechanisms will accelerate the design and development of gene targeted CED therapies for these sight threatening conditions. Mechanistic discoveries are also anticipated to offer novel insights into biomarkers and risk prediction strategies for other categories of human disease that are similarly attributed to mutations that affects a repetitive part of the human genome, such as Huntington's disease and myotonic dystrophy. In summary, this research program has the potential to transform CED patient care and generate broad reaching impact across the areas of ocular biology, personalised medicine, human genetics and functional genomics.


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