Triplet repeat expansion-associated inherited corneal disease: from genetic mechanism to clinical consequences

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Fuchs endothelial corneal dystrophy (FECD) is a common vision-impairing disease that affects 4.5% of the population over 50 years of age. Both eyes are generally affected, and this is because the cornea, the transparent window at the front of the eye, loses its ability to remove excess fluid from its outer layers and becomes swollen and cloudy. The only effective treatment for advanced FECD is corneal transplantation. In the UK, 80% of the FECD cases are caused by a common genetic disorder called a 'CTG18.1 repeat expansion', where this short sequence of genetic code repeats and expands to a threshold that causes disease. FECD is the most common reason for corneal transplant in the UK. However, the surgery is costly, and there is a global shortage of donor tissue. In an effort to reduce the demand for corneal tissue, multiple innovative treatment options are emerging, including a gene therapy developed at our lab. The long-term success of these therapies will rely on identifying individuals at risk of developing FECD and initiating early treatment before irreversible damage occurs. Having a better understanding of the genetic mechanism in FECD would help to achieve these. In other better-understood diseases caused by abnormally repeated genetic codes (eg. myotonic dystrophy), the more the disease-causing genetic code is repeated, the earlier the onset of disease and the more severe symptoms patients will have. Moreover, the number of these repeated genetic codes is larger in the affected tissues. We also know that in these conditions, the number of the disease-causing genetic code increases when the disease is passed down from one generation to the next, resulting in earlier and more debilitating disease in each succeeding generation. This project aims to find out whether these clinically important patterns also occur in FECD, which is currently a poorly understood disease. Our study will take place in the laboratory setting at UCL Institute of Ophthalmology, where we have already performed extensive genetic analysis of a large group of FECD patients. Aim 1. I will generate new genetic data and use statistical models to examine the relationship between the number of CTG18.1 repeats of our recruited patients and their age when they require a corneal transplant. Following my preliminary work, I expect to see a trend where patients with larger CTG18.1 repeats require corneal transplants earlier. This knowledge will enable us to predict how fast disease will progress based on genetic information. Aim 2. I will use an innovative technique called Single Molecule (SM)-PCR to analyse the DNA in the affected corneal tissues removed from FECD patients during corneal transplant surgery. Due to technical limitations, analysis of diseased corneal cells has not been successfully performed before. As the cornea is the only tissue affected by FECD, I predict the number of CTG18.1 repeats in corneal cells may be a lot larger than in the blood cells of the same patient. Aim 3. I will analyse the DNA of FECD patients' siblings to assess the proportion of individuals carrying the CTG18.1 expansion that also develop FECD. Adult children of FECD patients will also be recruited to discover how the repeats behave (i.e. if it gets bigger or smaller) when passed onto successive generations. This will enable us to have a better understanding of how CTG18.1 changes within families and its risk associated with FECD. Currently, it is not known how the disease-causing gene of FECD modifies its clinical features. This important research will help us gain more in-depth knowledge about FECD, and potentially allow doctors to give more accurate genetic counselling on the progression of FECD and its risk implication to the next generation of FECD patients. Knowledge of CTG18.1 repeats in affected corneal cells may also open up research for new treatments options.