Overview
The cornea is the clear outer layer of the eye. It protects the eye and helps focus light. If it’s not clear, light can’t pass through. This is what happens in a group of inherited conditions known as corneal dystrophies. They cause pain and sight loss.
In most cases corneal dystrophy is caused by a genetic fault inherited from one parent (‘dominant’ inheritance), most often in the gene called TGFBI. But the faulty gene has been identified in only 5% of affected families at the team’s clinic.
Corneal transplant is an option of other treatments fail, but the donor cornea can go on to become cloudy too, so we need better options. One option could be a new type of therapy to ‘silence’ or ‘switch-off’ the faulty copy of the gene while leaving the healthy one alone to do its job. But first we need to know which genes to target.
In this project the team aims to pinpoint the genetic faults responsible for corneal dystrophy in the majority of their 400 patients. They are studying blood and tissue samples and will try to switch off the identified genes in cells grown from the tissue.
The results should mean that most families with corneal dystrophy will have a specific diagnosis and so can get better information and advice on their condition. And if the gene silencing works in tissue it will be a great first step towards a gene therapy that could perhaps be taken as non-invasive eye drops.
-
Publications
- Davidson AE, Liskova P, Evans CJ, Dudakova L, Nosková L, Pontikos N, et al. Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2. The American Journal of Human Genetics. 2016 Jul 1; 98(1):75–89.
-
Research update
PhD student Cerys Evans and the team have now identified the genetic change that causes corneal dystrophy for over 100 of their 400 patients. And they have discovered new types of fault in some genes. -
Scientific summary
Genetics of dominant corneal dystrophies and development of gene-specific therapies
Corneal dystrophies are characterised by bilateral progressive corneal opacities causing visual impairment and blindness, which often lead to a requirement for corneal transplantation. They are genetically and clinically heterogeneous, with the most common inherited cause being autosomal dominant mutations in TGFBI. The genetic cause of several dominant corneal dystrophies, however, still remains to be determined.The team has an extensive register of over 400 patients, however less than 5% have a molecular diagnosis for their condition. Here they aim to identify the spectrum of gene mutations in our cohort, and to test an allele-specific gene silencing therapeutic approach for dominant mutations in corneal fibroblasts from genotyped patients with dominant mutations. They are trying to determine the genetic basis of disease for the majority of patients by screening known causative genes, including TGFBI. They are uniquely placed, because of our extensive clinical resource, to identify a novel gene for dominant congenital hereditary endothelial dystrophy, and a gene for dominant Fuchs endothelial dystrophy, using next-generation sequencing strategies. Identification of the genetic cause of dominant corneal dystrophy in these patients will reveal the prevalence of specific gene mutations and their associated phenotypes. This will guide their development of TGFBI mutation targeted gene-silencing therapy for their patient group. They are establishing a bank of patient derived corneal fibroblast cell lines of known genotype.
Optimised TGFBI mutation-specific small interfering RNAs (siRNAs) are being identified and tested for allele-specific knock-down of the mutation in the cellular context. These studies will set the scene for pre-clinical development of gene-specific therapies for dominant corneal dystrophy patients.