Phenotype/genotype correlation of inherited corneal dystrophies v1
Research type
Research Study
Full title
A study to determine phenotype/genotype correlation of inherited corneal dystrophies with evaluation of potential gene silencing therapies in vitro
IRAS ID
129580
Contact name
Stephen Tuft
Contact email
Sponsor organisation
Moorfields Eye Hospital Research and Development
Research summary
Corneal dystrophies are characterised by bilateral progressive corneal opacification causing visual impairment and blindness, which may require corneal transplantation for visual rehabilitation. They are genetically and clinically heterogeneous, with the most common inherited cause being autosomal dominant mutations in a gene called TGFBI. The genetic cause of several dominant corneal dystrophies, however, has not been determined. We have an extensive register of patients who have been recorded as affected by corneal dystrophy, but as yet less than 5% have a molecular diagnosis for their condition. In this research we plan to clinically examine affected patients to determine the features of their corneal change (the phenotype) and examine available relatives to confirm the pattern of inheritance of disease. We then plan to to identify the spectrum of gene mutations in our cohort (the genotype) using DNA extracted from a venous blood sample. In selected patients that have undergone corneal transplantation we will use a portion of the excised corneal tissue to isolate fibroblasts to test in vitro a specific gene silencing therapeutic approach for the treatment of dominant mutations. The study will include patients with dominant congenital hereditary endothelial dystrophy, dominant Fuchs endothelial dystrophy, and granular and lattice dystrophies. This work will guide future development of specific mutation targeted gene-silencing therapies for this patient group. We will establish a bank of corneal fibroblast cell lines derived from individuals with a known phenotype and genotype. Optimised mutation-specific small interfering RNAs (siRNAs) will be manufactured and tested in vitro for allele-specific knock-down of each mutation. These studies will set the scene for the pre-clinical development of gene-specific therapies for patients with dominant corneal dystrophy.
We propose to include up to 200 patients for phenotyping/genotyping, of which up to 50 will have corneal surgery as part of their routine clinical care.
REC name
London - Brent Research Ethics Committee
REC reference
13/LO/1084
Date of REC Opinion
1 Oct 2013
REC opinion
Further Information Favourable Opinion