Creating a model to investigate corneal thinning in keratoconus

Research details

  • Type of funding: Project Grant
  • Grant Holder: Dr Veronique Vitart
  • Institute: University of Edinburgh
  • Region: Scotland
  • Start date: October 2020
  • End Date: December 2022
  • Priority: Understanding
  • Eye Category: Inherited Eye Disease
Brief Lay Background

The cornea is the window of the eye; a transparent outer layer that transmits and focuses light and provides a protective barrier. The corneal stroma accounts for 90% of corneal thickness in humans, and is composed of precisely organised layers of collagen produced by specialised cells called keratocytes. Disorganisation of these cells and thinning of  the layers are seen in corneal disorders such as keratoconus – affecting between one in 500 to 2,000 people worldwide, and the main cause of corneal transplants in the UK – and most devastatingly, in the very rare genetic disorder Brittle Cornea Syndrome (BCS).

BCS is characterised by extreme thinning of the cornea and can result from DNA variations in the poorly understood gene producing the protein ZNF469. It is suggested that the amount of functional ZNF469 in keratocytes may be very important both for development of the cornea, and in influencing production of collagen by these cells to maintain a healthy cornea.

What problem/knowledge gap does it help address

Understanding how collagen, an essential component of a healthy cornea, is established and maintained is still poorly understood.

Collagen cross-linking is currently used to halt keratoconus progression in 90% of cases but vision improvement remains limited (50% post treatment) and 3% of patients lose some vision as a result of haze, scarring or infection and still require corneal transplant. Alternative interventions are needed.

Genetic evidence makes the ZNF469 gene, and the pathway(s) it regulates, strong targets for early screening and therapeutic intervention in cornea stromal disorders. Characterisation of ZNF469 function may also provide better understanding of genotypic risk associations and prediction of keratoconus.

The cornea is particularly well suited to therapeutic intervention because of its accessibility. New pathways will be scrutinised to identify how they could alleviate stromal dysfunction.

Aim of the research project

To understand more about the role of ZNF469 in how the cornea develops and what goes wrong in diseases where the cornea becomes thin and disorganised.

Key procedures/objectives
  1. To provide novel insights into molecular mechanisms sustaining proper cornea development and maintenance.
  2. To document the cellular and molecular events leading to corneal thinning.
  3. To establish a model as a platform for investigating therapeutic strategies.
Potential impact on people with sight loss

Researchers need to better understand why some people develop corneal thinning, or whether it is possible to restore normal corneal thickness to protect vision.

This project will help researchers investigate what processes are affected in one of the most severe forms of corneal thinning in humans, and will also increase the understanding of factors that control corneal thickness in healthy eyes. In the future, the “disease in a dish” cell model may offer a platform for testing new therapies for  corneal disorders.