Breakthroughs in corneal dystrophy research

Exciting advancements in corneal dystrophy research

Moorfields Eye Charity is thrilled to highlight two recently published research papers from Professor Alison Hardcastle, Dr Alice Davidson and colleagues.  These research findings demonstrate the strength of the biomedical partnership between UCL Institute of Ophthalmology and Moorfields Eye Hospital and international collaborators.  Philanthropy has played a vital role with Moorfields Eye Charity’s support of Professor Hardcastle’s research.

Corneal endothelial dystrophies are conditions with various symptoms and different genetic causes. They all affect a thin layer of specialised cells known as the endothelium that line the back of the cornea.


Breakthrough discovery in the genetics of corneal dystrophies

Researchers at UCL Institute of Ophthalmology and Moorfields Eye Hospital London, in collaboration with colleagues in the Czech Republic, have discovered a new genetic cause of corneal dystrophy.

  • This discovery paves the way for further studies to understand the biological processes leading to corneal dystrophy and to develop new treatments, with the future hope of replacing the need for corneal transplants in this group of patients.

Corneal dystrophies are a group of inherited disorders that affect the transparency of the cornea, the clear surface at the front of the eye, and can lead to severe sight loss or blindness. The only currently available treatment for many individuals who are severely affected is a corneal transplant.

Posterior polymorphous corneal dystrophy (PPCD) is one form of corneal dystrophy that compromises the function of the cornea, due to abnormal corneal endothelial cells. The genetic basis of PPCD for many patients remains unknown.

  • endothelial cells have an ‘identity crisis’

Prof Alison Hardcastle
Professor Alison Hardcastle, UCL Institute of Ophthalmology

Published in the international journal American Journal of Human Genetics, the team describe pinpointing the location of a new PPCD gene and alterations in the DNA sequence that affect a gene called GRHL2.   They used new technological advances in sequencing the human genome to discover this genetic cause.  The gene is not supposed to be expressed in the corneal endothelium but the team show that the DNA changes cause the gene to be expressed inappropriately in the corneal endothelial cells. They have discovered that there is a convergent pathogenic mechanism for PPCD, where the endothelial cells have an ‘identity crisis’ and transition to a different state.

Professor Hardcastle said, 

this study is not only important for understanding what is required for a healthy cornea and how it is faulty in disease, but also represents an important advance in human genetics, enhancing our understanding of the ‘non-coding’ regions of the human genome that dictate where, and when, a gene should be switched on or off.


Promising results for the most common form of Fuchs Endothelial Corneal Dystrophy

In the UK more than 1,000 patients per year undergo invasive corneal transplant surgery to prevent sight loss caused by Fuchs endothelial corneal dystrophy (FECD).  The cornea is the transparent tissue situated at the front of the eye. The innermost part of this tissue is comprised of a specialised layer of corneal endothelial cells. FECD is a common age-related disease and is characterised by the death of these corneal endothelial cells. 

Dr Alice Davidson, UCL Institute of Ophthalmology
Dr Alice Davidson, UCL Institute of Ophthalmology

Dr Alice Davidson from UCL Institute of Ophthalmology and colleagues have been working on this condition for a number of years. In collaboration with the pharmaceutical company ProQR, they have developed an antisense oligonucleotide (ASO) drug which targets a specific genetic mutation in a gene called TCF4 that is responsible approximately 75% of Fuchs cases. ASOs are short strands of chemically modified nucleotides that are complimentary to mRNA; products produced by the disease gene of interest. They show that the ASO drug can reduce the harmful build-up of mRNA products that occur in patient cells due to the TCF4 mutation. 

Dr Davidson said,

I am hugely excited by the translational potential of this research’ which is has been recently published in the prestigious American Journal of Human Genetics


Using patient corneal cells grown in the lab, they demonstrate the utility of this treatment. With continued research and investment they hope their proof-of-concept study will pave the way for a new effective and less invasive way to treat this common and sight-threatening condition.