Searching for new treatments for aniridia
1 August 2023
Aniridia is a condition where parts of the eye, including the iris, fovea and optic nerve, do not form correctly. We have supported Professor Mariya Moosajee and her team to test potential pharmacological treatment options for this currently incurable disease.
Aniridia is a rare genetic eye disorder that results in complete or partial underdevelopment of the iris (the coloured front part of the eye) and the fovea (the area of central vision at the back of the eye).
This affects the appearance and function of the eye. Later complications such as cataracts, glaucoma and corneal opacity can lead to progressive vision loss.
Between 1 in 40,000 to 100,000
births are affected by aniridia.
Known cause of aniridia
Aniridia is mainly caused by mutations in the PAX6 gene, which encodes Paired box 6 (PAX6) protein. PAX6 has a fundamental role in the development and maintenance of eyes.
Around 40% of these mutations introduce an abnormal stop signal in the gene instructions. The faulty gene instructions cannot be read correctly, and the cell cannot produce enough of functional PAX6 protein.
The challenge is to find a way to override these abnormal stop signals so fully formed and functional protein can be produced and enable normal eye development.
Professor Mariya Moosajee, Professor of Molecular Ophthalmology and Consultant Ophthalmologist
Modelling aniridia
Professor Moosajee’s team generated several novel human cell models of aniridia.
Skin cells from two patients with different mutations in PAX6 gene were converted to stem cells using induced pluripotent stem cell (iPSC) technology.
Researchers then used these stem cells to generate 3D models of the early developing eye called optic vesicles, and 2D models of the front of the eye – cornea.
The team used RNA sequencing to study all the genes that were switched on or off in these developing optic vesicles and the analysis is under way.
Testing treatments
The team used the 3D optic vesicles and 2D cornea models to test two drugs, ataluren and amlexanox, which can override abnormal stop signals in the gene to promote protein production.
Drug profiles
Learn more
Ataluren
- Drug with read-through activity that overrides a premature stop signal introduced by a nonsense mutation.
- This enables the protein-making apparatus in cells to move past the defect, restoring the production of functional protein of interest.
- Approved for treatment of Duchenne muscular dystrophy
Amlexanox
- Drug with dual read-through activity and nonsense mediated decay pathway inhibitor.
- Before the protein can be produced, the gene instructions undergo a quality control assessment inside the cells.
- If they contain a mistake, such as a premature stop codon due to a nonsense mutation, they are destroyed.
- This drug prevents the gene instructions from being destroyed and overrides the abnormal stop signal, allowing for complete and functional protein to be produced.
Treatment with amlexanox increased levels of fully formed and functional PAX6 protein by 4-fold in the aniridia human cell models.
Further work will focus on testing whether amlexanox and other, similar, drugs such as 2,6-diaminopurine (DAP), can improve the development and function of the eye cells.
If successful, amlexanox could be repurposed as a treatment for aniridia, which in turn could benefit patients with mutations in PAX6 gene, in the future.
Focus on researchers
Professor Mariya Moosajee, Clinician Scientist talks about her work
Dr Dulce Lima Cunha is a postdoctoral researcher, who worked on this project in Professor Moosajee’s lab, and contributed to 10 peer-reviewed publications, presented data at several scientific conferences, and helped to organise the European Aniridia Conference in London in 2021.
Dr Cunha continues her research career at the Radboud University Medical Center in Netherlands.
