By researcher Martin Collinson
Aniridia, caused by mutation in the so-called eye ‘master regulator gene’, PAX6, can impact on vision in several ways. In addition to the absence or near-absence of the iris, people with aniridia are at high risk of cataract (cloudy lenses) and glaucoma.
One of the most intractable problems however is the deterioration of the front surface of the eye, the cornea, which can occur over time, leading to inflammation, opacity and irritation. Conventionally, this corneal deterioration (‘aniridia-related keratopathy’ or ARK) is treated as a failure of the stem cells that maintain the corneal epithelial
surface, and transplant of stem cells can improve vision, at least for a while.
However, there is a lot more going on: the corneal surface of people with aniridia is typically more fragile than found in the general population. Not only is it more likely to suffer small recurrent abrasions, it is also slower at repairing wounds, and metabolically slightly less able to respond to environmental stress. Corneas have fantastic powers of regeneration, but this ‘triple-whammy’ means that over time, the corneas of people with aniridia do tend to deteriorate, and there is no cure.
Typically, people with aniridia have only one functional copy of the PAX6 gene in every cell, instead of the normal two. The other copy has picked up a mutation that stops it from producing a functional protein, and of course these mutant genes can run in families. The mutations mean that cells in people with aniridia are not producing as much PAX6 protein as the eye needs to develop normally.
Recently drugs such as Ataluren and others have been developed and trialled that can
‘rescue’ mutant cells and allow them to produce more normal levels of protein. They show great potential to improve the eye condition in aniridia, but will only ever work for the minority of people who have a particular type of mutation where a single DNA base change ‘stops’ the gene somewhere in the middle. Drugs such as Ataluren allow cells to ignore such mutations, but are not designed to help the majority of people with aniridia who have different mutations, such as for example, the whole gene being missing.
To address this, we are working with researchers such as Professor Daniel Aberdam at INSERM (Paris) and Tel Aviv University. They have screened for new safe drugs that for one reason or other, can increase PAX6 protein levels in human cells that carry aniridia-causing mutations. They found two drugs that in cell culture tests in vitro, can safely raise PAX6 levels in mutant corneal cells, rescue gene expression and help with wound healing. We believe these are very exciting as candidate cures for the corneal problems associated with aniridia.
Fight for Sight have funded us to test whether these drugs can fulfil their promise. The intention is to test them in mice that carry Pax6 mutations equivalent to those found in people, to see if they are a viable oral or topical (i.e. eyedrops) therapy for aniridia. The Pax6 mice are perfectly healthy and live normal ‘lab mouse’ lives, but show the iris, lens and corneal problems associated with human aniridia. They therefore have relatively poor eyesight, and the idea of the project is to test whether these drugs can improve their vision. If it works on mice, there is good reason to think it will work on people too. It is a twelve-month project and so we hope to be able to report results by the end of 2020.
It is not intended that the drugs will make the iris grow back or give everyone with aniridia perfect eyesight – that’s a battle for another day. However, we are very optimistic that we will be able to ameliorate the corneal problems that can be an important component of the vision loss associated with aniridia, and a persistent irritation to people affected.
While a cure for aniridia is probably a long way off, there is hope that significant improvement of vision will become routine in the medium term.