Cure for aniridia under spotlight

A new study has suggested potential eyedrop therapy for aniridia. Is the hype justified and what are the details?

Aniridia is a genetic abnormality caused by mutations in the so-called ‘Master Regulator’ gene for eye development, PAX6.  Because PAX6 is used from the very earliest stages of eye development in the embryo, it has always been assumed that when a baby is born with aniridia, most of the damage has already been done. Sure, there are degenerative aspects to aniridia, which need to be managed carefully to minimise further damage to the cornea or the retina, but most clinicians would expect that there will never be a total ‘cure’ for aniridia.

Now a paper published by Cheryl Gregory-Evans and her colleagues, in the prestigious Journal of Clinical Investigation has raised the possibility that it may in future be possible to substantially reverse some aspects of aniridia in children, and it may be as simple as eyedrops.

The potential therapy would depend on some quirky bits of biology surrounding the DNA changes that affect the PAX6 gene.  Over 600 different mutations of PAX6 have been shown to cause aniridia in different people – in some people one copy of the entire gene is missing, other people have chunks of the gene missing, or changed in some way.  However about 50% of people with aniridia have only one ‘letter’ of DNA wrong that causes the cell machinery that makes the PAX6 protein (the ‘ribosomes’) to stop too soon, producing a short, non-functional PAX6 protein that is chewed up by the cells.

For some time it has been known that some types of drug called aminoglycosides (actually a type of antibiotic) can give the ribosomes a chance to ignore these early ‘stop’ signals in mutated genes and carry on regardless to produce a full length protein.

As a result, a number of clinical trials tried to use these drugs to treat other genetic diseases such as cystic fibrosis – without a lot of success, not least because long-term use of these drugs causes a lot of rather unpleasant side effects.

Pharmacological labs have therefore been looking for other drugs that retain the ‘good’ effects of aminoglycosides – the ability to allow ribosomes to ignore some mutations in genes – without the side effects.  One of the drugs they came up with is now called ataluren.

Cheryl Gregory-Evans and her colleagues at the University of British Columbia, Canada, used ataluren on ‘aniridic’ mice that had a PAX6 mutation similar to the ones that affect 50% of people with aniridia, where a single DNA letter mutation causes the production of a short, non-functional PAX6 protein.

Surprisingly, injecting newborn aniridic mice with ataluren produced very considerable benefit to the eyes of the mice: PAX6 levels went up, and the lens and retina of the eye looked and functioned much better than mice without treatment.

However the outer layer of the cornea had not improved much. Because the cornea does not normally contain blood vessels, they concluded that the injected drug was not reaching the cornea properly.  Although this was only a partial ‘cure’, it did suggest that the damage done to the eye by PAX6 deficiency during pregnancy could potentially be reversed after birth.

In order to deliver ataluren more efficiently to the eye and, in particular, the cornea, the scientists then formulated a sticky eyedrop solution that could be applied directly to the cornea of newborn mice. They called it START. When they did this, the results were even better – the retina and lens looked essentially healthy and functioned almost as well as normal eyes.  Furthermore the cornea got a lot healthier too, with a robust thick outer layer (epithelium) that contrasts with the thin fragile epithelium characteristic of aniridia.

Although the treated mice were still ‘aniridic’ in that iris did not grow back, the other, most troublesome, aspects of aniridia – the corneal fragility, cataracts and retinal degeneration – had effectively been reversed after birth by application of ataluren in an eyedrop formula applied directly to the surface of the eye.

This is a very exciting series of scientific results that of course raise the possibility that the technology may be applied to people too.  In the best case scenario, when in future a baby is born with aniridia, there may be an option of applying ataluren directly to the eyes to reverse the damage done to the eye by PAX6 mutation and give the babies essentially normal sight.

There is still a long way to go, of course before this scenario becomes reality. There are a number of issues:

  1. This effect has only been demonstrated on mice, and there would need to be a clinical trial on human volunteers before the treatment could become mainstream. Such a trial is now being prepared.
  2. exactly what ataluren does, and the long-term safety of ataluren in eyedrop form is unknown: some scientists dispute whether ataluren really can tell the cell to ignore DNA mutations, and the drug may have other effects or cause problems that do not affect mice but may become apparent in people using the treatment for a lifetime.
  3. Other potential treatments for aniridia, such as development of a treatment that stops blood vessels encroaching into the aniridic cornea, published in 2006, have never made it to the clinic.
  4. Even if it is safe and effective for people ataluren will only ever be useful for those 50% of patients with aniridia caused by single DNA letter changes that lead to premature termination of PAX6 production. Cheryl Gregory-Evans and her colleagues showed that it produced no benefit in mice with a different sort of PAX6 mutation, and it would be expected to be useless for people with, for example, WAGR syndrome, where the PAX6 gene is missing.

Notwithstanding the caveats, this paper demonstrates that the eye may have tremendous capacity to bounce back from aniridia, if treated early in life, Current therapeutic strategies for aniridia that focus on stem cell transplants are clinically complicated and probably only delay the progression of corneal disease. This research will encourage the many scientists looking for better ways to treat or reverse the condition.

Here’s a video interview of Cheryl Gregory-Evans talking about their work

The research was funded by the Sharon Stewart Aniridia Trust and the trial by Vision For Tomorrow .

Read more about the research and human trial of START eyedrop therapy.


Cheryl Y. Gregory-Evans et al. (2014). Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects.  J Clin Invest. 2014; 124: 111–116.

Article by Professor Martin Collinson, Medical Research Monitor for Aniridia Network UK

Update 2015

Video of Cheryl Gregory-Evans presenting at a conference by Aniridia Russia

This entry was posted in Medical staff talking, Research and tagged , , , , . Bookmark the permalink.

11 Responses to Cure for aniridia under spotlight

  1. Pingback: Charter for improvements in rare disease drug evaluation launched | Aniridia Network UK

  2. Pingback: Drug company donates £1,000 to ANUK | Aniridia Network UK

  3. Pingback: Emerging molecular therapies for aniridia presentation | Aniridia Network UK

  4. Richard says:

    Why it is not applied to people yey?

  5. Pingback: Lovende forskningsresultater for en kur mot aniridi – Aniridi Norge

  6. madvn says:

    Could you please any updates on this treatment? Thanks.

  7. Timothy Schultz says:

    I was the only person in my family to have this disease and now my son has it. I’ve had both of my eyes removed from the complications that can arise with this disease. When is this coming to the United States. My son is 12 years old and this is the age complications began for me.

  8. Pingback: £200,000 Aniridia drug research based and funded in the UK underway | Aniridia Network

  9. Ryan laws says:

    I have got anaridia, I would love if I could get treated

  10. Ryan laws says:

    I have got anaridia, I would love if I could get treated

  11. Pingback: Research into aniridia symptoms link to genetics | Aniridia Network

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