Preliminary research has shown that ataluren is effective in overriding the nonsense mutation in choroideremia patients, however, further research is needed.
Reviewed by Dr Mariya Moosajee
Choroideremia is a rare blinding genetic eye disease affecting approximately one in 50,000 people. Usually, the first signs are seen in young boys – sometimes as early as age five. In the disease, blood vessel networks, pigment and light-sensing cells in the eye’s retina slowly stop working and eventually die.
Initially, night-blindness and ‘blind spots’ (resulting from vision loss in the mid-periphery) typically occur, but as time passes, central vision is also affected, leaving patients with tunnel vision. With no cure currently available, the disease slowly progresses until vision is lost, resulting in blindness.
Choroideremia is caused by a genetic defect of the X chromosome and so it usually affects males. In approximately 30% of people with the disease, the defect is described as a nonsense mutation, which causes an abnormal ‘stop’ sign in the genetic code.
Dr Mariya Moosajee, clinician-scientist and consultant ophthalmologist at NIHR Moorfields Biomedical Research Centre in London, is looking into whether the drug ataluren (PTC Therapeutics) could help patients with nonsense mutations. The drug works by overriding the ‘stop’ sign, allowing for normal function.
It is currently approved by the European Union and the National Institute for Health and Care Excellence (NICE) in the UK under the trade name Translarna to treat patients with Duchenne muscular dystrophy. The orally administered drug is generally well tolerated, with few side effects, and is given to children from the age of two.
Thus far, ataluren has been shown to be effective in overriding the nonsense mutation in choroideremia, as seen in skin cells that were converted to stem cells in the laboratory and, subsequently, retina cells, which were administered with the drug.
An 18-month project involving 25 patients has started, to investigate choroideremia in greater detail. “This will enable us to map individual disease progression and help us to find the right time to intervene – ideally the younger the better,” said Dr Moosajee. She anticipates that the trial will be complete in Summer 2018, and that Phase II and III trials will swiftly follow.
Scope for this treatment could widen further, as it could also be used for other eye diseases involving the abnormal ‘stop’ system, according to Dr Moosajee, such as Usher syndrome, which causes combined deafness blindness, and Bardet-Biedl syndrome, which causes blindness but also affects many other parts of the body.
“It is estimated that about 30% of all genetic eye diseases are caused by this abnormal ‘stop’ signal. So the impact of a positive result will mean that many patients who currently have very little hope may have an opportunity for treatment,” Dr Moosajee explained.
The first patient to be invited to donate a skin sample for Dr Moosajee’s research was choroideremia patient and school teacher Matthew Murrell. He has also narrated a short film entitled ‘Partnership for Sight’, in which he explains what it is like to live with the disease and how a new treatment could transform his and other patients’ lives.
The film begins in complete darkness, but as Mr Murrell introduces himself, viewers experience tunnel vision on screen, representing the small amount of vision that Matthew has.
“When I was six years old, I noticed that I couldn’t see very well in the dark and as I grew older I started to lose my visual fields. Now, all that is left is a small area of tunnel vision. I know that eventually I will lose all my sight and I will go blind,” Mr Murrell explains.
Dr Moosajee felt that having a patient describe his experiences would pack a more powerful punch than if she had simply relayed her research herself, thus helping stimulate greater public engagement.
Members of the public who viewed the film, along with 26 other films in York, Sheffield and Devon, voted it as the most important research project. “This research is quite complicated and so for the public to vote it as the most important was a massive boost for us,” Dr Moosajee said.
“Losing your sight is one of the most feared health outcomes with an enormous impact on individuals and their families in day-to-day life, and people with genetic eye disease have no treatment available to them. This prize highlights that the public understand the importance of research into blinding conditions and the positive impact it can have.”
“My research communication aims to not only create awareness of choroideremia, but also increase knowledge of all rare blinding diseases that have no treatment,” Dr Moosajee said.
“These patients are told that they are going to go blind and there is nothing anyone can do. We must let people know that that there are teams of people working hard to change this, if not for them but for their future generations.”
“We also need to create a greater understanding of what it is like to live with these diseases. Since Mr Murrell’s colleagues and students have seen the film, they have shown greater support and have made many more adjustments to help him.”
Dr Mariya Moosajee
Dr Moosajee is a consultant ophthalmologist specialising in genetic eye diseases at Moorfields Eye Hospital and Great Ormond Street Hospital for Children. She has won 30 international and national prizes for her research and published over 40 peer-reviewed publications. Her current clinical focus is developing a genomic service for children and adults affected with genetic eye disease. Dr Moosajee has no financial disclosures.