What is LCA?
LCA is a group of devastating inherited degenerative disorders, primarily affecting the eye’s retina and causing severe visual loss. With this condition photoreceptor cells – the retina’s light-sending rods and cones – do not work properly.
LCA appears at birth or in the first few months of life and it is the earliest cause of sight loss in children, as well as the most common form of inherited sight loss in children. It affects approximately one in 80,000 people, and symptoms include poor and declining peripheral vision; night blindness; nystagmus (shaking eyes); and poor pupil reactions.
There are at least 20 different forms of LCA, with each type caused by defects in a different gene - a part of the DNA that provides an instruction to your body for normal physical development and is passed from parent to child – needed for normal visual function. In the case of LCA type 4, the problem lies with the AIPL1 gene (aryl-hydrocarbon interacting protein-like 1). LCA4 is a rare and particularly severe form of the disorder.
Earlier research has paved the way
Earlier research has paved the way
Previous research has shown that gene therapy can help people with LCA type 2, which is associated with the gene RPE65 (retinal pigment epithelium 65). Additionally, early clinical trials have shown that gene therapy can safely and successfully restore some vision in people with LCA connected to the gene PNPLA6 – the 20th gene linked to LCA and only recently identified.
This research has led the way to consider other forms of LCA that are likely to benefit from gene therapy – and this includes LCA4.
“In laboratory experiments we found that gene therapy can provide some benefit in LCA4 and we are very excited by those results,” says Professor James Bainbridge, Consultant Ophthalmologist at Moorfields Eye Hospital.
Following these hopeful findings, Professor Bainbridge and colleagues worked with Moorfields Eye Charity to set about raising £400,000 to fund the manufacturing process of a gene vector – a modified virus that is used to package the gene in such a way as to deliver it to the eye cells that require it.
Donations have come from around the world, with insurance entrepreneur Michael Wade holding a classical music concert and fundraiser for his 60th birthday and marking his debut as a conductor. Mr Wade had previously developed detached retinas in both eyes but his eyesight was saved following treatment at Moorfields Eye Hospital.
The Impact
Modest improvement, major impact
With funding now successfully secured, the production of the LCA4 specific vector got underway in early 2017 and is expected to take approximately six months. The vector will be sufficient for up to 100 children, but in the first instance will be provided for a small number.
“We are already aware of some children with the condition who might benefit and we expect more to be identified,” says Professor Bainbridge.
“The challenge with this condition is that there is a relatively short window of opportunity to intervene – probably just the first few years of life. We can’t expect gene therapy to work once the disease is very advanced.
“We will be conducting assessments after the first six months to year, and if the first indication is successful – as we hope – then we may consider a formal trial so that a treatment could become more widely available.”
But what sort of difference can children realistically expect? Considering the children’s very poor vision, even a minor improvement would have significant consequences.
“In mice that have the equivalent condition owing to a defect in the same gene, the provision of the gene resulted in an improvement in sensitivity to light,” explains Professor Bainbridge.
“In humans this could mean being able to use sight to help them navigate and see other people’s shapes. This would make a huge difference.”
As in any trial, there are risks involved, which include inflammation in the eye and the potential acceleration of loss of sight. However, in the laboratory there was no evidence of either, with the experiments going very smoothly. “In this particular condition the sight impairment is so severe that the balance of risk is very much in favour of intervention,” comments Professor Bainbridge.
Despite the hopeful aspirations, families’ expectations will be carefully managed. Says Professor Bainbridge: “It’s important that families have a very clear understanding of the aims, uncertainties and risks involved. We simply cannot predict if the gene therapy will work as well in children as it did in the laboratory.
“But we of course hope it will provide benefit in terms of protection of sight or improvement of sight. We cannot predict the extent of improvement in terms of its magnitude or duration.
“We are just very pleased to see that there is potential for benefit. If successful, the change could make a major difference to the children’s and their families’ lives.”
Nikhil’s Story
Nikhil’s story
When seven-year-old Nikhil Kamath was just weeks old, his mother Namita put him in a darkened room to find out how he would respond to a bright light. But, alarmingly, there was no reaction at all from him. It was clear to Namita that he could not see any light.
Mother’s instinct had told Namita that her son’s vision wasn’t normal and her suspicions were confirmed. She recalls: “Within the first couple of weeks after Nikhil was born, I noticed that there was something wrong with his vision. His eyes just weren’t following me at all. I also noticed that Nikhil had nystagmus – I could see that his eyes were shaking when he was attempting to focus.”
After a referral from their GP, Namita and husband Vikram were told that Nikhil could have a condition in infancy whereby his visual fixation is slow to develop. “I was hoping for the best – delayed vision,” says Namita, who qualified as a doctor herself. “Denial is your first reaction when you notice something is wrong with your child. I just denied it could be anything worse.”
Whenever Nikhil opened his eyes, he showed very little expression but at 10 weeks he began to smile in response to different sounds. At around the same time, he also finally started to follow light, which gave his parents some hope.
Meanwhile father Vikram was desperately trying to find more about the visual condition that his cousin suffered. “As soon as we found out that Vikram’s cousin had been diagnosed with LCA, I immediately knew that Nikhil had inherited this disease,” says Namita.
Nikhil then underwent a series of tests before his condition was eventually diagnosed as LCA4.
Says Namita: “Difficult as it was, I knew that we had no choice but to accept it and look at the ways in which we could support Nikhil.
“His milestones were all delayed. Getting him to crawl was very hard but he began to crawl at around 11 months, when we used a musical toy to get his attention.”
The family, who live in Reading, Berkshire, moved to a new property with a garden so that Nikhil could have more outdoor space. “He loves playing ball. He can follow a ball with a bell inside it and one day he picked up a black and white ball so I realised that he could see white against a contrasting background,” says Namita. “He has also maintained his ability to distinguish between light and dark, but I am aware that his condition can regress. Whatever vision he has now he may lose in the future.”
Despite his obvious limitations Nikhil has now developed excellent navigation skills. “He is brilliant at getting around a new environment. I only have to tell him once where everything is,” explains Namita. “He can also tell me where there is a tree or a lamp post, and when in the car he always knows when we are driving under a bridge. I truly don’t know how he knows these things!”
Nikhil attends a local mainstream school, where Namita believes he has excellent support. “There are two staff members always with him and any verbal learning is done in the classroom, with other children. He loves music and sport and he is particularly good at playing the piano. He recently completed his Grade One piano exam and played a five-minute Bollywood piece of music in front of 300 people,” says Namita, proudly. “He knows all the music notes and even teaches his dad how to play piano.”
Socialising and general communication for Nikhil can be more difficult but Namita and Vikram are working with his school to improve this. “He has a few good friends and he gets close to whoever has the patience to sit and chat to him!” says Namita. “He is really just a very normal little boy – very cheeky but very obedient.”
Namita is excited about any research that could improve Nikhil’s condition. She is nevertheless philosophical in her expectations. She says: “By the time human trials begin it will probably be out of Nikhil’s ‘treatment window’. But I look to the future and I wouldn’t want anyone else to go through what Nikhil is going through now. We have been told that as he gets older he will use whatever vision he has and in the meantime we will continue to do everything we can to ensure that he has as normal a life as possible.”
