Gene therapy is showing promise in certain forms of eye disease, and one of the pioneers of the field has just taken up a position in Ireland. CLAIRE O'CONNELLreports
A VIDEO CLIP on the YouTube website shows Steven Howarth entering a dimly lit maze. Viewed from above, we see the teenager – who has a form of blindness that makes it difficult to see in low light – lose track and bump into walls before eventually finding his way out in 77 seconds.
Cut to six months later and Howarth takes the task again. This time he strides in confidently and navigates through the darkened maze, error-free in 14 seconds.
What happened? The vast improvement was down to a clinical trial in which doctors inserted a healthy gene into the back of his eye to help overcome a rare condition called Leber’s congenital amaurosis (LCA).
People with this inherited condition lack a critical enzyme, RPE65, which means the light-sensitive cells at the back of the eye die off over time and the patient slowly goes blind.
But by providing a healthy gene to produce the enzyme, researchers hope to protect the light-sensitive cells.
The trial on Howarth and two other patients, which was published last year, could pave the way towards a licensed gene therapy product to treat the degenerative condition within two years, according to the trial’s director Robin Ali, professor of human molecular genetics at University College London.
It’s an example of how the eye is leading the charge for developing gene therapy, explains Ali, who has just become associate director of the Fighting Blindness Vision Research Institute at Dublin City University.
“The eye is a very small and accessible organ and one can inject very precisely into different compartments,” he explains.
“If we look at what we might be able to achieve with gene therapy, then I think initially the technology is allowing us to make relatively modest improvements in function.” But even the small victories in the eye can have a huge impact on a person’s life, says Ali.
“I talk to our patients all the time and they would regard restoration of light perception, or just preventing the loss of that light perception, as a huge advantage.
“They could go into a room and see where the window is, and the door, they can navigate their way around.
“Also, they find that lacking light perception affects their moods: they lose track of time, of night and day, so it becomes very depressing.”
Ali and his 25-strong team have been developing gene therapy for nearly 15 years to help protect and restore light sensitivity.
But the LCA trial, which was part-funded by Irish patient charity Fighting Blindness, was the first time it was tested out on humans.
Doctors at Moorfields Eye Hospital in London injected healthy copies of the RPE65 gene into the layer behind the retina at the back of the eye. And to sneak the therapeutic gene right into the ailing cells, the scientists put it into a virus-derived carrier.
“We use viruses because they are very efficient at introducing genes into cells, that’s essentially what they do, and they have evolved over millions of years,” he explains. “And we think a single injection will result in lifelong stable expression .”
Follow-up tests found the approach had worked modestly well, says Ali. “We shone very small spots of light into the patient’s retina at increasing intensity and we asked the patient when they saw the light,” he explains. “And we saw we had improved retinal sensitivity.”
Of the three patients, Howarth saw the most functional benefit, probably because his condition was the least advanced, according to Ali, who is now setting up to extend the trial to younger patients, where he believes the impact of gene therapy could be even bigger.
“There’s a much greater likelihood of improved function because there’s not as much damage,” he says. “If that didn’t happen we would be very, very disappointed, it would be a very unexpected result.”
Clinical trials in the US have also pointed towards the safety of gene therapy for LCA, and ideally Ali expects a therapy for LCA to be available within two years.
“I would anticipate that in a relatively small series of patients we would be able to establish efficacy and obtain a licensed product perhaps with as few as 12 individuals. And I’m hoping that within two years we would be able to achieve that, provided that everything goes well.”
And he anticipates that work on gene therapy and drug delivery for other degenerative eye diseases will now gather pace too.
“I think what we will see is accelerated timelines for the development of therapies for other forms of retinal degeneration because we have established a lot of the framework – proof of principle for injecting in the eye safely, the lack of immune response. We have established that the surgical procedure is safe.”
Meanwhile, he wants to build up links with gene therapy experts here, including Prof Jane Farrar at Trinity College Dublin, and develop patient-oriented research at the Fighting Blindness Institute.
“I’m here to facilitate those links and to help Fighting Blindness establish a translational pipeline here in Ireland and because research is very international and we want to see how we have got synergies and can build networks,” he says.
To watch the YouTube clip visit youtube.com/watch?v=K9HvnRJT-8A
For more on Fighting Blindness visit fightingblindness.ie