When Tim Wray was a student he noticed he was having difficulty seeing in the dark. Aware that his grandfather had gone blind in his fifties due to a genetic eye disease, he went to Moorfields Eye Hospital in London to have his vision investigated.
The diagnosis was choroideremia, an inherited condition caused by a missing protein that allows waste products to build up and eventually damage or kill retinal cells. The effect is to cause tunnel vision, which gets progressively narrower until all sight disappears.
“I was told that research in gene therapy might lead to treatments in 10 years,” Mr Wray says. A decade later, in 2016, he became one of the first to receive a pioneering operation that involves lifting the retina from the back of the eye and injecting a tiny amount of genetic material under it.
The injections have billions of genetically modified virus particles that “infect” diseased retina cells and deliver the correct DNA. This process lets the cells resume normal function and produce the missing protein needed for vision.
Robert MacLaren, who performed the surgery at the John Radcliffe Hospital in Oxford, says: “The aim is to protect the cells in their current form, thereby stopping or slowing eyesight deterioration.”
Eyes are particularly promising for gene therapy as they have relatively few immune cells, reducing the risk of foreign genetic material being rejected.
And although choroideremia is relatively rare, gene therapy could be applied to other more common causes of blindness, such as age-related macular degeneration.
The nerve cells in the retina are like those in the brain and spinal cord — they cannot be replaced or reconnected when lost because of a genetic defect. But with gene therapy, once the cells have been infected with the good genes they are permanent. Only a single treatment is necessary.
Mr Wray found that in a couple of days his eyesight returned to its previous level. “Time will tell whether it stops the disease permanently, but I have noticed minimal changes compared with previous years, which lead me to hope that it is working.”
At present, the therapy is being used to tackle central colour vision, so Mr Wray may continue to lose some peripheral and night sight. “But I will be happy in my fifties seeing the centre colour vision,” he says. “In my grandfather’s time, I would have had nothing.”
The treatment is still at the trial stage, but Prof MacLaren hopes it will receive approval from the US Food and Drug Administration within two years. He is currently “pushing the boundaries of what you can do with microsurgery” by using smaller needles and more delicate procedures.
Meanwhile, at the Bascom Palmer Eye Institute in Miami, ophthalmologist Janet Davis is exploring a technique that involves injecting the gene therapy into the vitreous fluid that fills much of the eyeball. “It is the surgeon’s job to place the gene therapy in proximity to the target cells,” Dr Davis says. “Subretinal injection is challenging, because the physical properties of the choroideremia retina differ among various diseases and individuals, according to factors including age.”
More doctors would be comfortable with injecting a product into the much larger vitreous cavity, says Dr Davis. “This would bring costs down, but it could be much less effective, as it is not targeted and probably causes more inflammation.”
Researchers are also focusing on corneal blindness, arising from damage to the transparent membrane at the front of the eye. It can be caused by infection and scarring or perforation of the eye wall and affects about 12m people worldwide. Some 75 per cent of cases are curable with transplants but this requires donors and proximity to hospitals. Only about one in 70 people in need receives a corneal transplant.
Subretinal injection is challenging, because the physical properties of the retina differ among various diseases and individuals
For the past 50 years, corneal perforation has been treated with cyanoacrylate glue, similar to that used to build model aeroplanes. This buys time for treatment by plugging the leak but prevents the tissues repairing so that patients normally need a follow-up corneal transplant.
An alternative approach is to use collagen gel-based materials as a framework for cell regrowth and corneal tissue regeneration. However, these do not have the tensile strength to be sutured in place like a conventional corneal transplant.
A project funded by the London-based Tej Kohli Foundation, a philanthropic institution, is working on a liquid form that sets as a gel at body temperature and can be modified to act as a tissue glue. This “liquid cornea” material seals perforations and prevents the need for subsequent transplants.
Collaborating on the project are eye institutes in Montreal, Canada; Odessa in Ukraine; and Hyderabad in India, as well as London’s Moorfields eye hospital and the UCL Institute of Ophthalmology.
At the London institute, Bruce Allan, a consultant eye surgeon, has been conducting pre-clinical tests of the liquid tissue filler for corneal repair. Laboratory studies have shown great promise, he says. “We aim to start human trials within three years.”
The cost of the filler is expected to drop from $3,000 per eye to about $500 within a few years. Moreover, it can be administered by a nurse and does not require a surgeon.
Prof MacLaren’s gene therapy operation costs about $800,000. This may seem expensive, he says. “But in return, with a single treatment, your blindness is cured for life.”
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