Gene therapy breakthrough in blindness researchThursday 16 January 2014 19.26
Pioneering gene therapy has restored vision to two men with a rare inherited eye disease who were told to expect to go blind.
Scientists hope early intervention with the surgical treatment will halt progression of the devastating disorder, choroideremia, before patients are robbed of their sight.
It is the first time gene therapy has successfully been applied to the light-sensitive photoreceptors of the retina, the digital camera at the back of the eye.
Preliminary results from the first six patients taking part in a Phase One trial surprised and delighted the Oxford University team.
Although the trial was only designed to test safety and dosages, two men with relatively advanced disease experienced dramatic improvements to their eyesight.
The researchers are now planning a larger Phase II trial that will focus on the therapy's effectiveness.
Professor Robert MacLaren, who led the gene therapy operations at Oxford Eye Hospital, said: "We're absolutely delighted with the results so far.
"It is still too early to know if the gene therapy treatment will last indefinitely, but we can say that the vision improvements have been maintained for as long as we have been following up the patients, which is two years in one case.
"In truth, we did not expect to see such dramatic improvements in visual acuity and so we contacted both patients' home opticians to get current and historical data on their vision in former years, long before the gene therapy trial started.
"These readings confirmed exactly what we had seen in our study and provided an independent verification."
The ground-breaking research could pave the way to gene therapy treatments for more common blinding conditions, including age-related macular degeneration and retinitis pigmentosa, another inherited disease.
Choroideremia is caused by a defect in the gene CHM and affects around one in 50,000 people in the UK.
Treatment could prevent patients from going blind
Currently there is no cure or treatment for the disease which progresses slowly, destroying retinal photoreceptors and often leading to complete blindness by middle age.
But the slow pace of the disorder offers a glimmer of hope by making it possible to step in with gene therapy before too much damage has occurred, Prof MacLaren explained.
The treatment involves injecting a harmless virus carrying a properly functioning copy of the CHM gene directly into the retina's light-sensitive cells.
"If we were able to treat people early, get them in their teens or late childhood, we'd be getting the virus in before their vision is lost," said the professor.
"If the treatment works, we would be able to prevent them from going blind."
Although Prof MacLaren describes the procedure as being similar to cataract surgery, it is a highly skilled and delicate operation taking up to two hours.
Nevertheless he insists it is well within the scope of other eye surgery centres.
If all goes well there should be enough data available for the experimental treatment to be approved as a licensed therapy in around five years, he predicts.
Findings published in medical journal
Findings from the first six patients with different stages of the disease are reported in The Lancet medical journal.
Each patient had only one eye treated, so it could be compared with the other.
Two of the six were not yet noticeably affected by their condition and had vision described as "excellent".
Another two had "good" visual acuity and two more - the pair whose results surprised the researchers - had eyesight that was seriously impaired.
Six months after the operation, the participants with excellent and good vision retained the same basic level of sight, but their ability to see in the dark had improved.
The two patients with damaged vision, Bristol barrister Jonathan Wyatt and London solicitor Toby Stroh, experienced marked improvements, which included being able to read up to four more lines on a sight chart.
Both Mr Wyatt, 65, and Mr Stroh, 56, were told early on by their consultants to resign themselves to going blind.
Mr Wyatt was just 20 when the bomb was dropped, describing it as a "sledgehammer blow".
He eventually stopped working as a barrister at the age of 53 after being rebuked by a judge for misreading a statement in court.
Mr Wyatt was the first patient to receive the gene therapy treatment. After the operation on his weaker left eye, vision in that eye underwent a dramatic transformation.
"Now when I watch a football match on the TV, if I look at the screen with my left eye alone, it is as if someone has switched on the floodlights," said Mr Wyatt.
"The green of the pitch is brighter, and the numbers on the shirts are much clearer."
He was also able to read the numbers on his wife's mobile phone for the first time in five years.
Mr Stroh, who was originally mistakenly diagnosed with retinitis pigmentosa, also had the operation on his left eye.
He too was in his 20s when a consultant broke the news that he was going blind.
"There has been a marked improvement in the number of letters I can read on a sight chart," said Mr Stroh. "It is such a dramatic improvement that as far as I am concerned, it must be as a result of the trial.
"I have said for a long time that as long as I can read and play tennis, I'll be happy. As a result of this trial there is now a chance I'll be able to do both these things for longer."
Higher dosages being tested
Another six Phase One patients are receiving higher doses of the gene-carrying virus.
Prof MacLaren added: "We are now trying higher doses of the gene therapy in the next part of the clinical trial to find what level is needed to stop the degeneration.
"I am incredibly excited to see what will happen. The difficult bits are done: we know the virus carrying the gene therapy gets into the cells and the retina recovers after the surgery. Now it's just waiting to see how the patients progress."
The trial showed that the genetically engineered adeno-associated virus (AAV) was able to deliver the corrective CHM gene without damaging the retina.
"This has huge implications for anyone with a genetic retinal disease such as age-related macular degeneration or retinitis pigmentosa, because it has for the first time shown that gene therapy can be applied safely before the onset of vision loss," said Prof MacLaren.
He stressed that the treatment could not supply the retina with new photoreceptors. Instead, it repaired damaged but still functioning cells and prevented others being affected by the disease.
"These cells do not replicate," said Prof MacLaren. "Once they are gone, they're gone."
The trial was jointly supported by the British Department of Health and the Wellcome Trust charity through a partnership scheme called the Health Innovation Challenge Fund.
A third of diseases affecting the eyes are genetic in origin.
Choroideremia is relatively easy to correct because it is caused by a single defective gene.
Other conditions involve more than one gene - possibly three or four in the case of macular degeneration.
CHM, which lies on the X chromosome, provides the manufacturing instructions for a protein vital to eyesight called rab escort protein 1 (REP1).
Loss of the REP1 protein causes retina cells to stop working and eventually die. The first symptom of the condition is usually poor night vision which can occur in early childhood.
Later, the field of vision progressively narrows to a "tunnel" until only a small central slit remains.