Promising first results in gene therapy trial for inherited blindness

Moorfields’ patients and consultants have been involved in the first clinical trial of a gene therapy for an inherited cause of progressive blindness called choroideremia. 

The promising initial results (at the six month stage) for the first six patients were published in The Lancet on 16 January 2014 and surpassed the expectations of the researchers leading the study. The aim of the treatment in this study was to get the gene therapy into the cells in the retina of the eye without causing damage. After six months, however, the patients actually showed improvements in their vision in dim light and two of the six were able to read more lines on the eye chart.

This is a multi-centre trial involving a total of nine patients, three of whom are patients at Moorfields, who have had one eye treated with the gene therapy. The therapy is given in one eye to allow comparison with progression of the disease in the other eye. Planning is also underway for a phase II trial which will be led by Moorfields consultant Professor Andrew Webster at the National Institute of Health Research (NIHR) Biomedical Research Centre at Moorfields.

The phase I clinical trial was funded by the Health Innovation Challenge Fund, a partnership between the Wellcome Trust and the Department of Health. The research study also received additional charitable support, including a substantial generous donation from Moorfields Eye Charity and the Lanvern Foundation.  This was a collaborative study involving the University of Oxford, Moorfields Eye Hospital, Manchester Eye Hospital and the University of Southampton. The majority of the patients were diagnosed and managed at Moorfields.

The first patient to have the operation has now been followed up for over two years. Based on the success of the treatment in the first six patients, three more have recently been tested at a higher dose.

Professor Robert MacLaren of the Nuffield Laboratory of Ophthalmology at the University of Oxford and an honorary consultant at Moorfields, led the development of the retinal gene therapy and this first clinical trial.  He said: ‘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 with 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 results showing improvement in vision in the first six patients confirmed that the virus can deliver its DNA payload without causing significant damage to the retina. This has huge implications for anyone with a genetic retinal disease such as age-related macular degeneration or retinitis pigmentosa, because it shown for the first time that gene therapy can be applied safely before the onset of vision loss.” 

Professor Webster who was the lead at Moorfields for the phase 1 trial said: “Although it is still early days, these first signs are promising, and suggest that a treatment has been developed that has the potential to prevent the blindness that would otherwise occur in men affected by this disorder. Importantly, this trial is a further step forwards towards treating other blinding retinal disorders using a similar strategy.”

Choroideremia is a rare inherited cause of blindness that affects around 1 in 50,000 people. The first signs tend to be seen in boys in late childhood, with the disease slowly progressing until vision is lost. There is currently no cure. It is caused by defects in the CHM gene on the X chromosome, which explains why it is almost always boys that are affected. Without the protein produced by the CHM gene, pigment cells in the retina of the eye slowly stop working, and then die off. As the disease progresses, the surviving retina gradually shrinks in size, reducing vision. 

The gene therapy approach taken in this trial uses a small, safe virus to carry the missing CHM gene into the light-sensing cells in the retina. In an operation similar to cataract surgery, the patient’s retina is first detached and then the virus is injected underneath using a very fine needle.

Professor Miguel Seabra, whose research at Imperial College London studied the protein encoded by the gene, says: ‘My team has spent 20 years trying to understand choroideraemia and develop a cure, so to finally see the rewards reaching patients is extremely gratifying, both for us and the families who supported our research.”

The phase I trial began with six patients: two with excellent visual acuity, two with good acuity and two with reduced acuity. Visual acuity is the acuteness or clearness of vision, and is measured by reading lines of letters on a sight chart.  Six months after the operation, those with excellent or good acuity had the same level of acuity they began with, but could see more in the dark when tested – despite the detachment of the retina during the operation.  The two patients with reduced acuity saw improvements in their visions, and were able to read two and four more lines on the sight chart.

One of these was Toby Stroh, a solicitor in London and a patient at Moorfields who has shown continued improvement at one year. Describing his condition and participation in the trial, Mr Stroh said:

 “After a medical at school when I was 12 or 13, the comment from the doctor was 'vision merits further examination'. After various tests, I was given a diagnosis of retinitis pigmentosa.  I had noticed from an early age (and before that examination) that my vision in the dark wasn’t great, but it wasn’t a disaster. Others talked about things I couldn’t see. My choroideraemia has been a gradual progression and deterioration in vision. The effect was minimal for a long time as core vision was unaffected. I played a lot of tennis for many years in both singles and doubles and enjoyed it greatly. At college, I played table tennis and my vision, at that stage, was fine when it came to a fast moving ball. Over time, however, my peripheral vision reduced. I haven’t been able to follow the rapid movement in table tennis for many years. And doubles, as I used to play it, is unfortunately no longer possible.

“Several months ago I started using a stick, largely to warn people that despite looking absolutely fine, I do, in fact, have a problem in that I am only partially sighted. My straight-ahead vision is fine, albeit limited in breadth (like looking down a telescope) which is why I can read and play singles but why crowds are extremely challenging. Unmarked steps – particularly patterned carpet steps and marble steps without edging – are a nightmare. Going down them is worse as it is very difficult for me to see where they start. Going up is less difficult, possibly due to inherent shadow. I simply can’t tell where the steps start.  I had the operation as part of this trial in February 2012. The operation was in my worse eye, my left eye.

“There’s been a marked improvement in the number of letters I can read on a sight chart. I cannot remember how hard I used to try to read the lines before the operation, but it is such a dramatic improvement that as far as I am concerned, it must be as a result of the trial.  I still don’t use my left eye for reading due to the core being affected by the choroideraemia. I can do so (using that eye alone) but it takes time and it’s tiring. A little bit of sight has come back and, to me, that’s fantastic. I don’t know how long it will last, but a few months ago it was still there.

“I have been living under this cloud for many years and have been concerned I’m going blind. I’m a solicitor and, although I know there are various software packages to help, at the moment I depend on my sight to read. It becomes particularly precious when I think it’s not going to last.  This result does not make me swing from chandeliers and I refuse to say everything is going to be roses. But, there is hope.  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. From an emotional perspective, it was great. Really was. Long may it last.”

This is the first time a gene therapy for an eye condition has been tested in people with full 6/6 visual acuity. This suggests the approach has promise for treating people early on before too many cells in the retina have been lost.

It is also the first time that a gene therapy has targeted the principal light-sensing cells in the retina. This means the approach has relevance for other far more common causes of blindness, where these light-sensing cells are affected, such as retinitis pigmentosa and age-related macular degeneration.

Professor Sir Peng Tee Khaw Director of the NIHR BRC at Moorfields and the UCL Institute of Ophthalmology said: “This study is excellent news for our patients. It confirms the safety to date of the first human retinal gene therapy in the world, performed at Moorfields, giving great hope for many patients with other currently untreatable conditions. It confirms the importance of the UK having centres with large numbers of patients with rare diseases and combining this with the leading university research centre to change our patients’ lives.”