Promising first results in gene therapy trial for inherited blindness

16 January 2014--The first clinical trial of a gene therapy for an inherited cause of progressive blindness called choroideremia has shown very promising initial results which have surpassed expectations of the Oxford University 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.

A total of nine patients have now had one eye treated with the gene therapy in operations at the Oxford Eye Hospital, part of the Oxford University Hospitals NHS Trust. The therapy is given in one eye to allow comparison with progression of the disease in the other eye.

The Phase I clinical trial is funded by the Health Innovation Challenge Fund, a partnership between the Wellcome Trust and the Department of Health.

Results at six months are now reported for the first six patients in The Lancet medical journal. 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.

The research has received additional support from the National Institute for Health Research Oxford Biomedical Research Centre and the charity Fight for Sight, the main UK charity that funds pioneering eye research to prevent sight loss and treat eye disease.

Professor Robert MacLaren of the Nuffield Laboratory of Ophthalmology at the University of Oxford, and a consultant surgeon at the Oxford Eye Hospital and honorary consultant at Moorfields Eye Hospital, led the development of the retinal gene therapy and this first clinical trial.

He says: '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 results showing improvement in vision in the first six patients confirm 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 has for the first time shown that gene therapy can be applied safely before the onset of vision loss.' 

The first patient to be treated, Jonathan Wyatt, 65, says: 'My left eye, which had always been the weaker one, was that which was treated as part of this trial...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. The green of the pitch is brighter, and the numbers on the shirts are much clearer.'

Wayne Thompson, 43, an IT project manager in Staffordshire, was treated in April with a higher gene therapy dose as part of the subsequent trial: 'One night in the summer, my wife called me outside as it was a particularly starry evening. As I looked up, I was amazed that I was able to see a few stars. I hadn't seen stars for a long, long time...For a long time I lived with the certainty of losing vision. Now I have uncertainty of whether the trial will work, but it is worth the risk.'

NB: Accounts from three of the participants in these clinical trials, and one of their opticians, are available in a separate documentImages of Professor MacLaren and B-roll video footage from an operation are also available

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, then die off. As the disease progresses, the surviving retina gradually shrinks in size, reducing vision.

The gene therapy approach developed by Professor MacLaren's team 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.

The aim is for the CHM gene, once delivered into the cells of the retina, to start producing protein and stop the cells dying off. '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,' explains Professor MacLaren. 'If the treatment works, we would be able to prevent them from going blind.'

Professor Miguel Seabra, whose research at Imperial College London identified the protein involved in choroideremia, 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 vision, being able to read two and four more lines on the sight chart. One of these, Jonathan Wyatt, a barrister from Bristol, was the first patient to be treated. He has shown sustained improvement in visual acuity for two years now. The fourth patient to receive the treatment, Toby Stroh, a solicitor in London, has shown continued improvement at one year.

Professor MacLaren says: 'What's really exciting is that the improvement in these two patients at six months is significant and it has so far been maintained.

'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.'

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, known as photoreceptors. 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.

Patients have come from Moorfields Eye Hospital, the Manchester Royal Eye Hospital and the University of Southampton.

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