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.

For more information please contact Professor Robert MacLaren of Oxford University on robert.maclaren@eye.ox.ac.uk

Or the University of Oxford press office on +44 (0)1865 280530 or press.office@admin.ox.ac.uk

Further media materials are available via a DropBox folder https://www.dropbox.com/sh/fvea6v7isjth54p/hk0wOKkKme, including:

  • Accounts from three people taking part in the clinical trial
  • Images of Professor Robert MacLaren and an operation
  • Video footage from an operation
  • Comments from the optician for one of the participants

 

The Lancet has also issued a press release. Please contact Daisy Barton at the Lancet press office on +44 (0)20 7424 4949 or daisy.barton@lancet.com for a copy.

Notes for Editors:

  • The paper ‘Initial observations in patients undergoing retinal gene therapy for choroideraemia’ is to be published in the Lancet.
  • 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’s caused by defects in the CHM gene on the X chromosome, which explains why it is almost always boys that are affected. The loss of the protein encoded by the CHM gene leads pigment cells in the retina of the eye to stop working then die off. People will first notice that their vision is lower than other people’s, particularly at night. Then as the disease progresses, their surviving retina becomes smaller until it is a little slit in the centre of their vision.
  • The gene therapy uses a small virus called AAV to deliver the correct version of the CHM gene into the pigment cells of the retina. The AAV delivery vehicle was developed and tested by Professor Robert MacLaren’s group at University of Oxford in collaboration with Professor Miguel Seabra at Imperial College London, with funding from The Tommy Salisbury Fund at Fight for Sight. While it can carry only a small amount of genetic material, it is enough to carry the CHM gene to the retinal cells, switch the gene on and produce the missing protein – hopefully halting the loss of cells and the slow degeneration of vision. The therapy should require just one injection, as once the AAV virus has delivered the missing CHM gene, the DNA is incorporated into the cells of the retina.
  • The clinical trial also involved developing a new surgery technique. This involved separate stages in which the patient’s retina was first detached in a controlled and gradual process, and only once that had been done was the virus encapsulating the gene therapy injected under the retina. This separation of the operation into two consecutive steps, rather than doing both together, minimised damage and improved recovery with no discernible effect on the patient’s vision. Professor MacLaren comments: ‘This move to two steps for minimal damage has shown excellent results in recovery. It’s not just the biological research that’s important. Surgical research is important too, and that’s often neglected.’
  • The technology is covered by a patent application owned by Isis Innovation, the technology transfer company of Oxford University. Work is in progress to develop the gene therapy into an approved clinical product through further clinical trials.
  • Oxford University’s Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK’s top-ranked medical school.

    From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery.

    A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.
  • The Oxford University Hospitals NHS Trust (OUH) is one of the largest acute teaching trusts in the UK, with a national and international reputation for the excellence of its services and its role in patient care, teaching and research. The Trust supports world-leading research programmes. It works in close partnership with the University of Oxford and is a leading centre for cancer, neurosciences, diabetes, genetics and many other fields. Research themes of particular strength are: cancer, cardiovascular science, diabetes, endocrinology & metabolism, infection and immunology, musculoskeletal science, neuroscience and reproduction and development. The Trust has been designated as a major trauma centre and is one of four UK centres for craniofacial surgery. The Trust employs 11,000 staff and consists of four hospitals: the Churchill Hospital, John Radcliffe Hospital and Nuffield Orthopaedic Centre in Oxford and the Horton General Hospital in Banbury. www.ouh.nhs.uk

About the Health Innovation Challenge Fund
The Health Innovation Challenge Fund is a parallel funding partnership between the Wellcome Trust and the Department of Health to stimulate the creation of innovative healthcare products, technologies and interventions and to facilitate their development for the benefit of patients in the NHS and beyond. www.hicfund.org.uk

About the Department of Health
The Department of Health (DH) helps people to live better for longer. The Department leads, shapes and funds health and care in England, making sure people have the support, care and treatment they need, with the compassion, respect and dignity they deserve. The Department funds health research and encourages the use of new technologies because it’s important to the development of new, more effective treatments for NHS patients. Innovation is needed so that decisions about health and care are based on the best and latest evidence. www.dh.gov.uk

About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk

  • The NIHR Oxford Biomedical Research Centre is a partnership between the research expertise of the Oxford University Hospitals NHS Trust and the University of Oxford. Its main aim is to enable clinical research for patient benefit and foster innovation to improve healthcare. It is funded by the National Institute for Health Research (NIHR). The NIHR provides the NHS with the support and infrastructure it needs to conduct first-class research funded by the Government and its partners alongside high-quality patient care, education and training. Its aim is to support outstanding individuals (both leaders and collaborators), working in world class facilities (both NHS and university), and conducting leading edge research focused on the needs of patients. www.oxfordbrc.nihr.ac.uk
  • The National Institute for Health Research (NIHR) is funded by the Department of Health to improve the health and wealth of the nation through research. Since its establishment in April 2006, the NIHR has transformed research in the NHS. It has increased the volume of applied health research for the benefit of patients and the public, driven faster translation of basic science discoveries into tangible benefits for patients and the economy, and developed and supported the people who conduct and contribute to applied health research. The NIHR plays a key role in the Government’s strategy for economic growth, attracting investment by the life-sciences industries through its world-class infrastructure for health research. Together, the NIHR people, programmes, centres of excellence and systems represent the most integrated health research system in the world. For further information, visit the NIHR website (www.nihr.ac.uk).

About Isis InnovationIsis
Innovation is the research and technology commercialisation company of the University of Oxford. We provide access to technology from Oxford researchers through intellectual property licensing, spin-out company formation and material sales, and to academic expertise through Oxford University Consulting. Isis is the highest university patent filer in the UK and is ranked 1st in the UK for university spin-outs, having created more than 100 new companies in 25 years. In the last financial year we completed 395 licenses and consulting agreements with clients in 21 countries. The Isis Enterprise innovation management consultancy works with university, government and industrial clients from offices around the world. For updates on innovations from Oxford, follow Isis on LinkedIn and Twitter or subscribe at www.isis-innovation.com