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Jonathan Wyatt

Jonathan Wyatt

Gene Therapy Clinical Trials for Choroideremia Commence

27 October 2011

A clinical trial to treat blindness caused by the genetic disease choroideremia has started in Oxford as part of a nationwide NHS study. Patients in the trial will have a virus injected into their eye which has been genetically engineered to carry a missing gene and has been modified to enable it to infect the light sensitive cells - photoreceptors - that line the back of the eye.

Jonathan Wyatt, a 63 year old barrister from Bristol, was the first patient to undergo this pioneering surgery at the Oxford Eye Hospital this week. The trial is led by Professor Robert MacLaren, Professor of Ophthalmology at the University of Oxford and builds on gene therapy research performed in collaboration with Professor Miguel Seabra at Imperial College London. Professor MacLaren said, “This disease has been recognised around the world as an incurable form of blindness for over a hundred years. I cannot describe the excitement in thinking that we have designed a genetic treatment that could potentially stop it in its tracks with one single injection.”

Professor Miguel Seabra, who played a key role at Imperial College in identifying the gene causing choroideremia and in eliciting the mechanism of cell death in the retina, added: "The ability to offer a gene replacement treatment for these patients was the final objective of 20 years of intense research in my laboratory. This is a moment of fulfilment for us and a dream come true for all choroideremia patients"

The clinical trial is funded by the Department of Health and the Wellcome Trust and there are 12 patients enrolled who will undergo gene surgery treatment to one eye. It is estimated that it will be a further 24 months to know whether or not the degeneration has been stopped completely by the gene therapy treatment.

The trial is non-commercial and is sponsored by the University of Oxford. It includes four NHS centres: Oxford Radcliffe Hospitals NHS Trust, Moorfields Eye Hospital NHS Foundation Trust, Manchester Royal Eye Hospital and Southampton University Hospitals NHS Trust.

Choroideremia was first described in Austria in 1874. It is a progressive retinal degeneration that generally affects males and there is estimated to be over 100,000 people with the disease worldwide. The diagnosis is usually made in childhood and leads to blindness in men by their forties. This trial represents the world’s first ever attempt to treat this disease and the first time that gene therapy has been directed towards the light sensitive photoreceptor cells of the human retina.

Robert MacLaren is Professor of Ophthalmology at the University of Oxford, Honorary Consultant Vitreoretinal Surgeon at the Oxford Eye Hospital and Moorfields Eye Hospital. Miguel Seabra is Professor of Molecular Medicine at Imperial College London. The Principal Investigators at each of the four study hospitals are Susie Downes, Consultant Ophthalmologist at the Oxford Eye Hospital, Andrew Webster, Senior Lecturer at the UCL institute of Ophthalmology and Honorary Consultant at Moorfields Eye Hospital, Andrew Lotery, Professor of Ophthalmology at the University of Southampton and Graeme Black, Professor of Genetics and Ophthalmology at the University of Manchester

This is a University non-profit trial funded by the Department of Health and a charity (the Wellcome Trust). It is important to stress that this is a study with no commercial backers or other parties with a vested interest. RP Fighting Blindness has not funded this research work though of course much of the underlying understanding of retinitis pigmentosa has arisen as a result of our research programme over the last thirty years. David Head, Chief Executive at the charity, said on his blog that “…we are on an exciting route, and there is so much effort being put into this type of technology around the world that we can now be sure that it will lead to available treatments…”

With this particular gene therapy treatment, the gene remains in the retinal cells indefinitely as far as we know. In other words, the gene therapy treatment is designed to be a one-off permanent correction of the disease. The viral vector carries a single stranded DNA genome which is then converted into double stranded DNA in the patient's retinal cells.

The trial is to assess safety and efficacy. Whilst safety appears so far to be fine, the efficacy will only be evident after 24 months because we need this time to measure any effect as the degeneration is slow. We are only treating one eye as we will use the other as a control against which to assess any treatment effect. We would however aim to go on to treat the second eye once the treatment is proven to be effective.

Gene therapy is ideally suited to the eye because most of the incurable causes of blindness are genetic and correcting the genetic defect would be the most logical treatment. Also, in the eye, a small dose of vector is needed compared for instance to the liver or lung, where up to ten thousand times as many viral particles would be needed to get an effect. The eye is also relatively separate from the immune system, which reduces the likelihood of an immune reaction to the vector and the cells in the eye do not divide, which means scientists can use the adeno-associated viral (AAV) vector which does not interfere with the native DNA in the host cells.

The team are still recruiting, but patients need to go via one of the four NHS centres, depending on their geographic location, Oxford (Midlands and Wales), Moorfields (London and South East), Southampton (South West) or Manchester (North of England and Scotland). 12 patients are required in total for the first trial and will be recruited from all four sites, although others will undoubtedly follow. To be included, patients need to have at least 6/60 vision or better in the eye to be treated and the disease needs to be fairly symmetrical in both eyes.

Further information is available at and people who require further information about the trials should contact the Nuffield Laboratory of Ophthalmology in Oxford, (01865) 234782.

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