INTERVIEW

IN CONVERSATION WITH Robert MacLaren, Professor of , University of Professor Robert MacLaren gave the Keeler Lecture at the Royal College of Ophthalmologists Annual Meeting in May 2019 on for . We caught up with him afterwards to find out more.

people in the developed world, since we now well and we will have treatments available have treatments for diabetic retinopathy. for our patients in the UK, but we’re not quite There is a huge unmet need. We have also got there yet. one gene that has been approved so it is up to us to try and find other genes and get them What do you hope will be made through to clinical trials. possible through gene therapy in the future? There was a lot of media attention The ideal, of course, would be to prevent earlier this year about gene therapy someone from going blind who would trials in age-related macular otherwise loose their sight from a genetic degeneration (AMD). How would disease. Genetic mutations are occurring What are the key messages of your this work? all the time, so when you have a baby, for Keeler Lecture? The concept of gene therapy is to use a virus instance, that child will have 70 mutations Gene therapy is now actually an approved to deliver a gene under the to the that are not in the DNA of either the mother treatment, so it is not just about research, retinal epithelium. We’ve demonstrated or the father. Most of them are silent and do but it’s actually something patients can have. how we can do that quite efficiently and nothing. That’s what we call genetic drift, it is how evolution is driven by genetic change. However, this is only for one rare disease. the gene therapy vector has But every now and then a mutation occurs What we are trying to do is to take the gene been developed. We know it is safe, we know in a gene that is important for photoreceptor therapy concept and make it relevant to how it is made, we know all sorts of things cell function, which means that child is going different genes so that we can treat more about it. It is relatively easy to take out the to get RP, so it is increasing and increasing. people. choroideremia gene and replace that with We need to tackle it somehow and gene a gene that is going to be very important for therapy is a really nice technology that is Can you tell us about your current AMD. That particular trial was funded and relevant to RP, but it is easy to see how it research in this area? sponsored by Gyroscope Therapeutics, but can also be translated to dealing with other some of that technology came out of the At the moment we are doing clinical trials neurodegenerative diseases like Parkinson’s gene therapy work we had done previously testing products that we have developed or Alzheimer’s, so there’s a lot of potential. It in the lab in Oxford, so it wasn’t just a clinical in the lab through the company Nightstar is the same principle; the gene therapy is very trial, but was also something we could work Therapeutics, which is a spin-out company, effective in the non-dividing cells using the on in the lab, which made it very exciting. I but we are also looking at things in the lab approach that we are doing and there may be should point out that it is a very early trial. As that may be helpful for other diseases that other applications for it. we can’t treat. So we are looking at having the in all Phase I trials the focus is on safety, we genes combined so that we can have larger need to build things up and eventually look What do you feel should be the for signals of efficacy. genes delivered by the adeno-associated top priorities for research in virus (AAV) vaccine, we are looking at a ophthalmology today? method where we actually switch genes off How close do you think we are to a I think we need to find a better treatment for using a certain type of silencing approach gene therapy treatment for AMD? AMD. I see more and more of it. Obviously, in an AAV vaccine, and of course we, like AMD is a genetic disease, obviously several the injectable treatments are effective, but others, are looking at CRISPR technology, genes are involved, and we already have a they really only slow things down, there are a gene editing, and how we can deliver that gene therapy treatment for a different type huge number of people affected and it is only by the AAV technology. These are the three of genetic eye disease, so if you put those two going to increase. things that will hopefully be clinical trials in facts together, I think we’re probably not that the future, but the research is both lab work far away. UPDATE and clinical trials which makes it much more interesting. Which eye disorders can currently In September 2019 the National be treated with gene therapy? Institute for Health & Clinical What will be the clinical The only one is Leber congenital amaurosis, Excellence (NICE) approved the first implications? which is an early onset retinal degeneration, gene therapy treatment, Luxturna We are trying to develop a treatment for caused by mutations in the RPE65 gene. The (voretigene neparvovec), as a retinitis pigmentosa (RP), which collectively, treatment has been approved in Europe and treatment for people with vision including all of the conditions that cause in the US, and patients have been treated in loss caused by inherited retinal retinal degeneration, is the most common the US, in France and, very soon, in Germany. dystrophy. cause of untreatable blindness in young I hope that the NHS looks favourably on it as

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