Gene therapy for blindness
If the eye is a camera, then the retina at the back of the eye is the light-sensitive “film”. It contains the crucial light-sensitive “photoreceptor” cells - known as “rods” and “cones” - that convert the light hitting the retina into electrical impulses the brain can interpret. If we lose the rods and cones, we can go blind. And this is what happens to people with a genetic condition called retinitis pigmentosa. Katie Haylor caught up with Oxford University’s Imran Yusuf who told her more about the disease and how he’s working on gene therapy treatments to stop it...
Imran - Initially it causes the rods, which allow us to see at night, to die off mostly. Peripheral vision often becomes affected too. And in the later stages it also affects central vision, which means that their ability to read and to recognise people becomes affected.
Katie - I've heard that there's a recycling issue going on in the eye.
Imran - Absolutely. So when light creates a chemical change within the eye, the eye then has to recycle that chemical so that it can receive light again. That's why when you look at a bright light and you look away, you get this black blob in your sight. That's because the eye is recycling these pigments so that it's then ready to receive more light. Any errors in these particular visual cycle chemicals are a prominent cause of retinal degeneration because they're so important for sight. And in particular, the first gene therapy treatment is available on the NHS now for a gene which encodes one of these visual cycle proteins, the recycling as you mentioned. Because it's a common cause of visual loss in children, often very severe loss of sight, and so it's very encouraging that there is a gene therapy treatment available on the NHS for these patients in the very near future.
Katie - What are you putting into the eye?
Imran - In the particular case that I mentioned... that's caused by a gene called RPE65 and the protein that it produces. So this protein is involved in the visual cycle and the recycling. So the gene therapy virus that we create in order to deliver genes to cells, we inject it underneath the retina. What that allows the virus to do is to enter the cells which we want it to enter into, which are either the light sensitive cells or the retinal pigment epithelium, and it delivers the copy of the gene that we've programmed it to express.
Katie - What kind of viruses are they?
Imran - A cousin of the common cold virus. These are viruses which generally are not disease-causing in humans. Viruses normally work by entering cells and reproduce copies of themselves, but we re-engineer that virus to instead produce a healthy copy of the gene that the cell is lacking. And the elegance of gene therapy is that it should only require a single treatment because we’re programming their cells to produce what those cells are lacking.
Katie - Does this cure or does it prevent further damage or both?
Imran - For gene therapy, the hope traditionally has been that we would stop the degeneration happening at the point at which that therapy was given. But in the clinical trial that's been taking place in Oxford under Professor Robert MacLaren, in the initial group of 18 patients who were treated with gene therapy, six out of the 18 showed an improvement in their visual function. That's at one month after treatment. And this is something really quite new for Retinitis pigmentosa. If it can be shown to be sustained in the later parts of the trial this is hugely encouraging.
Katie - You said the cells are dying. Does it work if they've died?
Imran - It's difficult to say that. I think the perception is once the cells have died, we can't replace them, at least not with gene therapy but we can intervene in cells that are, as you say, dying. So cells that would otherwise die, had there not been an intervention.
Katie - You are putting foreign material and a virus into the eye. Is there a danger of the immune system reacting to that or indeed that people could become immune to the treatment?
Imran - There are a couple of things which are in our favour in retinal gene therapy. The first is that the immune system doesn't see foreign material in the eye in the same way as it would if you injected it into the blood for example. That’s one big advantage. The second is that we try to make the genetic material within the virus as efficient as possible so that we can reduce the amount of virus that goes into the eye. The third thing is that we can inject the virus underneath the retina which is more hidden than injecting virus inside the ball of the eye, which is another approach for gene therapy that other people use. And the fourth thing is that we can use anti-inflammatory agents at the time of giving the injection which we then can stop in the weeks afterwards, which will dampen down the immune system just in that period in which the virus is doing what it needs to do. But you're right, the inflammatory reaction could be a concern particularly when very high doses of the virus are needed.
Katie - Could this same kind of approach be used for other eye conditions?
Imran - Absolutely. Really the floodgates have now opened. Now that we've shown that you can use a virus in this way to deliver a gene product, now the possibilities are very wide, not only for treating diseases caused by a single gene problem - they’re often good ones to work with because it's very obvious what gene needs replacing. But then you have other genes which are faulty in more complex ways and those need very specific approaches. In the era of gene therapy the possibilities are so wide for so many conditions. It really is an exciting time to be in the field.