Treating blindness with gene therapy

20 January 2014

Interview with

Robert MacLaren, University of Oxford

Blindness-causing diseases of the eye have for a long time been regarded as irreversible. ChoroideremiaBut now scientists have begun to explore whether gene therapy can slow down or reverse the damage.

Robert Maclaren is heading up one of these studies at the University of Oxford and joined Chris Smith after publishing the first clinical findings this week.

Chris - So, what's the disorder that you've been looking at specifically?

Robert - Well Chris, we're looking at a retinal degeneration which is basically a degeneration of the lining of the back of the eye, the light sensitive sort of film at the back of the eye. The particular disease is caused by a missing gene on the X chromosome. So, it affects males and it's called choroideremia which is an original description given to it, well over 100 years ago.

Chris - People who have this, what happens to them? How would they know they've got the condition?

Robert - Well, quite often, we diagnose it as a new genetic mutation, but sometimes there's a family history. So, a mother might be aware that her son is going to get it.  The initial signs would be things like difficulty with night vision, that would occur perhaps in childhood and then gradually, around about the age of 10, 11, 12, the visual field, the peripheral vision becomes constricted. They develop what we sometimes refer to as tunnel vision. So, they can see a little bit in the middle, but all around the outside is all dark. This tunnel vision gets progressively worse. And then sadly, by the time they get to 40s or 50s, they then become completely blind.

Chris - How does the intervention, your gene therapy approach that you're cooking up work?

Robert - Well, the patients have this retinal degeneration because they're missing the choroideremia gene, or the CHM gene for short. This gene is normally present in the light sensing cells and the lining of the back of the retina, the back of the eye. So, the principle of gene therapy is a relatively new concept in medicine. It's actually to try and correct the disease at the genetic level. In the case of choroideremia, what we do is we make a virus that carries DNA, because viruses do carry DNA or RNA, that's the property of virus. Only, rather than carrying the viral gene, the virus contains the choroideremia gene which we've artificially put into it. But nevertheless, the virus on the outside is the same. It retains its same abilities to bind to and infect the retinal cells. It gets into the cells. The virus then releases its payload, thinking it's its own DNA for replication. But in fact, it is the choroideremia gene that goes into those cells. Although we've taken out most of the viral genome, little bits at the very end which stabilise the DNA and allow it to sit in the cell dormantly for years and years, and years, all that is still there. So, as far as we're aware, so far, we are actually looking at in principle, a treatment which should have a permanent and lasting effect.

Chris - Do you administer this virus into the retina? Do you?

Robert - Yes. The patients have to undergo an operation which involves - first of all removing the jelly at the back of the eye and then injecting under the retina, a concentrated solution of virus. Of course, that's a rather tricky bit to do because it's a very delicate process. One of the concerns in our study at the beginning, we realised that gene therapy is really best applied before the onset of vision loss before the cells die. So, we had to really get the virus into the retina in patients before they'd lost their central vision. We did that on 4 patients and fortunately their vision did recover. In fact, what was remarkable was that actually, we could then see the further improvements from before they'd had the operation once the virus was working. So, it is a combination really of biological technology of the virus, but also, trying to develop the technique of surgery better.

Chris - How do you know that it's the virus improving the outcome for these patients and not just the operation or some aspect of having something injected into the eye because I presume, you didn't do the experiment where you just injected water or something into the eye without any virus, just to see what the injection itself does?

Robert - No and of course, that's a very good point. It's very difficult sometimes when doing clinical trials to have a true - what we call, sham injection. But the eye is quite useful because of course, we've got the other eye to look at as well. Also, we know a lot about the natural history of the disease. So when we initially notice the quite significant improvements in vision in these patients, with their permission, particularly the two who had the largest change, we contacted their home opticians to get their historical vision records over many, many years before the trial, and also, an up-to-date vision, just in case there might be something different about our trial system. That verified our findings in the fact that the vision had improved. This is a disease in which the vision gets progressively worse. It's very difficult to understand how it could improve by several lines without something going on and indeed, the effects we've seen in the first patient who gained more than three lines of the standard Snellen chart, the big chart you see at the opticians. He couldn't even see the top letter before the surgery. He can now quite confidently read the top two lines and that's being sustained now for 2 years. So, it's a very good question, I often get asked this and I say, well you know, if it isn't the virus that's doing this, it must be something else. It's still quite amazing. If it is a sham injection or something similar after 2 years, then obviously, it would be difficult to explain through any other reason than the missing gene is now doing its stuff. Of course, the patients do notice improvements in the quality of the visions. That's certainly the case.

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