OHSU pioneers gene editing technique for eye disease

Oregon Health & Science University has been on the forefront of using the genetic editing technique known as CRISPR for years. Now, it has successfully used CRISPR to edit the genes in patients with a rare eye disease. Mark Pennesi is a professor of ophthalmology at OHSU, and Carlene Knight is one of the patients who received this treatment.

The following transcript was created by a computer and edited by a volunteer.

Dave Miller: From the Gert Boyle studio at OPB, this is Think Out Loud, I’m Dave Miller. We turn now to a medical breakthrough at Oregon Health and Science University. Researchers there have been taking part in a nationwide study that’s the first of its kind. It involves CRISPR, the relatively new and very powerful tool for editing genes. In the past, scientists have done this gene editing outside the human body. This was the first time it’s been done inside the body. They used it on people who have a rare genetic eye disease. And in some of those people, this novel treatment worked. I’m joined now by one of those people, OHSU’s Carlene Knight lives outside of Portland. Mark Pennesi is a professor of ophthalmology at OHSU’s Casey Eye Institute, and one of the researchers behind this project. Carlene Knight and Mark Pennesi, welcome to Think Out Loud.

Carlene Knight: Thank you.

Mark Pennesi: Thank you.

Miller: Mark Pennesi first, can you explain to us what LCA is? That’s the particular eye disease that you have been working on here, and that you’ve been trying to treat.

Pennesi: LCA stands for Leber congenital amaurosis, and this is a genetic eye disease that causes severe vision loss. So patients are often born with severe vision loss, and it gets worse as time goes on, and they can be legally blind even as young as two or three years old. Some patients will have better vision than others, but many will only be able to see light perception. And so these are the patients that you often see who have white canes and need guide dogs at a very young age. So it’s a very severe form of vision loss.

Miller: Has there been any treatment for LCA in the past?

Pennesi: So there is one FDA approved treatment for a different kind of LCA, that’s something called LCA Type 2. And that was the first gene therapy approved. But that’s a little different than CRISPR. That was using something called gene augmentation therapy. And what we’re doing today is different because, rather than just adding in a new piece of DNA, we’re changing the native DNA in the patient, we’re actually editing their own DNA.

Miller: Carlene Knight, can you give us a sense for what your vision was like before this experimental procedure?

Knight: Well I had extreme tunnel vision. I liken it to looking through a window with a pencil sized hole and trying to find a piece of paper on the floor. I could see colors and shapes, but that’s about it. I had no peripheral vision at all and I couldn’t see details. I have nystagmus, which means my eyes jump and move around. So it’s really hard to focus on what I do see.

Miller: And what you could see was a tiny hole or area just in the middle of your field of vision?

Knight: Correct

Miler: Why did you decide to take part in this experimental treatment?

Knight: I was thinking about the children. Before their neural pathways in their brains are formed, I think that they will be able to have even better vision if they have the surgery, and it works for them. I also want to help adults, anybody that has the disease, and I would be lying if I said that it’s a little bit of it wasn’t for my benefit as well. I wanted to see what it would be like to be able to see even that amount again.

Miller: You talked about the children first though, What was your vision like when you were a child? As Dr. Pennesi said, this is a degenerative disease that often gets worse as people get older.

Knight: That’s kind of what I described. Things were a lot clearer though. I was able to focus more. I think that’s the main difference. I think my field of vision might have been a little bit wider when I was a child than it is now.

Miller: Mark Pennesi, can you remind us what CRISPR is? This is an acronym that’s been around for I don’t know a decade or so, but increasingly a reality as opposed to a promise.

Pennesi: CRISPR is a technique for making small cuts in the DNA. And so you can think of it like little molecular scissors. And so if you recall your high school biology, our DNA or genome, it’s like a long ticker tape of code, and that code tells the cells how to make proteins, all the different 25,000 proteins in the body. And sometimes you have a mutation where one of those letters is incorrect.

And so what CRISPR is, it’s like little gps guided scissors that go into where the mutation is, and it can then cut out that mutation, so that then the cell can make a normal copy of the protein.

Miller: So what did the procedure entail for Carlene Knight and about a half dozen people around the country total?

Pennesi: So there is a surgery involved. We have to get the crisper machinery to the photoreceptor cells which are the rods and the cones, and those are in the back of the eye. And so you can’t just inject this. You have to do a surgery where you make some tiny holes in the white part of the eye, and then you go in with a very fine needle, that’s maybe the diameter of almost a hair. And you inject a very small amount of fluid underneath the retina that’s filled with billions of little particles. We use a virus that’s been gutted out so it doesn’t cause any disease. And inside of that virus is the CRISPR machinery. And that goes and attaches to the photoreceptor cells, and the CRISPR machinery goes into the cell, finds its way to the DNA, and then makes the local edit.

Miller: Do you have a sense for how long that process takes, once you inject this now harmless virus that has the kind of the fix-it genetic mechanism, and it’s touching the cells that you want to fix, do you have a sense for the time there? How long it takes to actually make those changes?

Pennesi: We think that it probably starts working right away, but often we don’t really start to see the improvements until a month or two after the surgery. And part of that is you have to recover from the surgery itself. And also, even if the correction is made right away, it can take time for the patient to start noticing the change in their vision. And we’ve seen that, even when we treat patients, they might start to see a improvement at two months, but then as time goes on their vision even gets better as they get used to using that improved vision.

Miller: This is a piece I want to turn back to, because it gets to really an interesting aspect of perception that’s not just about vision, but hearing in the various ways we take in the world, how our brain processes that information. But Carlene Knight, to go back to you, what was your experience after that surgery?

Knight: Well, at first everything looked really strange. They had to inject some air into my eye, and I could see that air bubble. It was really very strange at first.

Miller: You mean that was during the procedure?

Knight: That was right after, probably for the first week or two.

Miller: Mark, what’s the idea behind injecting air into her eye?

Pennesi: So that’s a typical part of the surgery. So you can imagine the retina is layered onto the back of the eye, a little bit like wallpaper onto the back of the eye. And so right after the surgery, we put in an air bubble to kind of keep the retina pressed up against the back of the eye. So that’s just a technical part that we do. And the air bubble usually goes away after about a week or so.

Miller: So Carlene Knight, that was the first weird thing, to be able to sort of see a bubble. And then after that went away, what was your experience?

Knight: Well, it seemed like my field of vision was even more narrow, and things looked small. Then eventually that improved over time, and probably within two or three weeks that was clearing up.

Miller: How is your vision now different from what it was before this procedure?

Knight: Things are clearer. Colors are brighter. I can see lines very clearly. I still have the nystagmus though. I’m hoping my eye will get stronger and I’ll be able to focus better and read those eye charts, they won’t just look like lines that are moving.

Miller: Brighter colors and more ability to distinguish between lines. What about that narrowed vision that you described at the beginning, where it was as if there was a window, but you could only see through a pencil sized hole?

Knight: I still have a real narrow field of vision. I don’t think that part is going to change that much. But I could be surprised, this is something new, we’re in new territory. So we’ll just have to see.

Miller: Mark Pennesi, my understanding is that only some of the patients in this study reported improvements. Do you and other researchers yet have a sense for why this worked in some people and not in others?

Pennesi: I think it’s still very early in the trial at this point. And we do these trials as a progression. So we start with a very low dose of the treatment and then we increase. Carlene was in the second dose group. So it’s possible that if you look at the patients who got the lowest dose, maybe that dose was not high enough. The other part of it is some of the patients just have not been followed as long as Carlene. So we may still see improvement as time goes on.

Miller: So let’s turn back to what you were talking about before, that it may be, and you were saying it again there, that you might see improvement as time goes on. If I understand this correctly, part of this could have to do with the fact that our ability to see something is based on two separate mechanisms. The machinery in our eyes taking in visual information, and then sending that to our brains which have to somehow make sense of those neural messages and make it into a picture that we as people can actually understand.

Am I right in understanding that this CRISPR gene editing, it works only on the first part, on the machinery of the eye, but not on the way our brains piece that information together?

Pennesi: Yeah, that’s absolutely correct. We’re fixing the problem with the eye. And the reason this is an important issue is that, when you’re a child, there’s a critical window of brain development, where the brain needs resolution information in order for the brain to develop the ability to process that information. And so if the brain is deprived of that, that can limit the improvement. So we know that even as an adult, you still have some ability for the brain to rewire. But it’s not nearly as much as that ability that you have when you’re a young child. And so our hope is that as we start to treat children, we may see even more improvement from these gene editing therapies, because children have even more ability to rewire those connections.

Miller: So does that mean though that for adults or older adults, is one theory that even if you can fix the mechanism and send more color information or more higher resolution picture theoretically into the brain, that the brain may not, even if it gets better at processing that information, it may not ever be great at it?

Pennesi: Well, there might be an upper limit. And I think we knew this going into the trial. It was certainly possible that this therapy may not work in adults and might only work in children. And I think that’s why we’re so excited that Carlene did see some improvement, because that actually shows that, even in adults, we can still have an effect.

Miller: And this also goes back to Carlene, what you had said at the beginning, which is the first reason you gave for doing this was for children.

Knight: Right, that’s the main reason.

Miller: Mark Pennesi, is the hope that this treatment could lead to permanent improvement? And how would that work if a body still had directions embedded in the rest of its genome to not to have this mutation that causes this disease?

Pennesi: Right. Well, we hope that the cells that are being edited will be permanently fixed. The limitation right now is that we can’t treat the entire retina. We’re treating primarily the central part of the retina. But in theory, this is a one time treatment, and once we fix that particular mutation and edit the DNA, we should not have to treat it again.

Miller: Carlene Knight, what has the improvement that you have experienced meant for your daily life?

Knight: I can see doorways better. I can see objects a little bit better. I’m not running into quite as many things. Things are just enhanced. I can see colors better, and things are brighter. I just opened our front door this morning, and discovered I can see the individual boards on our porch. So that was pretty exciting for me. Just something like that.

Miller: What did it look like before? The porch?

Knight: Basically one board. Maybe a few different colors in it because there’s several boards, but it basically looked like one piece.

Miller: That was just this morning, so does that mean that every day now as you move around in the world you’re seeing more details that you just didn’t see before? You’re continually encountering a richer visual world?

Knight: Yeah I’d say so I don’t notice a change every day, but I’m sure there is.

Miller: And then there’s just a practical question of seeing a doorway which I imagine is immensely helpful.

Knight: Yeah it is. I can see closer to what I could as a child. I have lost a significant amount of vision since childhood, and I feel like I’m getting that back. So that’s really exciting.

Miller: I read that you dyed your hair green after the procedure. What was the thinking there?

Knight: I’ve actually been doing that for several years. It’s something fun. But now I can see it better. So it’s really fun.

Miller: So Mark Pennesi, as I mentioned in the beginning, this is not just a promising early data from one study about treating an eye disease, but this is the first time that this powerful gene editing tool, CRISPR, has been used inside a human body, in vivo, as opposed to in a test tube or something and then injected back after the fact. So it seems like a kind of first proof of concept. What other diseases could CRISPR could be used to treat inside the human body?

Pennesi: This just really opens the door to being able to treat so many other genetic diseases. CRISPR has been used before to treat diseases where you can take cells out of the body, like a blood disorder and put them back in. But if you think about things like nerves or muscle, you can’t do that. So this kind of therapy now opens the door to treat other eye diseases, other brain diseases, neuromuscular diseases that have a genetic basis. This is really kind of a breakthrough in terms of providing us with a brand new tool that we didn’t have before.

Miller: And then going back to the treatment of this one particular eye disease, LCA, both of you have been talking about the promise for children, where if it were approved, it could actually have a bigger effect. What is the timeline for that? What would it take for children to be able to be given this treatment?

Pennesi: Well, we’re still very early on in this trial. So we’re treating adults, and we’ve started to treat adults at an even higher dose. And we’re actually starting to enroll children in the near future. But even then, the time it takes from starting a clinical trial to getting FDA approval can be on the order of 5-7 years. So we’re still very early on in the process.

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