Examining Gene Therapy As Treatment For Blindness

Reporting in The Lancet, doctors found success in treating Leber's congenital amaurosis, a rare type of blindness, with gene therapy. Study author Katherine High explains how injecting a gene-carrying virus into the eye has improved vision in a handful of patients.

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A blind boy who could read only Braille can now see well enough to read print in a book. How? Via gene therapy. Last year, we spoke with a doctor who was working on treating a certain type of congenital blindness using gene therapy. Katherine High is back to tell us about how the patients are doing today. She's a professor of pediatrics at the University of Pennsylvania School of Medicine, the director of the Center for Cellular and Molecular Therapeutics at Children's Hospital at Philadelphia and Howard Hughes investigator and author of a study in the Lancet, describing the results of the treatment. Welcome back to SCIENCE FRIDAY.

Dr. KATHERINE HIGH (Professor of Pediatrics, University of Pennsylvania School of Medicine; Director, Center for Cellular and Molecular Therapeutics, Children's Hospital): Thank you very much.

FLATOW: Tell us - give us a little bit of up-to-dateness. What happened since the last time we spoke with you?

Dr. HIGH: Well, since the last time we spoke, we have added another nine subjects to the study. So in May of 2008, we reported the results on the first three, and they were all young adults. And in the interim, we've had the opportunity to inject another nine subjects, five of whom were children under the age of 18, and we have seen in all of those individuals improvements in retinal and visual function. And the most interesting finding out of the study, in my opinion, is that the most dramatic improvements were seen in the youngest subjects, particularly those in the range of eight, nine and 10 years old.

So for those individuals, as you discussed at the beginning, there's been a very marked improvement in vision such that children who were using Braille are now, as you said, able to operate in a sighted classroom.

FLATOW: And we also have on our Web site something from your lab, an obstacle course - if you go to sciencefriday.com�

Dr. HIGH: Right.

FLATOW: �where you can see these kids - treated eyes versus the untreated eyes. It's dramatic how well they can get around this obstacle course.

Dr. HIGH: Right, exactly. So in every case, people who come in for the procedure undergo extensive baseline testing. And we identify the eye with the poorer function, and that's the eye that's injected in an effort to preserve the better eye, although sometimes that's a very difficult determination to make. But as you can see on the video on the Web site, two or three months after the vector's been injected, the children do much better with the injected eye, which was formerly the worse eye.

CONAN: Describe for us exactly what you're doing, what the injection is, how it repairs the eye.

Dr. HIGH: Okay, so just first of all from an anatomic standpoint, the injection is going into a space, the sub-retinal space just under the retina. And what your retina basically consists of is a set of cells called the retinal pigment epithelial cells that are nurse cells, basically, for the photoreceptors, and of course, the business part of the retina are the photoreceptors.

And then from a biochemical standpoint, what's really happening in the retina is that it converts a photon of light energy to an action potential that can travel up a nerve and trigger vision.

FLATOW: A little electrical signal.

Dr. HIGH: A little electrical signal. And so in people with this particular variant of Leber's Congenital Amaurosis, they are missing a critical enzyme in that visual pathway. So in other words, the way that that works is when the photon of light strikes the visual pigment in the retina, it causes a chemical change, but eventually the molecule has to be restored. And for that recharging or restoration process, the molecule goes back into the retinal pigment epithelial cells. But if you don't have the enzyme that can recharge that molecule, then the visual cycle is broken.

So all we're doing in this procedure is making an injection, going into those retinal pigment epithelial cells, that gives the person the gene that encodes that missing enzyme.

CONAN: So you inject the gene, and it repairs - it creates that missing enzyme.

Dr. HIGH: Right.

CONAN: And how long does it last for? Is it forever?

Dr. HIGH: Well, that's of course a very important question. In pre-clinical studies that were done by my colleague, Jean Bennett and Al Maguire and others here at the University of Pennsylvania, she has shown that in dogs affected with the same disease, a single injection has lasted for periods up to 10 years. And that's really as long as the animals have been followed.

FLATOW: Right.

Dr. HIGH: So the evidence is that it's a long-lasting effect.

FLATOW: And the fact, when you say it's working better with younger kids, why would it work better the younger you get the kids?

Dr. HIGH: Well, the reason for that is that there are more cells left -remaining, that can be resuscitated by the enzyme. So in other words, if you don't have this enzyme, you eventually start to build up toxic metabolites in these retinal pigment epithelial cells, the nurse cells, and when they start to degenerate, they can't keep up their function of supporting the photoreceptors, and so they start to deteriorate. And this is a slow process that occurs over years. But if you can do the enzyme replacement at an earlier point, then there will be more cells left there to rescue.

FLATOW: And how much, what potential for restoring sight is there? I mean, how much better can the sight really become?

Dr. HIGH: Well, I think the answer to that, at least based on studies in animal models of the disease, is that the earlier you can treat, the better you can come to completely normal function. So I think if you projected what would this product look like eventually, what you would like to be able to do is to treat a child as soon as they're diagnosed and in both eyes.

FLATOW: I've got a question from Second Life from Laura Ginold(ph), who anticipated my next question, and that is, of course we're all going to be wondering what other similar treatments can be used for other vision problems. Can you actually do gene therapy on other retinitis pigmentosa, other kinds of things?

Dr. HIGH: Well, of course, people are working hard on all those kinds of things. And I think that within the next year, within the next 12 months, we will see trials initiated for other retinal disorders. Some of them will be additional inherited diseases, and others will be acquired conditions like macular degeneration. But I think people will try to explore this now as a platform for other diseases. And in addition to things like age-related macular degeneration, other kinds of trials that are already in the planning process - or, you know, getting close to initiation - would be things like X-linked retinal skesis, which is a disease that affects males with diminishing vision in adolescence and early adulthood. Leber heredic optic neuropathy is another disease for which people have trials in the planning stages.

So most of these are rare conditions, but I think that this kind of work paves the way to try to move into somewhat more common causes of inherited retinal degenerative disease.

FLATOW: Because, you know, we haven't heard a lot of success stories about gene therapy. There's a lot of promises, but this seems to be one success story.

Dr. HIGH: Well, you know, Ira, I think if you look across the spectrum of development of new classes of therapeutics, the reality is that the first clinical testing of gene therapy occurred almost 20 years ago, so - 19 years ago to be accurate, and to take something like 20 years to - from the beginning of clinical testing to real, demonstrated success is not really outside the common boundaries for new classes of therapeutics.

So if you think about how long it to develop monoclonal antibody therapeutics - you know, I remember when I was in medical school always reading about how monoclonal antibodies don't work. Now we have lots of different products that are basically monoclonal antibodies.

And similarly for bone marrow transplantation. And so the timelines can seem quite long, but you know, in fact for all new classes of therapeutics, what you see is that things tend to proceed quite slowly at first, as clinical testing reveals problems or issues that have to be taken back to the laboratory to solve, but then as those are worked through, the pace of development tends to accelerate. And I hope that we're coming to that stage in gene therapy. And I think that's probably realistic if you look at other successes that have been reported in the last 12 months. For example, for some severe combined immunodeficiency disorders that leave children at risk for life-threatening infections, you know, there's a very successful report published earlier this year in the New England Journal from a group in Milan. So I think that it is not unreasonable to suspect that we will, I hope, see additional successes in gene therapy going forward.

FLATOW: Ned Perry(ph) writes a tweet about why - how did researchers come up with this solution in the first place? How did they discover this approach? Is the retina a very good place to use this kind of therapy?

Dr. HIGH: Well, I do think it's a - you know, one of the important realizations as the field of gene transfer has developed is that there may be very important constraints on tissues where it's most likely to be successful. And an earlier observation using this type of vector introduced into other tissues - for example, the liver - was that the human immune response could shorten or block expression, but the beauty of the sub-retinal space and the central nervous system, as well - so this applies to some of the observations that have been made in gene therapy trials for Parkinson's Disease, too - these are relatively immuno-privileged sites. So the human immune response cannot come in and attack the transduced cells, or at least not as easily, and that may be an important key to success here.

FLATOW: You have the blood-brain barrier, you're saying?

Dr. HIGH: Yeah, the blood-brain barrier operating in your favor. When you go into something like the retina, you're using very low doses of vector. So you're less likely to trigger the immune response. So all of those factors, I think, probably helped.

FLATOW: And so you'll continue doing this research?

Dr. HIGH: We certainly will.

FLATOW: We'll be - it's exciting, have you back every once in a while and keep following how well you're doing.

Dr. HIGH: Okay, great.

FLATOW: Terrific. Thanks very much, Doctor.

Dr. HIGH: Okay, thank you.

FLATOW: You're welcome.

Dr. HIGH: Bye-bye.

FLATOW: Katherine High is professor of pediatrics at the University of Pennsylvania School of Medicine and director of the Center for Cellular and Molecular Therapeutics at Children's Hospital in Philly and a Howard Hughes investigator.

We're going to take a break, come back and switch gears and talk about the - this is the 40th anniversary of the Internet. Wow, 40 years ago, there was a seminal event, and we actually have one of the guys who was in the room at the time. So stay with us. We'll be right back.

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FLATOW: I'm Ira Flatow. This is SCIENCE FRIDAY from NPR News.

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