Advances in Gene Therapy Treatment for Blindness

IRA FLATOW, host:

Up next this hour, new hope for those suffering from a certain kind of blindness. Maybe you heard about this research. We're going to look into it carefully. Earlier this week, two teams of researchers reported success in using gene therapy to treat a form of inherited blindness in a small group of people. Here's how it works.

Using a modified virus - they use modified viruses here. The researchers introduced new DNA into the eyes of patients suffering from a disease called Leber's congenital amaurosis. The DNA was able to supply the patients with an enzyme that they had been missing. Now, these trials are very small, but at least four patients out of six reported being able to see better after receiving these treatments. And joining us now to talk more about the work is one of the researchers.

Katherine A. High is professor of pediatrics at the University of Pennsylvania School of Medicine. She's also the director of the Center for Cellular and Molecular Therapeutics of Children's Hospital in Philadelphia and an investigator with the Howard Hughes Medical Institute. She joins us from Philly. Thanks for being with us today, Dr. High.

Dr. KATHERINE A. HIGH (Professor of Pediatrics, Children's Hospital in Philadelphia): Yes, thank you.

FLATOW: This disease that you were testing, was it - is it - it's genetically caught, correct?

Dr. HIGH: That's right. It is an inherited condition.

FLATOW: Mm hm. So does that make it amenable for gene therapy?

Dr. HIGH: Well, gene therapy can actually be used for both inherited conditions, genetic diseases, and also for acquired disorders. But it's most commonly thought of in the setting of genetic diseases because, in a very straightforward way, we think if we could just supply the missing gene, we may be able to reconstitute a missing or defective important pathway.

FLATOW: So you must have tried this out in animals first there, I would imagine, with good results, before you went to humans.

Dr. HIGH: Well, that's exactly right. Other members of this team led the work in both a mouse model of the disease, and there is also, actually, a naturally-occurring dog model of this disease.

So Jean Bennett, who is a professor of ophthalmology at the University of Pennsylvania, had, along with her colleagues, published a paper in 2001 showing that exactly the same procedures, subretinal injection of this modified virus carrying the gene sequence for the missing enzyme, could restore sight in dogs with the same condition.

FLATOW: And...

Dr. HIGH: That was in 2001.

FLATOW: And so you moved on to humans?

Dr. HIGH: That's right.

FLATOW: And did they present any different kind of a challenge?

Dr. HIGH: Well, you know, what's really interesting, people have been attempting gene therapy for genetic disease using this sort of approach, where the gene-therapy vector is directly injected into the patient, for a number of years now, but it's been very difficult to move it to a successful conclusion, and one problem after another has occurred.

One of the most prominent problems that's occurred, with this particular vector, has been, in some circumstances, an immune response that seems to get in the way of effective expression of the donated gene. But the retina is, in that sense, a very special place to try to put a donated gene because, relative to many other tissues in the body, it's relatively immunoprivileged, so the immune system can't get to it quite as well.

So the retina is the situation where you can use very small doses in a relatively immunoprivileged site. And so, this was an instance where what happened in the dog model of the disease predicted quite accurately what happened in human subjects, at least so far.

FLATOW: Mm hm. 1-800-989-8255. We're talking about the gene therapy, and in this case, successful - was it four out of six patients?

Dr. HIGH: Yes, there were three subjects treated at the Children's Hospital of Philadelphia, and then an additional three at a hospital in London, University College in London.

FLATOW: And why do we suspect the other two failed to show that kind of improvement?

Dr. HIGH: Well, I think the most likely case is that there're minor differences in the vectors. It's not easy, sometimes, to show comparability between two vectors, and so it's possible that the effective dose in one case is a little lower than the effective dose in the other case. You know, these are things that will probably take time to work out.

FLATOW: Mm hm. 1-800-989-8255. But we're going to take a short break, and - just so that we don't have to start a question right in the middle of the break time coming up. With us is Katherine High. She's professor of pediatrics at the University of Pennsylvania School of Medicine.

If you have questions about gene therapy, why it's working, why it's not - it's an interesting topic. We'll try to get into these different permutations of gene therapy and what make it work sometimes, what makes it fail. So stay with us. We'll be right back after this short break.

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FLATOW: This is Talk of the Nation Science Friday from NPR News.

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FLATOW: You're listening to Talk of the Nation Science Friday. I'm Ira Flatow. We're talking about gene therapy this hour and focusing on this successful test of new therapy that allowed the retinas to be restored to three out of six patients. We're talking with Katherine A. High, professor of pediatrics at the University of Pennsylvania School of Medicine.

Dr. High, you know, we've heard stories in the past about people who do not have sight and then regained their sight, and they have to learn how to see all over again. Or if they couldn't for the first time, did these patients have to do that, too?

Dr. HIGH: Well, that's a really good question, and it may prove to be a limiting factor in some circumstances. A fortunate circumstance in these initial subjects, who were studied here in Philadelphia, was that two of them, at least, had sight when they were children. So they had, for example, gone to school, to regular school.

And so all of the neural pathways and connections required for sight were more or less in place. And although the sight deteriorated over time, the restoration of the enzyme in this case occurred against the backdrop where all the necessary neural connections were - had been laid down initially.

FLATOW: Mm hm. 1-800-989-8255 is our number. Why was - you used a virus - as they say, the vector that carries in the gene, why was the virus not rejected? Is it because, as you say, it is the retina and it's maybe a poor place of circulation, it wasn't rejected by the body? Or is it something different about this virus?

Dr. HIGH: Well, yeah, what's really interesting, of all the - you know, viruses, as you know, are great at getting into cells and harnessing the synthetic capacity of these cells for their own purposes. So, in some ways, they are ideal gene-delivery vehicles, but you're right. Many times, the immune system will pick up on their presence and reject any cell that's harboring them.

This particular viral vector, adeno-associated viral vectors, AAVV for short, is one that seems to trigger very little in the way of immune responses. And so, in fact, it has been used to cure a wide range of genetic diseases in animal models. It's been very successful in mice, dogs, non-human primates. And it's not rejected by their immune systems.

But earlier work, in which the same vector had been injected into different sites, like skeletal muscle, like the liver, had shown that in humans, as opposed to all those other animals, occasionally one does see an immune response that seems to wipe out the expression. But that's the great thing, as I mentioned earlier, about the retina, is that compared to many of the other tissues in the body, it's relatively shielded from the immune response.

FLATOW: So you must have had some trepidation, then?

Dr. HIGH: Well...

FLATOW: I mean, was it given in both eyes?

Dr. HIGH: No, actually...

FLATOW: Just one eye?

Dr: HIGH: The way most eye trials are done, actually, and this was done in trials for new therapies for diabetic retinopathy as well. The usual approach is to select the worse eye, and then that is the eye that the new treatment agent is administered to. And so that was what was done in this case as well.

FLATOW: Can we use this technique now - of course, I'm sure you've been asked this a hundred times at least - for other type of blindness?

Dr. HIGH: Well, you know, it's really interesting. The number of genes that are required to have effective eyesight is really amazing. You know, it's hundreds of genes. And so there's a great deal of work going on to try to develop these kinds of approaches for other causes of genetic, you know, retinal-degenerative disorders.

So certainly, a lot of pre-clinical work is going on, and I think there's a lot of excitement about the possibility of moving to other disorders. But you know, all of these things, of course...

FLATOW: Yeah.

Dr. HIGH: Take a lot of time. I think it's fair to say that, you know, where we are now is really standing on the bottom rung of a tall ladder. But the rung isn't giving way. So that's good.

FLATOW: That's good. Let's go to Christie in Palo Alto. Hi, Christie.

CHRISTIE (Caller): Hello. I have a question about, how fast do you think that ladder is going to be climbed? I'm 42 years old with retinitis pigmentosa and wondering, what the odds are that, in my lifetime, I would be able to have any assistance from this therapy?

Dr. HIGH: Well, I have to say, Christie, that I've learned not to try to make prognostications about the speed of development of novel therapeutics. But I do think that this is encouraging, and you know, as I've mentioned before, there are many potential defective genes.

And so, the answer to your question depends on all sorts of things, like is the gene that's defective in this case small enough to fit into this vector? We can't really put things into it that are much smaller than five kilobases in length.

FLATOW: Yeah.

Dr. HIGH: So, you know, all sorts of things like that will enter in the answer to your question.

FLATOW: How - what were the ages of these patients?

Dr. HIGH: These patients were 26, 26, and 19, and the subjects in the trial in London ranged in age from 17 to 23.

FLATOW: Does - was age correlated with success at all? In these patients?

Dr. HIGH: In this situation, there is an important element to the age, just in the sense that, over time, the cells that you're trying to target deteriorate, and there's not really a target cell toward the gene to go to. And so the ideal situation, in this condition, is probably to try to treat individuals as soon as it's feasible after the time that they're diagnosed, which is usually in infancy or early childhood.

The trials have started out within individuals at least eight years of age, and as I've said, the youngest subjects injected so far have been age 17, but the eventual goal, if the work continues to prove to be safe, would be to try to extend to younger subjects who really have the best chance for a good outcome.

FLATOW: Now, ever since the death of Jesse Gelsinger, the field has been slowed. Do you feel that successes like these might help things pick up a bit? Again?

Dr. HIGH: Well, I think, in any type of novel therapeutic, not necessarily just gene therapy, but you know, there's always slow development at the beginning, because what one finds is that not every single problem or every single issue for human therapeutics will have been accurately predicted by work in animals.

So at the beginning, as the clinical work starts, problems are uncovered. And sometimes it means the people have to go back to the laboratory and sort out what's going on and make a new attempt. But as experience accumulates, these problems are overcome and worked through more rapidly. And so I think that we can expect that the pace of this sort of work will pick up as more experience is gained.

FLATOW: You know, why use viruses at all? In this age of polymers and nanotechnology and things like that, could we not design a nanoparticle or something that could carry the gene in?

Dr. HIGH: Well, you know, that's a really good question, too. And I have to say that, you know, when you think about it, viruses have evolved over millions of years to be really good at what they do.

So they have a pretty good head start on us in the laboratory. So you know, this viral vector, for example, was actually a fairly simple sort of thing. It's got 60 molecules that assemble together to make a little capsid, and then you just put a piece of DNA inside that.

FLATOW: Yeah.

Dr. HIGH: So, you know, it's hard to imagine that you could come up with something simpler than that would work so well.

FLATOW: So if this is working so well in the eye, why not use it for other gene therapy?

Dr. HIGH: Well, people are definitely trying to do that.

FLATOW: Yeah.

Dr. HIGH: So that's underway.

FLATOW: Mm hm. And they'll be watching the results of your research. Do you have to watch these patients any more, to see if there might be an immune reaction? Or are you pretty safe in assuming they're safe now?

Dr. HIGH: Well, typically, an immune response will come up fairly early after a person is exposed to something. And so, of course, all patients who enroll in gene therapy studies are followed for a period of many years, in the United States, for at least 15 years. But if what you're looking for is an immune response, you'll probably going to see that fairly early.

FLATOW: 1-800-989-8255. Let's see if we can get a few questions in. Joe in Tucson. Hi, Joe.

JOE (Caller): Hey, how are you doing?

FLATOW: Hi there. Go ahead.

Joe, are you there?

Joe, did we lose you?

JOE: No, I'm here. Can you hear me?

FLATOW: Yes, go ahead. Can you hear me now?

JOE: Oh, OK.

FLATOW: Sure.

JOE: Yeah. I was saying, that sounds great. Fantastic research, and I'm just wondering if you've been adopting some of the new research models to try and get some of your findings, when you come to your conclusions, to get some of your findings to the implementation part of it a lot quicker. Because right now, on average, whenever we have a good promising research, it takes about 17 years for it to get in to practice.

So, right now, to fill the gaps, they've been doing away with a lot of the masters', like nurse practitioners, and they've been making them doctorate level. Like, I know the University of Washington has gotten rid of their master's level and there're just doctorate-level nurse practitioners now. And the hope is, is that they'll help fill the gap and get some of this research in to the practical application a lot quicker than the 17 years it takes now. So...

FLATOW: Let me get an answer - let me get an answer to that. Dr. High?

Dr. HIGH: Well, I would certainly hope that forward progress, in this situation, will not require 17 years. I think it's probably important to point out that for rare conditions like this, typically, the drug or the therapeutic can be licensed, following a relatively small trial.

So, for example, some of the drugs that we used to treat hemophilia were licensed on trials of 50 patients. And I would expect that for this sort of condition, which is much rarer than hemophilia, that a relatively small trial, if it continues to demonstrate safety and efficacy, would be acceptable for licensing of the therapy.

FLATOW: Mm hm. Let's go to Justin in San Antonio. Hi, Justin.

JUSTIN (Caller): Hi. I just wanted to start off by saying this is my favorite radio show. And I was just curious...

FLATOW: Thank you.

JUSTIN: I know viruses are contagious. Is it all possible that a vector could mutate or affect a person who is not getting the therapy?

Dr. HIGH: Well, that's a really good question, but the way this particular viral vector is made, the genes that are usually part of the virus and that are required in order for a virus to replicate have been completely deleted. So, they are not present. The only piece of DNA there is the DNA encoding this protein that should be in the retinal-pigment epithelial cells. So, it cannot replicate because it doesn't have the viral genes that it needs to replicate.

FLATOW: Will you have to retreat these patients at all later on?

Dr. HIGH: Well, of course, that's a really important question. In the dog studies, the dog that was first treated was treated eight years ago, and a single treatment, eight years ago, which is long in a life of a dog, and that animal still has vision.

So, certainly it's been the case in animal studies that gene expression from these vectors has been very long-lasting. But of course, we all know that the FDA doesn't license drugs based on results in animals, and that's why it's important to do clinical trials in human subjects, and we'll have to see.

FLATOW: Mm hm. Talking with Katherine High on the Talk of the Nation's Science Friday from NPR News. Talking about gene therapy and the success in treating Leber's congenital amaurosis. Did I pronounce that correctly, I hope?

Dr. HIGH: Yes, absolutely.

FLATOW: And so, you'll be watching these patients to see how long this lasts.

Dr. HIGH: Right.

FLATOW: Why would it not last - if you've changed the gene, why would the gene suddenly wear out, so to speak?

Dr. HIGH: Well, there are a lot of reasons that that sort of thing might happen. We talked earlier about immune responses. That doesn't seem to be going on here. The cells that this donated DNA went into are very long-lived cells. But one can imagine a situation where, for some reason, the cell just didn't last. You know, the cell lived out a natural life and didn't make it anymore. So, that shouldn't happen to these cells. But you know, one can imagine a situation like that.

FLATOW: And that is the challenge, isn't it? To try to get the genes to as many of the cells that you have to get them to...

Dr. HIGH: Right.

FLATOW: And why you use a virus which infects you, and now it goes to all those cells.

Dr. HIGH: Right.

FLATOW: And that's why, you hope, that it stays in the body, that the virus can go to all the places it needs to go.

Dr. HIGH: That's right.

FLATOW: And I guess the body, seeing it sometimes, tries to get rid of it because it doesn't recognize it.

Dr. HIGH. Well, it recognized it as something foreign.

FLATOW: It's something foreign. Again, is there any cloaking mechanism you could put on the virus, so it doesn't even know it's there?

Dr. HIGH: Well, that's a good question, and people are looking at that sort of thing.

FLATOW: Yeah, to make - to hide the virus from knowing the immune system knows that it's even there.

Dr. HIGH: Right.

FLATOW: And I guess, if you used some sort of cloaking device, or you could use an artificial virus, so to speak, from nanotechnologies or something...

Dr. HIGH: Right.

FLATOW: Then it wouldn't - it might not recognize it.

Dr. HIGH: Well, yes. And people are definitely interested in those kinds of strategies.

FLATOW: So, where do you, in this research - what is your follow up? And where do you go from here in this work?

Dr. HIGH: Well, I would say that, you know, what we're hoping - this was initially design as a trial for nine subjects, and so the first order of business is to continue increasing the dose. And so, this is a typical dose-escalation study. So, since the first dose looks safe then you can go up to the next dose and so forth. So, the first order of business is to try to identify the optimal dose.

And then the next order of business would be to try to extend the work to younger children, if it seems to be safe, and people who are eight years old and up. Then what you would ideally like to do is see if it's safe in younger children. And then eventually, I think, a bridge that has to be crossed is to ask, when would you get to the point that where you would fill that it would be safe to do this in both eyes?

FLATOW: Well, I would imagine that you must be very encouraged, because with the - just the first test dose, you got an 80-percent positive outcome, and you haven't even increased it yet.

Dr. HIGH: Well, let's see, if you put both of the studies together...

FLATOW: You got 60 percent.

Dr. HIGH: Sixty-seven.

FLATOW: Sixty percent...

Dr. HIGH: All right.

FLATOW: Sixty-seven percent.

Dr. HIGH: Right.

FLATOW: You must - it still must be encouraging.

Dr. HIGH: No, no. I think it's very exciting.

FLATOW: And when would you start with your next round of tests?

Dr. HIGH: Well, the next round of subjects are already under way.

FLATOW: Oh, you can't give us a hint.

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Dr. HIGH: It's too early.

FLATOW: I see. How long does it take to notice if it's working?

Dr. HIGH: Well, typically, people were reporting a response within a few weeks.

FLATOW: Oh, so...

Dr. HIGH: And that's pretty typical, actually, for the time course of this vector. It takes a little while to get going.

FLATOW: All right, we'll have to check back with you, watch the papers coming out with you later.

Dr. HIGH: OK. Great.

FLATOW: Thank you very much, Dr. High.

Dr. HIGH: OK. Thank you, Ira.

FLATOW: Katherine High is a professor of pediatrics at the University of Pennsylvania School of Medicine, also director of the Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia and investigator with Howard Hughes Medical Institute.

Short break, changing gears. Up next, we're going to talk about why the life expectancy for certain Americans, certain segments of the American population, is actually down, when it's been going up for lots of years. So, we'll scratch our heads and talk about that. Stay with us. We'll be right back.

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FLATOW: I'm Ira Flatow. This is Talk of the Nation Science Friday from NPR News. Transcript provided by NPR, Copyright National Public Radio.