Gene Therapy Aims to Switch on Hearing

JOHN DANKOSKY: This is Science Friday, and I’m John Dankosky. All right, I’m going to ask you a weird question– how old are your ears? And no, I’m not talking about how long they’ve been sticking out there on the side of your head. I mean, what hearing age are they? How well can they pick up sounds at different frequencies? Sounds like this–

[VARIOUS RINGING TONES].

Our friends over at WNYC’s Only Human podcast have been quizzing their listeners to find out. Mary Harris is here to fill us in. She’s the host and managing editor of Only Human. She joins us here in our New York studios. Welcome to the show.

MARY HARRIS: Hi.

JOHN DANKOSKY: So you’ve been polling your audience on their hearing age. What have you found so far?

MARY HARRIS: Well so they can download an app; it’s called Mimi. If you go to onlyhuman.org/listenup you can see all about it. And you take this test which is basically like the hearing test you might have gotten in school. But it’s really, really fun. I was a little bit worried– a lot of people have actually emailed me saying, oh my gosh I’m scared to take it, I don’t want to know what my hearing age is. But it takes you through a test and it gives you at the end, it compares your score to other people from audiology tests from decades and decades, and gives you a hearing age of how old are your ears. So my ears, shocking, I was so nervous, they were 18.

JOHN DANKOSKY: Really?

MARY HARRIS: Twenty years younger than me.

JOHN DANKOSKY: That’s amazing. See, I took the test in a really loud room and I scored way at the bottom of my age range. And then I took it in a quiet room and I scored at the top. So I’m feeling a little bit better about myself, but I worry about too much rock and roll his dimmed it a little bit.

MARY HARRIS: Yeah that’s kind of the worry, isn’t it?

JOHN DANKOSKY: Yeah, okay, so a lot of people are taking this test. Are you finding anything about this?

MARY HARRIS: So what’s interesting is that we wanted to offer this because so few people get tested. And we’re finding that’s really true. When we ask people at the end, have you been tested, have you gotten your hearing tested? Only a third of people have. And even if their hearing is worrying them, only 43% of those people have been tested. So that’s kind of alarming.

JOHN DANKOSKY: You’ve been doing a whole series on hearing, beyond just a taking this poll. And you introduced us in one of your stories to a deaf composer named Jay Zimmerman. Tell us a bit of Jay’s story.

MARY HARRIS: So Jay Alan Zimmerman is a composer. He wasn’t always deaf. He kind of came to New York with this dream of he was going to, you know, be the next great composer, write for musicals, write for movies. And he did that. And then he had this realization that he was losing just a little bit of hearing at the top of his range. And he didn’t quite know what to do about it.

JOHN DANKOSKY: Yeah, we have a clip, actually, about that moment when Jay realized that his hearing was fading.

JAY ALAN ZIMMERMAN: So we wanted to start the track with the sound of these birds. And so the engineer found different bird sounds, whatever, so he puts them in the track. And I’m like, where are the birds? Turn up the birds. And that’s when I realized, uh-oh. Because he’s like, they’re playing.

JOHN DANKOSKY: And you can hear the kind of panic in his voice from remembering that moment.

MARY HARRIS: Yeah. And so, the thing was it started off with just losing a little bit of his hearing, and then it got much more profound. And he had to really make a decision, what am I going to do with my life? Because his whole world is based on sound and audio and the richness of that. He talks about how much he misses the tiny little tambourines and triangles. And he decided to soldier through and keep composing music. And he’s come up with all these interesting workarounds to keep doing that. He has an audio visualizer, so if he has someone singing for him, he can see that they’re hitting the notes. And it’s kind of amazing.

JOHN DANKOSKY: Did he consider any sort of treatment?

MARY HARRIS: So he did, but he decided something like a cochlear implant, which was the perfect thing for him, wasn’t what he wanted. He wanted to preserve the rich experience of music that he’d always had. And he really worried that if he got a cochlear implant, that might go away.

JOHN DANKOSKY: And he actually gave you this comparison about how cochlear implants might affect the ability to hear things like music. Let’s listen again.

JAY ALAN ZIMMERMAN: I think your listeners have to realize that any treatment for hearing loss is not remotely like getting glasses for your eyes. It’s not regular hearing again. It’s an altered reality.

JOHN DANKOSKY: And you actually present a bit of sound that kind of mimics what you might hear. It’s clearly audible music, but it really doesn’t sound like the type of music that Jay is used to listening to.

MARY HARRIS: Yeah, it sounds digitized, because the cochlear implant it sort of rewires how you hear things. And it allows you to hear voices, but Jay made this really painful choice. He decided not to hear his child’s voice because the music was so important to him.

JOHN DANKOSKY: Now, Jay was at a meeting for people with hearing loss and he heard about a potential new treatment; a type of gene therapy aimed at growing back cells in the inner ear, and hopefully restoring some hearing. The person he heard speaking at that meeting was Dr. Lawrence Lustig. He is a professor and chair of the Department of Otolaryngology at Columbia University Medical Center and New York Presbyterian Hospital here in New York. And welcome to Science Friday, Dr. Lustig.

DR. LAWRENCE LUSTIG: It’s great to be here. Thanks a lot, John.

JOHN DANKOSKY: I’d like to bring on another guest as well who’s also investigating a genetic treatment of a different kind, Dr. Jeffrey Holt, an associate professor in the Department of Otolaryngology at Boston Children’s Hospital and Harvard Medical School. And welcome to the show, Dr. Holt.

DR. JEFFREY HOLT: Thanks very much, it’s a pleasure to be here.

JOHN DANKOSKY: So I want to turn to you first, Dr. Lustig. One of the interesting things is that even though humans can’t regenerate our hearing cells, other animals can. And what can learn from that?

DR. LAWRENCE LUSTIG: Well it’s been known for years that birds can regenerate their hair cells. It was discovered in a series of experiments over a decade ago. And it’s really taken us a long time to figure out all the molecular steps that occur to allow us to sort of rewire what we do our own inner ear, to allow us to regrow hair cells in mammals.

JOHN DANKOSKY: So tell us about how your treatment is supposed to work.

DR. LAWRENCE LUSTIG: Well what we do is we take advantage of some recent research discoveries that happened around the mid to early 2000s, where it was discovered that a particular gene called the atonal gene, which was originally discovered in the fruit fly, that if you made a mouse that didn’t produce that particular gene, the mice are completely normal in every single respect except they didn’t make these critical hair cells, the cells that we use to sense hearing and balance. Then in another series of studies that happened at the University, initially at the University of Michigan, they took a virus that was loaded with that same gene, it’s called the atonal gene, and they put it back into the mouse. And the mice, lo and behold, grew new hair cells. And if you deafen in those mice and then added this gene back in on the virus backbone, the mice were able to regain some hearing. And then Dr. Henrich Staecker from the University of Kansas did essentially the same studies looking at the vestibular system. And it also showed that if you wipe out the vestibular you can then regrow some of those hair cells, and also get some functional balance recovery back in those animals as well. Those happened around 2005 to 2007, those studies. And it’s taken us this long now, with the help of Novartis, to now finally apply that in humans.

JOHN DANKOSKY: If you have questions about treatments for hearing loss, (844)724-8255. That’s (844)SCI-TALK. So Dr. Holt, the treatment that Dr. Lustig is talking about is meant for people with acquired hearing loss, like Jay, who we heard about before. You’re developing a gene therapy for people with genetic hearing loss. What can you tell us about that?

DR. JEFFREY HOLT: That’s right. We think there are about 70 to 80 genes that, when mutated, can cause deafness in humans. About 1 in 1000 babies are born with hearing loss, and we think about half of those are due to genetic causes. So unlike Dr. Lustig’s approach, what we’re trying to do is to repair the broken genes. So genes that are carrying a mutation leading to hearing loss, our strategy is to use similar viral vectors and then use those vectors, inject them into the ears of patients with genetic hearing loss, to attempt to reintroduce the correct DNA sequence and restore auditory function.

JOHN DANKOSKY: So how similar or how different is it from the treatment that Dr. Lustig is talking about?

DR. JEFFREY HOLT: Well, what we’re doing is really trying to fix [INAUDIBLE] that are broken. These are the sensory cells that are not functioning properly, and if we can introduce the correct DNA sequence, we can make those cells functional again. We’ve demonstrated that with one gene in particular, called TMC1, and it works quite well for that gene. Now we’re trying to tackle some of the other forms of genetic deafness.

JOHN DANKOSKY: So we’ve heard about these couple different treatments that are out there. And Mary, I want to turn back to Jay, who you profiled; his dilemma about whether or not to get treatment. Your team gave him a recorder and he recorded some diary entries, including this.

JAY ALAN ZIMMERMAN: I have to decide what I want. In this case– in this case, the world would prefer I was hearing, I think it would make it easier on everybody around me. And I don’t know how to process that because I’ve always wanted of my hearing back. Primarily so I could enjoy music, which I guess makes me selfish, rather than thinking about other people in my life. But the sounds of flutes and piccolos and birds and tiny little triangles, they were so gorgeous.

JOHN DANKOSKY: So Mary, he clearly wants to be able to hear again, but tell us about his decision, what he decided to do. Did he go through this gene therapy treatment?

MARY HARRIS: Well he really decided to wait. And you can kind of understand, it’s early days for these treatments. And the other thing I think it gets to is when you’re a person with an illness like deafness, and some people wouldn’t even call it an illness, you adjust. Your life becomes something new. And he’s really in a great place. He has adjusted to being a deaf person, he’s known as a deaf composer. And his life is going well, so he doesn’t really want to disrupt it unless he knows this is the thing that’s going to absolutely solve it.

JOHN DANKOSKY: Is he worried at all about the risks of having this therapy?

MARY HARRIS: I think so, I think so. But I just, I think, for him the timing wasn’t right. He wants to wait a little bit longer.

JOHN DANKOSKY: Dr. Lustig, are there risks for this type of gene therapy? Maybe for people who have a very little bit of hearing left, like Jay Zimmerman?

DR. LAWRENCE LUSTIG: Yeah, there’s always a potential risk. The approach that we use to inject the virus is something that we actually do routinely in the operating room for patients who have, say, a fixed stapes bone and they can’t hear as a result of that. We put the patient to sleep, we raise the ear drum up like a little window shade. We make a laser opening to the inner ear and very slowly, over a couple minutes, infuse the virus with the gene. And then we put a little fat plug in and the whole thing takes under an hour. It’s very simple. But even the simplest operations have potential risks, and losing residual hearing is one of them. Fortunately we really haven’t seen that in the trial to date, and it appears to be really quite safe. But like I said, we’ve got a very limited number of patients that we’ve enrolled so far, partly because most patients who have Jay’s level of hearing have already gone cochlear implantation. And the way the study is designed at present, those patients currently aren’t candidates.

JOHN DANKOSKY: And Dr. Holt, for someone who was born deaf, I imagine the risks associated with any treatment might be somewhat different, right?

DR. JEFFREY HOLT: Sure, that’s going to be a different set of risks. There’s not the risk of losing hearing in that case. There might be some other risks associated with it, but I think those are minimal. We know that these viral vectors have already been demonstrated safe in humans, and so there’s little concern about that. One of the other advantages of treating the ear with gene therapy is that it’s an enclosed, fluid filled space. So anything we inject into the inner ear, we think will stay there and not cause systemic side effects.

JOHN DANKOSKY: I’m wondering, Dr. Lustig, if there is any differences in the risks for gene therapy from what one might have with cochlear implant, say, something else that Jay considered.

DR. LAWRENCE LUSTIG: Well, you know, first of all, I’d like– Jay was right on, in terms of his concerns about an implant and his ability to appreciate music. Implants are fantastic with regard to spoken language and speech. Talking one on one. But they really just don’t work that well with music. It’s a higher order listening task that we have and implants, while they are great for language and speech, they’re just not that good for music. And someone like Jay, who really, his whole career is relying on music appreciation, an implant may not be the way to go. So from that standpoint, I think, if we could regrow the hair cells of the inner ear of the humans, there’s no question that the hearing would be better than it would with an implant. And that’s why I think those of us that are involved in the study, the three sites that are involved– Kansas, Johns Hopkins, and Colombia– we’re really excited about this. It’s the first time this has been tried in the ear and we can demonstrate very clearly that in animals we can regain hearing. But what an animal can’t tell you is what the sound is that they’re hearing. And only a human can tell us that, and that’s why the study is so important and so exciting.

JOHN DANKOSKY: I’m John Dankosky, this is Science Friday from PRI, Public Radio International. I’m going to go to the phone. David is calling from Hammond, New York. Hi David, go ahead.

DAVID: Hi there, guys. My question is regarding tinnitus. I’ve had it since 12, age 12, and I know I recently heard some advertising on commercial radio about some kind of miracle drops or pills you can take. My doctor prescribed something, I can’t remember the name of it now, but I believe it started with a “C”. But when I got it home and looked at the precautions it said this could lead to suicide. So is there anything out there that’s safe to take without any weird side effects?

JOHN DANKOSKY: My goodness. Dr. Lustig?

DR. LAWRENCE LUSTIG: Do you have about an hour to talk about this? Tinnitus is one of those really challenging problems. There are a number of different treatments. Unfortunately there is no magic red pill that’s going to make it go away. Part of it is because we have lots of people with tinnitus with hearing loss, but we have many patients with tinnitus without hearing loss and many patients with hearing loss without tinnitus. So we really don’t have a great understanding of what the nature of tinnitus is and in some cases, where it even resides. There’s a large body of evidence that shows it starts in the ear, but then sets up in the brain stem. There are a number of different treatments that have been tried that seemed to work for individuals, but when you do a blinded study with a placebo control, nothing really seems to work. The good news is there’s a lot of research in this area, and a number of new chemical compounds that seem to be coming out on the market over the next couple years that we’re hopeful will help people with chronic tinnitus.

JOHN DANKOSKY: Mary, one of the interesting things about hearing is it doesn’t really just stop at the ears, it’s a brain phenomenon, too. And it could be involved in overall brain health. Will you talk about that a little bit?

MARY HARRIS: Yeah, so we’re going to do a story in a few weeks about this researcher named Nina Kraus out of Northwestern University, and she looks at how the brain processes sound. And what she’s found is that when you look at how the brain perceives sound, it can tell you all sorts of things about the person you’re looking at. So for instance, she can give three-year-olds something she’s calling a CAVR, it’s an EEG. And she says she can predict reading difficulties just by looking at how the brain is looking at sound. And it seems strange when you think of it on its face, but then you think a little deeper. When you’re looking at the page, if you don’t recognize the word there, if you haven’t been hearing that word, it makes it much more difficult for you to read. And she’s done fascinating work looking at dyslexia and whether you can treat it by treating hearing.

JOHN DANKOSKY: And also looking at things like dementia and how it plays into dementia or Alzheimer’s.

MARY HARRIS: Yeah, so there’s some really interesting research at Johns Hopkins tying together whether untreated hearing loss may be somehow linked with Alzheimer’s. And it’s very early days, very hard to tell what the chicken and egg is here with this story, but it’s fascinating. The researcher now is going to try whether he can see if treating the hearing loss can stave off the Alzheimer’s, because so many people just aren’t getting the hearing aids and treating their hearing loss.

JOHN DANKOSKY: Dr. Holt, before we run out of time, with your approach to treating genetic hearing loss, would you need to develop custom therapies for each type of genetic hearing loss to fix all these various mutations? I mean, how would this work?

DR. JEFFREY HOLT: Yeah, unfortunately hearing loss is a multi-factorial problem, meaning it can arise from many different sources. And I think that each particular source is going to require its own precision medicine, sort of, treatment to intervene. So what we’ve got is a platform for delivering genes into the inner ear, and now we need to really look at them one at a time to see which ones are going to be amenable to intervention, gene therapy interventions. Some of them will be, but some of them may not be.

JOHN DANKOSKY: Jeffrey Holt is an associate professor in the Department of Otolaryngology at Boston Children’s Hospital and Harvard Medical School. Thank you so much for your time. I also want to thank Dr. Lawrence Lustig, professor and chair of the Department of Otolaryngology at Columbia University Medical Center and New York Presbyterian Hospital. And Mary Harris, the host and managing editor of WNYC’s Only Human podcast. Thanks so much, Mary.

MARY HARRIS: Thank you.