Gene Therapy and the Future of Hearing Care: A Conversation with Dr. Jonathon Whitton

Gene therapy is no longer a future possibility—it’s here. In this episode, Emily Venskytis and Maggie Kettler sit down with Dr. Jonathon Whitton, Vice President and Global Program Head of Genetic Medicines at Regeneron, to discuss the first-ever gene therapy for genetic hearing loss. From molecular diagnosis and genetic testing to changing standards of care and emerging treatment pathways, Dr. Whitton shares how precision medicine is reshaping the future of hearing healthcare and why audiologists will play a critical role in this new era. 

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Welcome to Science Meets the Sound Booth, sponsored by the AAA Foundation, where hearing meets understanding. We're your hosts, Emily Vinceitis and Maggie Kettler, and in this podcast, we'll explore evidence-based clinical care in audiology. Science Meets the Sound Booth aims to translate research into real-world application. We're finally stepping out of the booth, metaphorically at least, to support informed decision making and better patient outcomes. Whether you're an audiology professional, a student, or you've spent so many hours wearing that monitor headset that you've forgotten what daylight looks like, you're in the right place. Today we are joined by Dr. Jonathan Witten. Jonathan Witten, AUD PhD, is vice president and global program head of genetic medicines at Regeneran, where he leads efforts to develop innovative gene therapies for serious diseases, including genetic hearing loss. A clinician scientist by training, Witten has spent nearly two decades advancing translational and clinical research in hearing imbalance disorders. He is widely recognized for his leadership in pioneering gene therapy approaches, including programs aimed at restoring hearing in children with rare genetic conditions. Prior to joining Regeneron, he held senior leadership roles at Decibel Therapeutics and co-founded Source Bio, bringing deep expertise in clinical development and biotechnology and innovation. He earned his PhD in health sciences and technology from the Massachusetts Institute of Technology and his Doctor of Audiology from the University of Louisville. Thank you for joining us. Welcome, Jonathan. So where we want to start today is looking at the very beginning. You started your career in clinical audiology as a fellow before moving into research and then transitioning into your role now as the VP of Regeneron Genetic Medicine. What sparked this transition from the booth to the biotech industry? Well, first off, uh great to be with you, Maggie, to see you after so long. And Emily, great to meet you. Um okay, so what sparked that transition? Well, it started uh a long time ago, really. So it started when I was actually like a first-year AUD student. So I came into the field of audiology, not really knowing much about it, to be honest with you. My background before that was in uh science and linguistics, languages. That's what I was interested in. Um I came, I kind of came into the field, you know, walking backwards almost, like trying to figure it out. Um, and uh I was pretty naive, I guess. So I came in, I was excited about doing something that could help people. I was really excited about exploring my own intellectual interests and uh language and the science of language. Um and uh I was at University of Louisville and they started us at that time into clinical rotations pretty early. So pretty quickly I came into a clinical rotation in pediatrics. I was under the impression I knew nothing about the devices that were used for managing patients, but I was just under the impression that you put in the device and everything is fine. So like I was pretty excited about being that person who got to do that for people. And within that first year, I saw, oh wow, like the different management strategies we're using with patients. These kids actually still have a lot of challenges and the families still have a lot of things they need to do. Um, and so it actually started very simply for me. I felt like, hey, I want to do this as my career. So I want to do this, but I I'm only gonna feel good if I'm able to say, hey, this is what we're gonna do with you now, and I'm working on something else because we're gonna try to do even better for you tomorrow, basically. So that was like my desire, and it was honestly that simple, but I realized like I literally don't have the skills to do anything. So I I have the desire, but like I don't have skills to actually make anything new. So while I had never honestly considered research before, people had proposed that to me back when I was an undergrad. Oh, you should do research. And I thought that's the most boring thing I've ever heard of. Like that doesn't sound exciting to me. But from a very applied perspective, then I said, well, I'm gonna need to develop the skills so I can actually start making something. So that set me on a very long journey where even while I was doing my clinical training, I applied and received some of those fellowships from NIH to actually go start doing research training. I was sort of taking some extra courses to try to increase my breadth of knowledge and my skills. And um before I even came to the end of my time as an AUD, I realized it's gonna take even more. I don't think that I still have enough skills to really do something yet, at least for me. And so I knew, hey, I think I'm gonna have to uh do some additional scientific and technology training. And that was gonna take the form of a PhD after I was done. Um, so so for me, it was all very applied. Um, like my interest uh and the whole path that I went down and started basically at the beginning of my clinical training, to be honest. Unexpectedly to me, unexpectedly. Well, thank you for sharing that. It sounds like really you've been, as you said, you've been working on this for so long. And and congratulations are in order because you were recently named the 2026 Time 100 Health List for your for your pioneering work in genetic therapies. So, you know, continue telling us about as you were in the clinic um during your schooling, during your AUD, and even um if you continued on during your PhD time. What other insights from patient care do you think shaped your approach as a leader in this biotech space? Okay, that's a great question. Um, let's see. Um it was pretty fundamental because you know, I didn't spend a long time in the clinic. I spent my time training and then uh during my fellowship, which I did at Cincinnati children. So I was spending a lot of time with with families um and understanding the big challenges that they talked about uh in you know dealing with hearing loss in their their everyday life. That was pretty much internalized for me. So I focused my research on well, what are those big challenges essentially and how do we address them? I honestly didn't care what the technology would be. So when I was doing my PhD work, I did a lot of work with uh digital technologies, um, which I remain pretty excited about, different opportunities on that front. Um, and we did some cool things, I think. Um I'd worked with genetic medicines uh only peripherally, really, um, when I was doing my scientific training. It wasn't until I moved out into um biotechnology field that that became sort of the main thing I was focused on uh for a while. Um so I think you know, if you come from a clinical background, uh then you're pretty tuned in to just wanting to solve the problems that actually patients are talking about or their their families are talking about. So it makes you kind of laser focused on them. So um it's a blessing, honestly. Like if you come from that background, it's a blessing because it gives you the North Star always in everything that you do. So I would say it's like totally ingrained from the very beginning. Um, I'm sure if I thought hard enough, I could come up with like a few like specific things, but I would just say that it's honestly just like a fundamental part, and it's the it's the nice part about being a clinician scientist. You you really know the patients tell you what to do, essentially, and then you just go try to make something that will do that. That's like what your goal is. So it's great. It's wonderful to hear that you've always had the perspective of the patients at the front of all of the work that you've done. And really, such exciting work has been done. So, we in this field are really um all excited about the FDA approval of OTARMony. Tell me about this. Tell me for those of us who are just for the first time hearing it, what is this therapy designed to do and what specific clinical needs does it answer? Sure. I'll do that. And hey, you know what I realized that I didn't exactly tell you because you asked me before how I ended up in biotech, and I kind of skipped that part of the story, but this is part of it. Um, so I'll I'll weave it in. Let me tell you what it does. So, first off, um, as probably many people who tune into this podcast know, if you think about uh pediatric hearing loss and particularly um congenital hearing loss, many children who are born with hearing loss have as the cause of their hearing loss some genetic protein deficiency. If we go back to the beginning of my career, you know, people kind of knew that a bit. I remember some people were doing a little bit of genetic testing in kids who had hearing loss, but it wasn't like everybody was doing testing and making diagnoses based on um genetics. I would say the field at that time, and still to some extent now, it's it's changing over time, would arrive at what all like call geographic diagnosis. So basically you'd say, okay, this child is unable to hear certain sounds, and so you'll give them some uh severity level of their hearing loss. You might say they have severe hearing loss or something like that. You'll then say something about the location that you think this is happening in. So you might say it's conductive in some cases, so that gives you a location in the middle of the ear, or you might say it's sensory neural. So you're saying it has something to do with like the cochlea or the nerve or both. Like we don't know, but like we're localizing it on this thing. Um and uh over time, even during the course of my early career, people were getting their heads around going a bit a step further. So people started making diagnoses around, for instance, auditory neuropathy. So why could you do that? Well, all of a sudden, people developed new technologies and they were able to measure clinically. It took a while to incorporate clinically, but clinically, you could start measuring outer hair cell function independent from hearing ability. Well, and so that then let you say, oh, there's some kids that it seems like they have pretty normal outer hair cell function, but they still are unable to hear. And so you started getting a new diagnosis. So now the location shrunk from all of the cochlea and the nerve to like, well, maybe it's like the inner hair cell or the synapse between the inner hair cell and the nerve, or the nerve, it's like somewhere in there, right? So that's like how things were moving. What has happened over the last couple of decades is we've realized most of these kids have a genetic driver to their hearing loss. And you can actually take a step further in diagnosis and make a molecular diagnosis. So now you can say, these children, they have a hearing loss. You can describe it the typically way, the typical way. But in addition to that, you can say, I actually know that it is a single protein that is not functional for this child, maybe in a single cell type. And so now your diagnosis is very, very specific. And so the point I'm trying to make is when you get to increasing clarity of understanding the underlying biology of the condition that you're seeing in the clinic, all of a sudden there's new ideas about how you might actually intervene. You could have never thought up this therapy I'm gonna tell you about until you actually were able to get to a molecular diagnosis in a very specific cell type. Because I'm gonna tell you what the technology does, and it just goes and tries to do exactly this one thing. So, um, so okay, so we know that most kids are like this. They're they actually have hearing loss because they have a genetic protein deficiency. There's some protein that's really important for their ear to work and to send messages to the brain that isn't being produced normally. And that's happening because most of the cases it's recessively inherited. So meaning that they've received one uh copy from mom, one copy from dad that are not are making non-functional protein. So the parents actually have normal hearing because they're only carrying one of these copies. The child, though, ends up with um hearing loss. Okay, so that's like the background is that's happening in the field. Oh, like while I'm in school, while I'm training, as I'm going through, the field is building out an understanding of the underlying uh causes of childhood hearing loss. So by the time we get to you know, 2016, this is when I was uh taking next steps in my career after I'd done all my research training. I was starting an academic career. I always wanted to be a clinician scientist. Um, and so uh that's what I was doing. I was starting at HMS then and gonna have a lab, going to have a clinic. And uh right at about that time, actually before I even signed my letter, I said my offer letter, I hadn't signed it yet. I was still thinking. And um group of uh venture capitalists from a group called Third Rock uh ventures, which is based in Boston's successful biotech venture capital group. So they they build new companies, they fund the start of uh these startup companies. Uh, they came by because they said, hey, we we're gonna try to build a hearing company, be like a first of its kind, where we're actually gonna make medicines. We think the time is now, the biology is understood well enough that we could actually build a company to make new medicines for hearing. We're gonna call it decibel therapeutics. That's the name. And so they came by and talked to our chair and they said, Hey, we want to do research with you guys, um, you know, partnerships, you know. And he said, Oh, you should go talk to the new guy. And so that was me. So they came down the hall and they talked to me and they said, So what are you all about? And we were talking and they found out what I was all about is I wanted to make new treatments for patients. And they're like, you have to come help us. Like, come help us start this company, right? So I had never considered that as like a pathway for myself. It was hard to let go of like the path in my mind that I thought was right for me to go down. But honestly, it came down to this. I met some of the scientists uh who had already been recruited in. And um I thought, you know, over the next 10 years, what do I think I'm gonna be able to accomplish on my own? So I'll set up my lab. These are all the things I can do on my own. What is the probability that we actually meaningfully can get something done? Like we can make something for patients in the next 10 years if I go row in the same direction. And so I decided the probability's higher here, I think, that we'll actually get something done. I really felt like someone we had some talented people coming into this small company. We were in a little incubator space. And um, and so anyhow, that was the decision. That's how I went down this road. Turns out it was right. So um, it was a good decision. Um, it has been basically 10 years since then. Exactly. So we were able to do something over the course of 10 years. So, so okay, so what did we do? Well, we started looking into uh genetic forms of childhood hearing loss and asking the question a do we think that there are forms of these genetic protein deficiencies that we have technologies uh that could be used to improve hearing today? Do we think the technology exists? Can we develop it? And so we looked through and we decided yes. This one we uh prioritized, this first one, um, which is a protein deficiency uh for the Otaferolin protein. So why did we do that? There's all sorts we could have chosen, right? And in fact, we did choose. We have a long list and we're still working on many of them right now. But why did we choose this one to go first? Well, so it turns out if you see kids who have uh the phenotype of auditory neuropathy, which I described earlier, where outer hair cells are functioning, but for some reason they still have profound hearing loss. Um the most common genetic cause of that, genetic protein deficiency cause, is missing functional uh otoferolin protein. Um, what this protein does, um, it's expressed in the uh inner hair cell. So if you think about the inner hair cell, the top of it has your little stereocilia that are going to let ions come into the cell to depolarize it. The bottom of the cell is connected to the eighth cranial nerve at a lot of different synapses. So, you know, maybe like 15 or more synapses on each one of these cells. And so you you have all these synapses at the bottom. These are specialized synapses, as probably listeners of this podcast know, specialized for speed. Um, and part of that specialization is this protein called odofherolin. So when the cell depolarizes, and you need to actually take synaptic vesicles that have your neurotransmitter in them, and you need to pull them down, connect them to the bottom of the hair cell, and actually push them outside, open up and let neurotransmitter go and signal the nerve. Odoferolin's part of that. It actually helps tether these synaptic vesicles to the presynaptic membrane. So just think about a bunch of little balls with all of the messages in them at the bottom of the hair cell, kind of lasses, pushes them down into the membrane, lets the neurotransmitter release, so it'll signal the nerve. It also helps recycle the vesicles because you got to use them again because you're going to do a lot of rapid neurotransmission. So these kids don't have functional odopharin. So everything else actually happens the right way in their ear. So, like, you know, you have the traveling wave, cells get depolarized, calcium rushes into cells, they're ready to drop some transmitter in the cleft so they'll signal to the nerve. But right when they need to do that, nothing happens. And the message doesn't get sent. So we thought, hey, we're trying to do something totally new. No one's ever developed any therapeutics, no medicines at all for kids who are born with inherited hearing loss. Um and so there's a lot of things we don't know when you're doing something for the first time. So we need to choose a case where we think the biology uh is tilted towards a therapeutic working. And so, what would tilt it towards that? Well, the cells all seem to be there. So it seems like the cells in these kids develop normally. Their ear looks good, we think, um, based on all the modeling we can do and looking at animal models and things like that. We think all the cells are there, so the structure is all intact. They're really just missing one protein and one specific cell type. So it's a simple uh problem uh that we're really trying to solve. Um, and so that would stack the deck towards hey, something should work if we can actually make the technology work. So the idea here then, um going back to the beginning with diagnosis, the idea here is actually very simple. You can diagnose that a kid is missing a single protein and a single cell type in the ear. What do you want to accomplish? I now want to deliver the instructions to make the protein that they're missing in that one cell type and in that one cell type only. It's as simple as that. And if I do that, I think, boom, I flip the switch and the system actually starts to be able to work. Um, and so that's the idea. All of that is actually very simple. I hope very easy for everyone to understand. Making that happen is complicated. So, like being able to actually make it happen is actually really uh complicated. But that's the idea of what we wanted to do was so simple. Use nature's uh uh structure, use all the beautiful parts of the ear and the mechanical tuning. Everything is exquisite. It's really hard to engineer your way to that the point of what nature creates in the ear. So use everything nature already has, just get this protein back into the right uh cell type. Okay, I can pause for a second or I can keep going on how do you get it in there? Um, because I can tell you that. Do you want me to just keep going or do you want to jump in? Sure. I I really appreciate the overview that you shared about auditory neuropathy and how that pathway works. I think that's so valuable to understand it at that level. Um, as someone who works with students, I teach students often about um I teach their electrophysiology course. I'm often trying to explain this differentiation, as you said, narrowing it down to what's that specific site of lesion rather than just that sensory neural mechanism. I it would be valuable, I think, to hear from our for our listeners to hear um about how we or Tarmany recently had accelerated approval from the FDA following the cord trial, right? So Many of our uh listeners are clinical audiologists. So how do you envision then this fitting into the typical audiology care pathway from getting them getting that specific diagnosis? Uh how do you anticipate them referring or ongoing management? What might that look like for a clinical audiologist? Sure. Well, so uh I'll start here, which is uh I won't do the details on how it how it works. You guys can tell me if you want those later. But basically the idea is we deliver the instructions one time. So you this is a one-time uh treatment. So you deliver using what's called a viral vector locally in the inner ear. The instructions for making a protein that these kids are not making, it gets inside the cell and then it actually starts making that protein. And what we've seen in clinical trials now is that within a few weeks, those children start to hear. And within maybe a few months, some of those children have normal hearing sensitivity. Um, and so it's a remarkable, robust result, which is really driven by um precision of getting the right payload to the right cell type, um, and the natural ability of the ear. What we're trying to do is return natural hearing ability. Okay, so how does that fit into um audiology? Well, I think here's what's to me, what's exciting about audiology right now. I think that there's like a couple different things that are happening in the field that I personally think are very interesting. They've been happening for um about a decade now. And I was talking to someone the other day who went down one of the paths and I ended up going down kind of the other, but they're both, to me, very interesting ones. So one of the things that's happening is that we're we're building more and more biological insights for the underlying causes of hearing loss. And uh that means that we're all understanding patients, the people who are actually interacting with, we're understanding them, or we can, if we choose, you can understand better than you ever have been able to before. So you go back 30 years or so, and you know, maybe if you're like in the 80s, even if you go back and like in the 80s, and somebody who had auditory neuropathy, basically no one knew. Like some people were doing research where they're like, oh, there's some weird thing where sometimes people have something that looks like outer hair cell function. But most of the time you go to the clinic, no one knew anything other than to just say you just have profound hearing loss, right? And that would be what they say about those patients. And those would be really smart clinicians who are like, and then they'll manage them in a certain way, all of that. And then eventually people figured out, oh, you can make a different diagnosis because they have new technology, they understand the condition better. And so now they're giving them a different diagnosis, and now they're thinking about things differently. Oh, wait, this might work for you, this might not work for you, and go through a whole period like that. We're in another phase now, and it's gonna continue building, by the way, not just for pediatric hearing loss, but for acquired hearing loss as well, where you the level of diagnosis is gonna fundamentally change, where you really do understand exactly what's causing the hearing loss within a patient. That's a big thing for the field to take on. That's a big change for the field to start to have the bar raised on how deeply do you actually need to understand what's going on with this patient so that you can provide the best treatments for them. The bar was lower before because people didn't understand. And as you keep building understanding, the bar gets higher and higher, and the expectations for clinicians should be higher and higher. I should expect even better and better and better outcomes for patients because I understand more. And then now I'm able to bring better and better treatments to patients. I should keep raising the bar. So I think that's part of it. That's gonna mean that audiologists from a training perspective are gonna have to train in additional things. Um, like even during their education, gonna have to train, take on different things. People who are already in the field are gonna have to do some additional training. I think that starts with pediatrics, probably. So the pediatric audiologists have now in existence in their own clinics the possibility to send people down a path for a gene therapy. Like, and that's taking a lot of people by surprise, I would say. Um, because it seems like, wow, where did this come from? What's happening? You know, it's it's a it's a very new thing for the field. But that's already a reality for pediatric audiologists. So today, for instance, in terms of practice change, if you were a pediatric audiologist, um, as soon as a child's coming in, you know, they failed a newborn hearing screening or the parents have concern, and you find out there's some hearing loss. I mean, I don't see any reason why you're not getting genetic testing right away. And that's not commonplace at every center in the US. There's a lot of families who do not get offered any genetic testing for their child. But if you didn't, then that means the child never knows what's going on and you're treating them like it was 10 years ago now. Like you're not actually doing what um you're not actually like raising the bar, essentially is the point. So I think that's the big change. Um, and I think it will just continue. It's gonna, like I said, because of where we're at right now, I think pediatric audiology gets hit first with change here. Um but you know, there's plenty that's going on now around acquired hearing loss as well. And I mean, even with this one, uh otarmony, um, you know, adults can get otarmony. And, you know, we've we tested people within the trial up to 16 years of age and saw benefit. So um I think even people who are seeing adults may find that they have patients come in who say, hey, I want to get genetic testing. I want to know if this is causing my hearing loss, right? So that may even happen for people who are uh managing adults right now. I do think in the future there'll be even more of that for adults as we we know a lot about the underlying cause causes of hearing loss in children. Um, in adults, we know less about many of the acquired forms, but that those are the insights we're building now. Um and in fact, we're using genetics to build a lot of those insights. I'm happy to tell you guys about that at some point if you'd like. But that that I think is it's on its way. It's just it's not the the vanguard. You know, the tip of the spear is pediatrics, I think, in this case for our field. Okay, so this is really exciting and really interesting because I have been a part of many conversations over the last few months, few years about how this is going to impact our patients and how this is going to change our practice. And as a pediatric audiologist, there's no doubt that this is going to impact our profession in a very positive way. But how do we, as audiologists and as these upcoming students, do exactly what you were saying? How do we get and stay informed about how this care model is evolving and how we are able to make sure that our kids or our adult patients as that um progresses are able to connect with the correct groups? It feels like there's a lot of information out there that we need to have a better idea of how to grasp and incorporate into our own practice. Yeah. Well, I think um, well, one on one side of this, one thing that's tricky, I'll just I'm gonna focus on this particular case because I think that's Maggie, what you're saying. That I was talking about things that are present and future, and now I'm just gonna focus on the present things. So present day is that there is a gene therapy now that's available for um children with a specific form of genetic hearing loss. And so, how does that change things today? Well, number one, the audiologists need to be comfortable with genetics and being able to talk about genetics with patients and be familiar with what are the what happens. So, like uh if I have a patient come in, like back in the old days with me a long, long time ago, people talked about doing, you know, testing one gene or something like that. It'd be like, oh yeah, it's like you need to send out for GJB2 testing first or something. And then if you didn't see something, then maybe there'd be reflex testing for other genes because there's, you know, hundreds of genes that potentially can cause hearing loss in children. And back in the old days, genetic testing was so expensive and the way it was done, you know, you really tried to be very focused about only testing like the most common gene first, and then you'd kind of move on. All of that has changed. The math around genetic testing has changed dramatically now to where you should really start thinking about genetic testing in the same way you think about like an imaging study or something. So it's like a child is going to be born with hearing loss. Every kid is getting imaging, right? I assume across most centers, like that's part of the workup is like we need hearing tests. You know, it's usually ABR and such at first when they can't respond uh behaviorally, but you do this kind of physiologic test, you do imaging, there's like medical exam, and you kind of pull things together and say, what do we think is going on? I mean, you should do genetic testing for all those kids. And you don't have to do one at a time. Right now, the panels, it's like the same. You should just do a hearing loss panel and look for do I have any hits that are causative for hearing loss within this uh child? So audiologists need to understand stuff like that. It's, you know, the this is really there's some fundamentals to understand about genetics, but and then after that, there's some fundamentals to understand about well, how do I get this patient down the right path so that they actually get have genetic testing, you know, ordered um for them. Um and some of that uh is taught at some schools, uh, and in a lot of schools it's not. So there's a lot of clinicians, even new ones coming out, who may have very little background in any of this and may be very uncomfortable having those kinds of conversations with families. So they just feel like not competent enough to do it. So we have to do two things. One is the training programs have to take this on. Like you need to add this in so that the clinicians are competent coming out of school. And so that needs to be part of the curriculum. For those who are not, you know, we need to have training uh available for, particularly, I would say, for pediatric audiologists in this area so that they feel comfortable, that they know what's going on. I'd say there's deep understanding of genetics. There's also like the level you need for clinical practice, and I would say, and there's an understanding of just the logistics of how does all this happen. What's going to happen? There's gonna be a report that comes back, it's gonna provide different types of information. You know, sometimes it's very clear where what comes back is a diagnosis that's like exactly this is what's going on. And sometimes reports come back and it's not clear. It's like there's some hit, but then we're not sure because um, you know, getting a diagnosis for something like this, it's an evolving practice. So what I mean by that is we can detect variants, for instance, in a gene. And sometimes it's the first time that we detect them, but we know that it's a variant. And it's not clear yet whether that variant is what's called pathogenic, meaning that it actually causes a problem in the protein or if it's a variant that doesn't actually cause a problem in the protein. So I'm just saying this to say that genetic testing results, when they come back, sometimes it's a very clear, easy answer that goes back. And sometimes it's a little more complicated where we're in a situation of we see something and we're not sure if this is exactly the cause or not. You get definitive causes a pretty reasonable percentage of the time. But I'm just saying that that that this is the kind of knowledge that audiologists have to have, the basics, the logistics, you know, how it all works, the the process. There are um, so like the one of the subsidiaries, I think it's called Hearing First from the Obercotter. I think they have a genetics training program that's I think pretty dense that they put in in place. And so there are free resources that audiologists can use now if they say, oh man, I'm already out in my career. You know, I'm seeing these, I'm seeing patients all the time. But my, you know, my training program had little to no training in genetics, and I feel uncomfortable, you know, uh talking about these things. Well, there's there are ways to get that training now that are free. I'm not sure if the academy might have training like that as well. And so I think there are there are ways to do it for people who are, you know, who are already practicing, basically. So I think that's step one is getting comfortable. So then you can talk with families because audiologists are the ones who spend the most time with these families when after the initial diagnosis. They'll have an ENT get involved as well. Their pediatrician is involved, you know, and SLP will eventually get involved. But the audiologist for these families is kind of the main person that they're with most of the time. And so I think audiologists should um take on the responsibility for ensuring that these families have information about getting early um genetic testing. Because frankly, this stuff can be done so easily now. It's uh it's not a blood test necessarily anymore. You could just do a saliva sample and send it off, do a whole panel, get the report back. It's not complicated anymore. Um, so I I think that that could be a big change in pediatric audiology is the starting today is like the level of involvement and getting um very robust diagnostics in all patients who are coming through the clinic. I completely agree. I, you know, the training programs are hopefully starting to adapt to the times of how the field is expanding and current audiologists seeking out those resources. Because as you mentioned, the the audiologist develops such a relationship with these patients, and we are that trusted resource for them, right? And so if we are educated when the parents have questions for us, then we can feel so much more confident in guiding them to what is the most up-to-date uh pathway for them, right? So I'd love to hear if you can share information then, what is the patient experience when they're undergoing this treatment? Or is there anything that audiologists should know that families may ask us about if they're planning to receive this gene therapy? Well, yes. Let me tell you, I have a few things on my mind that would be good to talk about. So, okay, what's it like? The experience is gonna be in terms of like the uh uh engagement with the healthcare system. The beginning parts of it I think are gonna look pretty similar to what it looks like when you go through a cochlear implant process. So this is a medicine that's locally delivered to the ear, so delivered directly into the inner ear. Um, the surgery that's done to deliver it looks um almost the same as the cochlear implant surgery. So the way that the ear is accessed is the same surgical route that's used for a cochlear implant right now. Um so then you think about the postoperative care, everything like that. That's all the same. So that path, that part of the pathway looks exactly the same. After that, it diverges. Okay. So like all of that, the workup, figuring everything out, getting the patient in, that's all kind of this, that's all the same. I mean, one part that could be different is how early you do it. So with these kids, you get the diagnosis. You could you could know that this is what's happening with the kid within months of life. And now you, if you decide to go down a gene therapy path, you know the treatment, you know, that you're you're going to do. So it might happen even earlier than a cochlear implant. And in fact, you know, I hope you know the field is thinking that way to intervene as early as possible, basically. But uh then it's going to be different. So after the treatment, um these children have uh this gene therapy that's been delivered to the ear. What's going on during that time? Well, we've delivered these little um call them packages, basically, a bunch of these little packages into the inner ear fluid space. So it's like floating around in the perilymph. So you have the two types of lymph in your ear. Uh the perilymph, so it's floating around, it's these little packages that have the instructions for making uh the protein that these kids are missing. They bunches of them are floating around the ear. They'll come around and they'll bump up against the inner hair cells. The inner hair cells have receptors for these packages, so they'll pull them inside the cell. So now you have the package and the little thing it's supposed to deliver, so inside the cell. Think about it like you know, you order something from Amazon, comes in a box, you pull it in your house. Okay, it's just like that. So it's like in the cell now. It'll actually open up, the box opens, and this little set of instructions comes out in the cell. It actually goes into the nucleus of the cell. This is not like a gene, we hear people talk about gene editing, where that you're like, oh, I'm gonna change something about the genome. It's not that. It is that we have some DNA, which is the instructions for making the protein, but it doesn't um integrate into the chromosomal DNA. It actually sits in the nucleus of the cell, it makes a little circle, and it just makes protein. So think about it as like a protein factory, is what we've done. So what happens day, like we do the surgery that's delivered, and then think about the days after this is this process is happening in these children. Boom, hit the cell. Uh, the package gets pulled inside the cell, it opens up the instructions around the cell. Now the instructions are going to start making this protein. What we see if we do this in an animal model where we can measure all these things, you can't measure everything in a human, but what we see is you'll go over the course of days, uh, you'll start being able to measure that protein. So the protein will be made within the cell. The amount of protein will keep increasing over the course of weeks. So it's call it about a month. You'll see increasing, increasing, increasing protein in the cell, and then it plateaus. So it stops there and it's flat after that. Okay. Over that time period, you can measure this in animal models. So we already knew this, but I'm just gonna flip to humans again. In humans, what you see is over the course of the first few weeks, the child will start to respond to sound. This is what's totally different than an implant, right? Where the first person who's gonna know something's happening is the parent. It's not gonna be sitting in the clinic and the audiologist is at their computer and they're like, push a button, what happens now? Usually the kid cries, but like, uh, it's not gonna be that. It's gonna be they're at home and something's gonna happen, and the parents are gonna notice, wait a second, what did they just do? And so it might be we've seen videos like this that have been shared with us. The parent, you know, these parents have been testing their kids their whole life, right? They're behind them and they clap like that. And all of a sudden, for the first time in this kid's life, they flip around like, what was that? You know. So that part is fundamentally different. It's it's biological. So it means it kind of happens more slowly and then emerges essentially. So you see that happen over the course of weeks. The kids start responding to sounds. Usually they only respond to loud sounds at first. So if you go like four weeks in, it's not always some of them respond to soft sounds very quickly, but many of them it might be, you know, call it like 80 dB sounds they start responding to for the first time or something something like that. Um then by the time you get a few more weeks in, many of them are detecting softer sounds and they might be detecting like speech-level sounds, you know, call it like in the 50 dB range or something like that. And then some of these kids will, as I said, make it all the way up to normal hearing sensitivity. So they're going to start detecting whispers. But the point is that's a little more of a process. Whereas the implant is kind of, if you were managing a kid that way, it's like you wait for some time to activate and then you go into activation. And of course, you still do a workup after activation. But the point is that's kind of like all at once kind of thing happening. This is more biological, so it's going to be a merge over the course of weeks, and um you'll see it continue to improve. In fact, like even out to a year, you keep seeing improvement over time. So, for an audiologist, think about this. Not all kids in the clinical trial got to completely normal hearing by six months. Some of them might be more in the like 40 dB range or something like that. Audiologists are gonna have to be really mindful here because their hearing is changing, like it's undergoing change. So if you went in and you were like, Oh, I need to put a hearing On this kid, you know, today, you need to be very careful about that and think about how you need to monitor them because we see it's a moving target at least for a year. It might be even a moving target for longer than a year. We're going to see that, but like at least for a year, it's a it's a moving target of sensitivity improvement in these kids. The other thing I do want to do, like a little PSA. Um, so here's something that a lot of people don't know. And the data haven't all been shared yet. Some of these data have been shared, but I want to raise this to people's awareness to think about. Many people, or maybe not all, so the pediatric audiologist who would listen to this podcast might know that one thing that people sometimes observe is that when kids have auditory neuropathy, they start out having outer hair cell responses so they can measure OAEs. And then over the course of time, sometimes they lose their OAEs. And people say, why is that? Why do kids lose their OAEs with age sometimes when they have auditory neuropathy? So that's been studied more generally, like auditory neuropathy as a class. It's been studied specifically for kids who have auditory neuropathy due to this very specific uh otoferlin deficiency. And it's pretty consistent. You see that a lot of kids will lose their outer hair cell responses with age. So why? Why? Like, why is this happening? There was a hypothesis, and some people have tested this a little bit. Um, that hey, I wonder we put hearing aids on a lot of these kids. And in fact, we put uh power hearing aids on some of these kids very early because they have a lot of hearing loss. I wonder if we're actually causing noise trauma to the ear with our hearing aids early in life. We might actually be traumatizing the outer hair cells because the outer hair cells are functioning normally. The kid can't hear, but we are putting in maybe very loud sounds continuously to the ear. We may actually be doing trauma to those outer hair cells that are normal because we're mechanically traumatizing these guys. So that was a thought, and people have some data that suggests that could be true. I that that's not a uh it's not the the most rigorous studies, usually like uh small samples, you know, different comparisons, whatever. Well, why could that be? Well, certainly the trauma could do it, but the other thing people have thought about, and maybe not everybody knows this part, if it's if it depends on uh how deep you've been on the biology within the inner ear, but our inner ear has different pathways to protect it. And so one of the pathways our ears all have that help protect us against noise, is an is a pathway that goes from your inner hair cell, it goes to your brain stem. So the signal, when you have sounds come into your ear, signaling the inner hair cell, it signals, it goes to the brain stem, and then it comes back out to your outer hair cells. And when you're exposed to loud sound, particularly like a continuous loud sound, this pathway will be activated and the outer hair cells will actually be protected. And the way it does this is that this stimulation through this pathway actually does something which is shunting current out of your outer hair cells. So it kind of like dials your outer hair cells down. It's like, hey guys, chill out, chill out, chill out. It's really loud right now. Just chill out. And that protects you. So it saves your hearing. It's a constant feedback loop that you have running right now that makes your ears more resilient than they would be otherwise. These kids don't have that protection pathway, remember, because the inner hair cell can't signal the nerve. So their outer hair cells are even more vulnerable. And in fact, people have tested this now in animal models. So you can take an animal model that has the same genetic hearing loss and expose them to noise and say, hey, does it cause more hearing loss? The permanent noise-induced hearing loss if I have a deaf mouse versus a normally hearing mouse? And the answer is yes, you can cause more hearing loss, substantially more, permanent hearing loss. So the thing that I want to say, this is the PSA part for me, is like audiologists should be very aware of this, should be aware that, uh, and it's never mattered before, guys. It's never mattered before because no one was ever actually going to use the structure within the inner ear to provide hearing for these children. You were going to use a device anyway. So maybe no one cared. Because it didn't matter. But now it does matter. So, like, if you did put on hearing aids in a child like this when they were young, you are potentially impacting their ability to use their hearing years down the road because you may be doing trauma. I'll add, it's still to be seen. We've provided a gene therapy in one of these children, okay? And then now they're going to be moving through their life. We don't know yet. You need to look at longer-term outcomes. By restoring hearing, were we able to adequately restore this protective pathway in the child? We don't know. That needs to be measured still. Does there protective pathway, or was there something in development that was really important and the protective pathway can't be restored? We have to find that out. And so I'm saying that to say even once a child has a gene therapy, audiologists should be. So let's let's say they did go down this pathway. No one gave them a hearing aid before, they got a gene therapy, now they can hear, and then the audiologist is managing them and they're following them over time and they're watching this kid's hearing. They should be cautious for now because these children may not have a robust protective pathway against noise. So be thinking about high-level sound for these children. For now, I would say you also need to consider counseling parents too, right? Like your child, we don't know yet. Your child may have more sensitivity. Like, think about concerts or other things that maybe it may need to be extra focused on hearing preservation. You don't want to have this incredible therapy that, you know, now the child is able to hear and then lose outer hair cell function, you know, through noise trauma. So that's something I think that still has to be studied. Um, this is all new for the whole field. This is all pioneering. But I wanted to raise those things because I don't think it's things people would think about yet, but it's something I'm thinking about a lot, which is where our places where our current practices, because they were all built for just devices, might not be best when you're thinking about a gene therapy. There are new things you need to think about now. And audiologists are going to need to figure out what all those new things are around these technologies. Um, but in the meantime, I just wanted to raise that because it's like it is an a thing that that I think audiologists should be aware of and should think about, and we'll have to figure it all out to maximize the outcomes for these kids. Uh the other part I would say, just in general, you know, no one, there is not some established protocol for how audiologists should be managing these kids going forward. Like people over time have built protocols for cochlear implants and exactly what all the visits look like and exactly when you're going to do what, and etc. These kids have a very different type of hearing. They have natural hearing ability, but they were still deprived of hearing for the first X months or years of their life. And so, what do you need to do? The next thing I'll say is these kids get treated in both years bilaterally. For the first time, you're thinking about kids who are later in their life. So maybe they maybe it happens at a year and a half or something in a kid. You treat them bilaterally with a gene therapy. A question for audiologists is how is their binaural hearing going to emerge from that? You know, is there anything I need to do to help maximize the outcomes of for binaural hearing and hearing and noise for these children? You mostly aren't doing that right now. I mean, we have some limitations of what we can do with our devices when it comes to spatial hearing, but that's an open question. I think it's an opportunity for audiologists to say, hey, what can we do? Let's figure out what happens. And then what are the different things we can do to take it from level whatever to, you know, plus that some amount? Like, how can we maximize what these kids can actually do, given that they've all of them will have had some period of deprivation before they, you know, receive treatment, um, even if they end up with normal hearing sensitivity, you know, by age two or something. So I think those are open things right now to this sort of question that was raised. And I think to me, that's super exciting. There's super exciting things to do on the front end on diagnosis. There's super exciting things now to do that never were able to do before on the treatment side. Um, so that's all about a path that I mentioned. And man, I gave a super long answer here. I'm realizing, but like that is all the path of like deeply understanding the biology, developing new types of medicine, whatever. The other path I think is so interesting, which I won't say more about because I've talked too long, is access. So consumer electronics have gotten so great that we're now moving into a period where you can think about scaling access to different types of um screening tools around hearing, uh, even in some cases, devices that people can access to help improve hearing. So, to me, the access side, based around consumer-facing uh products, is incredibly interesting. And of course, now getting lumped into that and also prescription level stuff is AI. So there's a whole new world emerging in the other side of audiology, which is not necessarily about deeply understanding biology, but it's about improving the use of machines, um, right, in terms of how we can improve outcomes in patients and scaling them more broadly than they've ever been able to be scaled before. So if you're in audiology now, to me, you like you have great opportunities. The field is changing a lot in multiple ways. Um, and those are both like super exciting cutting edge places to spend your career. So I think that part's fun. Yeah, it is, it's an amazing time, really. In the profession, every day feels like there is something new to learn and something new to explore, which is great because I feel like there there were a few years there where things were definitely evolving, but not quite at the pace that they are now. Yeah so we're gonna wrap up. Do you have any other topics that you want to talk about before I ask the last question? Well, I think one thing I would say, um, like as a topic, because I I only alluded to this, you know, I think that the way people should think, and people certainly people in the field should think about um these like this entry of medicines into the realm of of audiology and hearing uh treatments, is that really this is just the beginning. So you have your first um program, first medicine that's been approved now uh for use. It will be it's uh it's a very specific medicine for a very specific population. Um but we and others are uh working on this across other forms of hearing loss, other forms of pediatric hearing loss, um and other forms of uh adult onset hearing loss as well. So it starts small, that's how things go, but it's building. So I think it's a it's an area worth um you know learning about and spending time on, even if it doesn't hit you directly today, because it starts small and then it works out. Because I I think there's we've made some breakthroughs here, and after those breakthroughs, then other things get easier for people to do. It's hard to get the first thing done. The pioneering thing is really hard to get done. But after you can do it, it's like whatever the four-minute mile or whatever. So, like after somebody does it, then people start being able to do it more and more. And so I think think about it as the beginning, particularly if you were early on in your career, I'd be thinking about, I'd be imagining what are things going to probably look like 10 years from now, 15 years from now, you know. Yeah, great. It is so exciting, and there is so much opportunity to come. So I I'm really excited to be at the point I am in my career where I have been able to see where we were 15, 20 years ago and will still be here to see where we are 15, 20 years from now. So great spot. Yeah. All right. So for a fun question. So when you're not at work, when you're outside of the sound booth, which you're often outside of the sound booth, when you're outside of the lab or not at your day job, what do you do for fun? What is a habit, a hobby, or a mindset that helps you stay balanced and focused? I mean, the the thing I honestly spend the most of my time doing is like hanging out with my kids. So I'm a dad, I have two kids, and um, and they are a lot of fun. So honestly, that's probably what I spend most of my time doing. And anybody who's a parent kind of gets that, that essentially you go through the hours of the day and you kind of want to fill any of them with your kids that you can. Um, so I think that's probably it. The other thing I do, like hobby-wise, I started practicing yoga a few years ago and I found it like um uh deeply helpful to me. So I love it. And uh when you think about mindset, that's what helps me get to the mindset that I like to be in, like to operate in. So wonderful. Well, thank you, Jonathan, for sharing your knowledge and your ex experiences with us. Uh, I learned so much during the podcast today. I I actually can't wait to listen to this all again and um really share it with my my colleagues because I think there is so much that's going to happen in the next few years, and your insights have been invaluable for um my career as well as um, I'm sure everybody listening. Yeah. Yes. Yes, thank you. Thank you very much. It was it was a pleasure hearing from you and and learning all about the work that you've been doing. And I'm feeling invigorated for the future of audiology. I think there's so many exciting things, and each time we have someone new on, I'm like, I can't wait to learn more about that topic, even than what we shared today. And then you certainly gave us a lot to think about. So we really appreciate your time today. Well, hey, it was great to be with you both. That was a lot of fun. Um, so I feel invigorated too. And to our listeners, thank you for listening to Science Meets the Sound Booth, sponsored by the AAA Foundation. We hope today's discussion provided clinically relevant insights you can apply in your practice and professional development. For references, additional resources, and future episodes, please be sure to follow the American Academy of Audiology to stay connected. If you found this episode valuable, consider sharing it with audiology colleagues, friends, and students. Until next time, this is Science Meets the Soundbooth, translating research into better patient care.