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EHDI Annual Conference
Regeneration/DB Lunch Session
March 19, 2024
12:55 P.M. - 2:40 P.M. CDT
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	>> KARL WHITE:  Welcome, we're delighted to have all of you here and grateful you're willing to spend some of your lunch hour with us.  
	Talking about an important topic.  
	If you look back historically at how identification of infants and young children with hearing loss has evolved, it has consistently focused on what is the best clinical practice, where the science is taking us, and as we implement those things, sometimes we find that it doesn't work as well as we thought it was going to.  
	There really has been a very long history of innovation and then change and discussion.  Sometimes that's worked better than other times.  
	And we hope that around this topic our main goal for this afternoon is to stimulate a lot of discussion among people.  This is a tossing that is -- it's a topic that's important.  But it's not a topic that's going to be fully implemented in the next two weeks.  
	So we're trying to get a head start on raising what the issues are.  And the questions are.  So that we, as an EHDI community, can talk about this.  Discuss it.  
	We have three very distinguished panelists with us today.  Our first speaker will be Dr. Aaron Tward, who is an Associate Professor at the University of California San Francisco.  But also the Chief Scientific Officer for Akouos.  
	Our second presenter will be Vassili Valayannopoulos, who is the clinical lead for Auditory Sciences for Regeneron.  
	And then our third speaker will be Teresa Blankmeyer Burke, who is a professor of philosophy at Gallaudet University.  
	They will each make relatively short presentations.  And then we've held a significant amount of time at the end for questions and answers.  We'll be doing those questions and answers a little differently than we have done it so far at this conference.  Those of you who are signed on to the conference app, the cVent app, which I hope is nearly all of you, will see that you were automatically enrolled in this session.  And there's a button there that says ask a question.  
	And so if you have a question while you're listening to the presentations, type it in, send it off.  We have moderators here who will be curating those questions, eliminating duplicates, they will pass them to me.  And then I'll direct the questions to the members of the panel.  
	We use that option because we want everyone to have equal accessibility.  We've seen in the past that some people are a little hesitant to come up to the front to ask a question.  
	Or may not just want to have that kind of spotlight on them but would really like to text in a question.  
	So we anticipate that there will be a lot of questions around these presentations.  We don't have as our goal that we will resolve all of those questions in an hour and 15 minutes today.  
	We look at this as the start of an ongoing discussion.  
	And we will get to as many questions and answers as we can during that time.  
	But I apologize now for those that we won't be able to get to.  So with no further ado, we're going to turn the time over to Aaron Tward to introduce the topic and start the discussion.  
	>> DR. AARON TWARD:  Do we have the remote?  
	Terrific, thank you so much for the opportunity to chat today.  I'm going to tell you about some work that we've had going on, which is very exciting.  On gene therapy for hearing loss but I first wanted to talk a little bit about the importance of genetic testing and the diagnosis -- in the diagnosis of hearing loss.  
	Just by way of disclosures, in addition to being an academic, I am an employee of Akouos, which is a wholly owned subsidiary of Eli Lilly I have a few other disclosures but I will point out these views articulated are not necessarily those of one of my employers, Eli Lilly so if I say something controversial that's my academic hat on.  
	And then this is a standard legal disclaimer.  
	So we know that worldwide probably if you counted up somewhere around 1 of 500 newborns is born with very substantial hearing loss.  
	Of those children that are born, about 65% give or take, depending on the study that you read, are attributable to genetic causes.  And about 35% are from some other etiology like congenital CMV, ototoxicity or hyperbilirubinemia.  
	Amongst the subset caused by genetic causes the majority is what we would call nonsyndromic that is it confers hearing loss but not other conditions in the body that we identify whereas the remainder are part of syndromic causes in addition to hearing loss there are other conditions in the body that can affect things like the heart, the brain, kidneys, et cetera.  
	So one question is, why do we think it's important to have genetic testing?  And let me clarify here that by genetic testing in this context, I mean diagnostic genetic testing.  
	So this is not preemptive screening of babies that have not been identified before but rather if you already know that you have hearing loss, that you can get this in order to get better information about what the cause and the nature of that hearing loss is.  
	And in particular, there are a number of good reasons why having this information in hand can be beneficial to the care of individuals that have hearing loss.  
	The first I mentioned before, which is for evaluation of syndromic causes of hearing loss.  
	So when babies are born, and they have hearing loss, in the absence of having a genetic test you might not be able to know that that child has Usher syndrome for example and is expected to develop vision loss progressively and having that information in hand will greatly change the way that you think about the care of that individual and the nature of the team of people that you're going to bring together to care for that individual and what their communication choices are going to be.  In addition some things would predict cardiac abnormalities for example like sudden death that you can preempt and prevent sudden death in cases of things like (inaudible) Nielsen and I would say these things of things are one of the primary reasons why it's important to have this type of diagnostic information.  
	The second is in a lot of cases you can prognosticate for hearing so you can predict whether or not you expect the hearing will stay roughly where it is right now or if it's going to progress and in some cases the rate of progression.  
	One important example is there's a gene called SLC26A4 which caused nonsyndromic hearing loss and in the case of SLC26A4 half of all the children that have this particular -- these variants will pass their Newborn Hearing Screening and then lose their hearing very, very rapidly so they are at very high risk of potentially being missed by screening programs and not getting to appropriate services in a timely fashion.  
	An additional piece of information is inheritance risk.  You might be able to predict, what are the chances that another child in my family might have the same condition?  And also with other family members.  If you have something that's going to be late onset, you might not know, what are the chances that your brother or your sister or your cousin might also have a progressive hearing loss.  
	Then finally, I think it's important for personalized medicine.  So I'm going to talk about gene therapy in particular.  And genetic testing is an obligate entree to gene therapy trials and is one of the critical eligibility criteria.  Because the nature of the gene therapy is tailored to the individual genetic factor that you have in the individual.  
	Genetic testing, although it is very effective as a diagnostic test, that is the diagnostic yield is on the order of 40 to 50%, give or take.  And by diagnostic yield I mean what is the chance that if you have a newborn that has substantial sensorineural hearing loss that you will be able to identify the cause, it's probably on the order of about 40 or 50% and getting better as we get more information.  
	It is much less utilized than other things like EKG or CT scans that have less diagnostic yield and in some cases are less informative.  
	Now, it's not an either/or.  These things should be done, also, it's a complementary technology.  But genetic testing should not be the last part of the algorithm.  Or an afterthought.  
	Finally, I will mention there are over 200 different genes that have been identified as being contributing to hearing loss.  Those genes are affect people in different individual ways.  And knowing which one you have will allow us to prognosticate to a certain extent about what you can expect from your hearing loss in particular.  
	I will also mention that from my perspective as a molecular biologist and somebody that makes drugs, these different individual genes are produced in different cells within the inner ear.  And therefore, having an understanding of what they are doing at the molecular level informs our ability to be able to create new medicines on the basis of this knowledge.  
	So gene therapy, which I will define broadly as using some vector to deliver genetic material into cells in the body in order to have some salutary impact on the impact of the functioning on those cells is not brand-new.  
	People have been trying to do gene therapy types of things for many, many years.  And we already have multiple approved gene therapies in the United States.  I have listed five of them here for conditions like spinal must collar atrophy, hemophilia, as well as RPE65 mediated retinal dystrophy and all of these things I've put up here use a very vehicle called adeno-associated virus to the one I'm going to be talking about momentarily.  
	I just throw this up here briefly to mention there are a number of things we are working on the first thing we have been working on which is most advanced is gene therapy for individuals that have otoferlin mediated hearing loss which I will describe more.  On its heels we've got programs for CLRN1 as well as vestibular schwannomas and further is those with individuals with GJB2 variants.  
	So what is otoferlin?  So otoferlin is one of those 200 genes that is known to cause hearing loss.  
	When particular variants in that gene are present and the particular nature of the hearing loss that is caused in individuals that have variants in the otoferlin gene is in particular an auditory neuropathy phenotype so children are born with present Otoacoustic Emissions typically and absent ABRs.  
	This is extremely important from a newborn screening perspective because a lot of these kids are missed by programs that exclusively screen based upon Otoacoustic Emissions alone and can present late to care and communication options and have never been exposed to either a medical Care Team or sign until much later and this is a major concern.  
	What otoferlin does in the cell, the way that hearing works normally is that sound comes into your ear, hits your eardrum.  
	Goes through the little ear bones behind your eardrum to a hollowed out space in the bone which is filled with fluid called the inner ear.  
	Once the vibrations are in the inner ear, they impact these cells called hair cells within the cochlea.  Where those cells will then convert that mechanical energy into an electrical signal.  And at its base in response to that electrical signal will release a signal called glutamate that then sends the signal onto nerves that go and send the signal to the brain.  
	In individuals who lack a functioning copy of otoferlin, those chemicals cannot be released by hair cells.  And therefore, there's no onward transmission of that signal to the brain.  So the brain does not perceive the sound.  
	So what we're talking about doing here for gene therapy and one thing that I want to emphasize, the number of individuals who have these otoferlin variants is a small fraction of the total number of individuals who have hearing loss.  
	So the idea of gene therapy here is that we are going to take a functioning copy -- sorry.  
	A functioning copy of the otoferlin gene.  Place it into a virus.  In order to deliver that.  
	Inject it into the ear.  And then have that genetic material delivered just to the cells within the inner ear.  In order to potentially restore physiological hearing to individuals.  
	That have this particular mutation.  
	A couple of things to mention about gene therapy in this particular case.  
	The doses that we are using here, because we are delivering it locally, are on the order of about 10,000 fold less than the doses that are used for some of those other gene therapies that I told you about.  Which are given systemically so the risk of it getting out of the ear and having any major impact on other parts of the body is very, very small.  
	The other thing to mention about this gene therapy is that this gene therapy does not impact the germline we are not talking about something that can be transmitted to children.  This is something that is just delivered directly to the ear and that stays within the ear and affects the function actually of only that individual ear.  
	So in order to get the DNA in, if you just put DNA on top of cells, the cells won't take it up and it will just get degraded so you need some sort of vehicle to deliver that genetic material into the cells.  And in this case we are using a non-pathogenic virus called adeno-associated virus that's had its genetic material removed and replaced with the functioning copy of this gene.  
	Just a technical point, because this gene is actually too large to fit into a single virus we had to split it into two parts, into two separate viruses which are then injected and when both of those viruses go on to the same cell their genetic material can then recombine to create a full length copy of the gene.  
	The administration procedure was the result of many years of work from a lot of our colleagues at Akouos.  
	And the nature of our surgery is relatively minimally invasive.  So you just gently lift up the eardrum it's done through the ear canal no incisions behind the ear no drilling on the mastoid bone you lift up the eardrum.  
	You expose what's called the round window membrane which is an entry point into the inner ear then you inject the genetic material through the round window membrane into the space of the inner ear.  
	We create a little vent hole in the stapes footplate that allows the fluid of the inner ear to be displaced and replaced by the fluid containing the viruses that we are putting in.  
	This is just a brief point to mention that when we do this, we are able to deliver that genetic material to nearly 100% of the inner hair cells in the inner ear and we have proved this in both mice as well as non-human primates.  And we can do this very efficiently using the particular viral capsid or shell that we have selected.  
	We have mice that look very, very similar to the humans that have variants in otoferlin and these mice like humans have profound hearing loss but presence of Otoacoustic Emissions and we were able to show in the mice that when we deliver this virus with the functioning copy of the gene, we are able to restore hearing based upon awe Auditory Brainstem Response measurements back to within the range of wild type mice that don't harbor these variants.  
	So with that background, I will move on to show you a little bit of preliminary data that we have generated from the clinical trial that we are running currently in humans that -- for individuals with otoferlin mediated hearing loss.  
	So the clinical trial design for this initial Phase 1-2 trial is a relatively limited number of patients overall.  And is divided into a few different cohorts.  
	The first cohort was in two children ages age 7 to 17.  That was largely for regulatory reasons.  
	And then subsequent cohorts we can recruit children down to age about 2 or so.  
	With the hope ultimately in the future of extending the ages beyond that.  
	The important eligibility criteria, you have to have a diagnosis where you know that you have mutations in the otoferlin gene confirmed by genetic testing.  
	Absent Auditory Brainstem Responses.  But the presence of Otoacoustic Emissions.  And not have bilateral cochlear implants.  
	The presence of Otoacoustic Emissions is extremely important because that tells us something about the integrity of the cochlea and as the cells of the cochlea become lost over time, you lose the Otoacoustic Emissions and therefore the cells that you would be trying to deliver this genetic material to are no longer present and you would not benefit.  
	So the first two participants in the trial are as follows.  Our first participant was an 11-year-old child who came from our Barcelona site.  He was male.  He grew up in Morocco and had minimal access to services, minimal access to sign, minimal access to hearing care really of any kind.  Then when he was 8 years old moved with his family to Spain where he was now given proper services and started acquiring sign, which he does primarily for communication now.  
	The administration was done in the right ear on October 23rd.  And we've got data through the Day 60 visit.  
	The second participant was a child who is 8 years old from our site in Taiwan.  He received a cochlear implant at age 3.  Then had this administration five years later.  And overall he had done well with his cochlear implant with good language development.  
	I will just mention that the Otoacoustic Emissions for both of these participants because they were a little bit older and obviously I think going younger would probably result in more robust effects showed that both of these participants, their Otoacoustic Emissions were present but far from perfect so their cochleas were likely in a pretty substantial state of decline.  
	So the most important thing in this trial, this is primarily a safety trial, and so the good news is that neither of these participants had any serious adverse events.  There were minor events that were related to the surgical procedure which we would expect for any minor surgical like this but overall they are doing very, very well with no substantial long-term sequelae.  
	So what are the results?  So for our first participant, here is a picture of his baseline behavioral audiogram so you can see that across different frequencies he had essentially no detectable behavioral audiogram at baseline and his ABRs similarly showed no detectable hearing at baseline.  
	30 days after administration he had substantial restoration of his pure tone averages.  With some of them even at 30 days out at high frequencies within the normal range of hearing.  
	And these have continued to improve out at 60 days.  And we anticipate potentially continued improvement beyond that but it's early days yet so we'll see as time progresses.  
	With regards to his click ABR threshold you can see in both his Natural History Study and his baseline study there was no response on his click ABR thresholds at Day 30, they were about 40 decibels and by 60 days they were back to the normal range.  
	Our second participant, who you recall had Otoacoustic Emissions that were actually even less detectable than the first at his baseline you can see his audiogram here, he had minimal detectable hearing on audiograms by Day 30 he had substantial improvement.  We're continuing to monitor him for continued improvement.  
	But the part that I found most impressive, because this child has a cochlear implant, and has developed some spoken language, as well, even at the Day 30 time point, he has started to develop open set speech recognition in that ear.  
	And we are continuing to monitor that to see how this continues to develop with our additional participants.  
	So we're continuing to recruit participants now and we're excited to report back as more data comes in but I just wanted to summarize that this particular candidate or investigational therapeutic achieves high levels of expression of this gene.  The initial clinical data demonstrate the potential for restoration of hearing to within the normal range as early as 30 days following administration.  
	Otoferlin can restore hearing in even these older children.  And that the presence of Otoacoustic Emissions is likely an important factor in assessing for potential benefit and the clinical trial is actively recruiting eligible participants currently include children as young as 2 years of age.  If you go to clinicaltrials.Gov and search for Akouos you can find the trial or go to our website.  And with that, I will thank you.  
	>> VASSILI VALAYANNOPOULOS:  Good morning, everyone, thank you very much, Karl, for the opportunity to speak here.  
	I'm going to shift a little bit gears and talk a little bit more about gene therapy in general.  
	My background is in biochemical genetics so I'm pediatric biochemical genetics and pediatric neurologist by training I dedicated 20 years plus of my career in diagnosing, managing patients with various rare genetic conditions.  
	And also in my industry career I focused my efforts on rare disease drug development including gene therapy.  
	And I am the Executive Director and clinical program lead for Regeneron Pharmaceuticals based in Boston.  
	I want to emphasize that this presentation is primarily intended for healthcare, health-related professionals and researchers.  
	And the goal of this presentation is to share important disease state information, including with respect to genetic testing for hearing loss.  And updates about our ongoing studies.  
	So I want to start just reminding some key principles of gene therapy, some of which you heard before.  But I want us to be all on the same page of what we are talking about.  
	So gene therapy in general is the use of genetic material to treat or prevent genetic conditions.  
	This material is usually DNA.  Or RNA.  It contains the information to instruct cells to produce proteins.  
	The most frequent approach, the one we'll be talking about today, is gene addition in which it consists in delivering a copy of a working gene into the nucleus.  
	What happens here is that copy of this additional gene stays in the nucleus but doesn't integrate in the host genome.  
	So there's no potential for this gene to be passed into other cells or also in the germline cells.  So there's no theoretical risk for the offspring.  The caveat of this is when the cell expires, so the benefit of that additional gene disappears.  
	This contrasts with other approaches such as gene editing which replaces part of the DNA with another one and that can be passed on through cell division to other cells and has different risks.  But also different longevity.  And is more suitable for conditions that involve dividing cells.  
	Now, as you heard from Dr. Tward's talk, the delivery of DNA and RNA viral and knob viral vectors or genetically modified cells today we'll focus more on viral vectors and specifically we'll talk about AAV-based gene therapies.  So I want to give you a little bit of an overview of the history and some of the advantages and potential caveats of AAVs.  Which as you heard earlier stands for adeno-associated virus.  
	What are AAVs?  They are small non-enveloped DNA viruses that belong to the parvoviridae family they have been isolated a while ago and one of the first things that was identified is that these viruses are able to infect cells without the help of another virus that's called a helper virus.  
	And also they are very, very common.  So most of us have already have been exposed to this virus, if we do some blood testing, we'll realize that over 50% of us have been exposed to some kind of AAV over time.  And most of the times we might not have had any symptoms at all.  
	Now, scientists discovered over time that various capsids, whether they are natural AAVs or some of these capsids that we can engineer in a laboratory have variant cell and tissues.  In the look at the left panel you can see all of the variety of organs and different serotypes of AAVs that can efficiently actually infect these organs and transfer their genetic materials.  
	So this has led to various approaches of gene therapy that you heard a little bit earlier.  And we know that many of those are approved to treat hemophilia in babies, spinal muscular atrophy and retinal dystrophy and there are about 100 others that are in clinical trials right now.  
	Now, what are the advantages of AAVs?  One of the key advantages is that they create a stable transfection of dividing and non-dividing cells.  They have a low risk of integration in the host genome and they have a low risk to what we call mutations in germinal cells that could be passed up to the offspring.  
	What are some of the caveats of AAVs?  Again, because moth of us have been exposed to these viruses before is that when they are injected and we do not know if prior -- we have been exposed to these viruses or not, it can trigger an immune response the same way that if you've had a prior disease, you have antibodies raised against this infectious disease that can trigger some inflammatory reaction.  
	And then at high doses it's been shown especially when administered through systemic routes through IV routes they have been shown to have a certain toxicity.  
	The other limitation that is very relevant for our discussion today is that their clone capacity, the capacity to integrate a new genome that could be the therapeutic gene that we're trying to impact here is limited to around 4.5 kilobases which for a gene like otoferlin as we see it's way too small which explains some of the strategies of breaking this down into two pieces.  
	All right.  Now why this is important for the inner ear.  And why the inner ear makes a lot of sense.  And why there are so many groups that have been interested in this.  Is because it's a smaller and closed compartment that requires actually naturally a lower dose to be able to transduce a large number of cells.  
	There's better control of the contents.  What we heard earlier from Aaron's presentation.  
	So the experiences that AAVs will not get out of the ear and be spread across the body.  
	And there's going to be a high ratio of drug product to the target cell numbers because the target cell numbers is more limited.  
	With regards to exposure as we said, there's minimal distribution outside the ear, which actually allows a better toll -- tolerability in general the ear is considered immune privileged space whether we have existing antibodies against AAVs or not might not impact our ability to receive an AAV vector and not trigger an immune response in the inner here.  
	And then regarding the target cells, it's a single location.  
	It's surgically accessible.  We'll talk a little bit about the way we do this a little bit differently than what Aaron showed you.  
	And actually our target is non-dividing cells, which promote more of a durable expression.  It has a low risk of integration into the genome.  
	And very low risk of inclusion as we mentioned in cells to the offspring.  How does it work I'm sure you're all familiar with Amazon Prime.  How it works, you order a package, it arrives to your home and then you open it and here is your new machine.  So gene therapy works pretty much the same way.  
	So actually who delivers your package is not Amazon Prime but it's an AAV vector.  Instead of bringing it to your home it goes into the type of cell you select so here for example we selected the inner hair cell for otoferlin.  
	And then what it makes actually creates a new machine that is able to produce the missing protein.  
	So it is as simple as it shows.  
	So when we translate this into animal experiments, so we take -- we took these mice, they have this name quite exotic name Q828X which is actually short for the time of the vector of the gene they carry as you can see in the middle picture these mice when they are untreated they don't express the otoferlin protein which is the nice round same circle that you see on the right heterozygous animals who have normal hearing show.  They have a very flat Auditory Brainstem Response.  
	So these animals cannot hear at all.  
	While their heterozygous animals so the ones that have only one copy of the mutation gene can hear -- of the mutant gene can hear normally.  
	So what we did was took the untreated animals.  We inserted the AAV viral vector with the two fragments of otoferlin that we engineered in a way that they can recombine, meet each other and produce a fully functional protein ones in the inner hair cell we did this by using what we call a promoter which is something that allows the expression in specific hair cell types.  As you see on the right-hand side panel, the treated animals express again otoferlin.  
	So that nice red line that you see there.  
	And most importantly, their ABR is restored close to what a normal ABR would look like in the healthy animals on the left-hand side panel.  
	So that was the first signal that actually this is something that we could leverage and use.  For human clinical trials.  
	And some of the key advantages of this approach was the very cell selective suppression to the inner hair cells.  
	You are all aware and you heard it several times in this conference what otoferlin-related hearing loss is.  So I want to emphasize one key point that allows us to identify these individuals early in life as babies is the discrepancy between a flat ABR on the left-hand side panel and present Otoacoustic Emissions, which also emphasizes the difficulty sometimes to take these babies through newborn screening because if the hearing newborn screening is done with OAEs they are likely to pass it.  If it's done with ABR then they will have an abnormal test and they will be identified.  
	Also I want to emphasize that these two tests actually express the function in inner hair cells.  So that's the ABR.  
	And the Otoacoustic Emissions actually showcase outer hair cell function so here our target is mainly inner hair cells but we know that these individuals will lose over time their outer hair cell function, as well.  And as mentioned previously, the loss of outer hair cell function might be an indicator on the overall status of the cochlea.  And that's why we did implement also in our clinical protocol presence of Otoacoustic Emissions as one of our inclusion criteria in the clinical trial.  
	So we were more confident that we have given these individuals a best chance to see a response through gene therapy.  
	Moving on, on to the clinical trial.  And I want to emphasize that this gene therapy that we developed for the permanent-related hearing loss it's called DB-OTO an investigational gene therapy and is not approved for use outside of clinical trials.  So we developed a global first in human Phase 1-2 trial.  DB-OTO in infants and children with otoferlin mutations and profound hearing loss in the U.S. in the UK and Spain.  
	Key inclusion criteria are pediatric patients.  
	We also had an age stagger in the U.S. we had to start with older patients.  In other geographies, the regulators allowed us to start from the get-go in younger children.  And so that the study is ongoing and enrolling patients right now.  
	So in this study, we have first part which is a unilateral injection of gene therapy.  So the participants can have a cochlear implant in the other ear or a cochlear implant can be chosen to be placed by their investigator during the same surgery.  
	In Part B, once we have confirmed the safety and efficacy of DB-OTO in one ear, we plan to do a bilateral injection with a selected dose.  So both ears will be dosed during the same surgical procedure.  
	Of course as in early Phase 1-2 trials what's paramount is safety.  But also we want to make sure that this provides some benefit for participants, as well.  
	So this is the overall design of the study.  So we have a baseline in which we verify all the inclusion/exclusion criteria.  We assess all the hearing functions.  And then we get into the perioperative period in which surgical takes place I will explain in a minute how we do this.  
	The participants are covered by a course -- by a short course of steroids to prevent any potential inflammatory response post surgery and accelerate healing.  
	And then they start entering a short-term follow-up phase that lasts in all 72 weeks.  And then each one of these patients enter a long-term follow-up that goes all the way up to five years.  So we can assess the long-term safety, tolerability and of course efficacy of this gene therapy.  
	And you saw on the bottom briefly the clinical trials number where you can find more details around the design of this clinical trial.  
	So a little bit about the surgical technique employed here.  And so we chose a different approach than the one that you heard before.  
	For us, it was important to choose delivery method that was widely available and that we could train a lot of surgeons around the world minimally.  
	So we took the route of the cochlear implantation that involves an incision behind the ear.  What we call a mastoidectomy that allows to expose the facial recess and the round window.  So this is the little hole that you see on the middle panel.  
	And then we do an opening in this round window.  We insert a catheter, which is a repurposed IV nutrition catheter that's used for premature babies.  
	And then we do a slow infusion around 15 minutes through the round window.  
	Before starting the infusion, we do another small incision in the lateral semicircular canal so as you can see on the bottom right, it allows the fluid to escape and not cause any hyperpressure in the inner ear.  
	And this whole thing takes about 15 minutes.  Then the surgeon closes all the surgical wounds.  And then generally the participant can go home the same evening.  
	Now I'm going to switch gears and talk about our first experience which occurred in an 8-month-old female with congenital bilateral profound hearing loss and auditory neuropathy that was screened qualified and enrolled in this trial.  
	She had an older sibling that had been diagnosed previously with otoferlin mediated hearing loss that was treated with cochlear implants.  
	The parents wanted to participate in the clinical trial so that the child was enrolled after verification of all inclusion/exclusion criteria.  
	At 10 months, she received a single unilateral dose of DB-OTO so this is the dose we used 7.2/10 to the 12th which again as emphasized before it's 10 to 100 times less than what's given in systemic gene therapies and a cochlear implant was placed in the left ear during the same surgical procedure the procedure was uneventful followed the protocol with antibiotics, steroids and the patient was discharged the same evening and able to go home.  
	Now, first of all, safety, as we said so we are 12 weeks not know but at -- not now but at last data caught that we did and actually we haven't observed anything related to DB-OTO in a Phase 1/2 clinical trial we capture every little event that happens, so any infection, upper airways infection, any issues vomiting, et cetera, this is something we monitor and we disclosed all of this here.  Nothing very serious as you see.  And all of these were qualified as unrelated to drug product or to the procedure.  
	We were more particularly interested to look into adverse events related to vestibular symptoms such as dizziness, falls, et cetera.  
	We have not seen any of these.  Because every time we open either the round window or anything else that touches the cochlea or vestibular system there is a risk for this.  For this patient we have not any of those -- we have not observed any of those.  
	We did record an infectious episode in the other ear the one that received the cochlear implant but obviously this was unrelated to the surgical procedure for the gene therapy or to the gene therapy itself.  
	I want to switch gears and talk a little bit about the early results as you all know, the audiogram is the traditional measure of hearing.  And actually gives you an idea of where you know an individual with hearing loss is situated with regards to the severity of that hearing loss.  
	And so the more we're on the top of this curve, on the x-axis, we have all of the various frequencies and on the y-axis all of the intensities so the more we're on top of this curve the more we're closer to normal hearing and of course with regards to frequencies, some frequencies matter more than the others.  
	And what is included in that yellow banana, I know many of you know this, is more the frequencies and also the intensities that are used to understand perceived speech and they are crucial for an infant of this age to develop language.  
	With that in mind, I'm going to show you how this looks like over time.  
	As you can see on the left-hand side panel, at the beginning, this child had no response for up to 110 decibels.  
	So no response in pure tone audiometry at all.  And already at four weeks and six weeks we start seeing a change.  In getting outside the profound hearing loss zone.  And then nicely at 12 weeks landing in the moderate hearing loss zone.  
	And when we compare it to the non-treated ear as expected the non-treated ear did not experience any change in these hearing thresholds.  
	Now of course we wanted to corroborate this with a more objective method, which is the Auditory Brainstem Response.  I know most of you are very knowledgeable with what this is.  For those who have not seen this before, this is a way to measure the electrical waves that are generated in the inner ear.  When a sound reaches the inner ear.  And actually the different waves or waveforms that we study in this type of assessment allows to show the progression of the electric signal throughout the different structures.  
	Starting from the spiral ganglia.  All the way to the auditory cortex.  
	And here the responses, the threshold we observed for this child.  So as you can see on the DB-OTO treated ear they corroborate nicely with what we observed in pure-tone audiogram.  So we at the beginning there was no response.  And then there was a slow response between 4 and 6 weeks.  And a more overt response at 12 weeks positioning the hearing thresholds in the moderate hearing loss range and conversely the non-treated ear has not shown any change in terms of ABR thresholds.  
	Most importantly, I mean, these are objectives or tests that require participation of a young infant that can be challenging sometimes.  But what did the family observe?  And what did the audiologist observe?  So they did observe that the child could hear sounds even when the cochlear implant in the contralateral ear was turned off.  Indicating a good hearing equity in the DB-OTO treated ear.  The parents also indicated that very often they noticed that the child's voice was less screechy when they turned the cochlear implant off.  And they were very inclined to do this more frequently.  
	The global auditory skill development was formally assessed on the Auditory Questionnaire as you can see on the graph on the right-hand side panel she has a normal auditory development of a child of that age.  
	And up to date continues to make progress.  And the parents tend to use less and less as they self-reported the cochlear implant.  
	I want to also emphasize that this is not the only clinical trial that is happening here.  
	So there is a first report that came out this year from China reporting two children that were treated with a single dose of another AAV otoferlin construct, 5-year-old and an 8-year-old.  Both of these children had profound hearing loss.  And both showed nice recovery of the hearing thresholds over time, almost 1 month after they received treatment.  
	And both assessed both by ABR and pure tone audiometry and also from a safety perspective no serious adverse events occurred and no treatment-related adverse events were reported.  
	Similarly there was another publication a little bit later reporting 6 children with severe to complete hearing loss with confirmed otoferlin mutations.  That's another Academic Center in China.  In Shanghai.  They reported recovering 5 out of the 6 children with a 40 to 57 dB reduction, the ABR thresholds and also speech perception improved in patients who had hearing recovery they reported a certain number of adverse events, no dose limiting toxicity or serious adverse events occurred with this drug product.  
	And then we heard from Aaron that the results earlier from Akouos.  So I won't detail those.  
	But I do want to summarize the findings up to date.  
	So we have four studies so far that have reported a positive first in human experience with a AAV-based otoferlin gene therapy.  Some of them reporting experience for at least 12 months post gene therapy.  
	All these studies have demonstrated good tolerability preliminary safety and efficacy of AAV dual vectors designed for cochlea delivery of the otoferlin gene all but one participant most importantly have shown improvements in hearing thresholds in the order of 30 to 70 decibels improvement or more many of them normalization of the hearing thresholds.  
	Many of these patients have shown clinically meaningful improvements in speech perception and language development.  Recent updates in scientific conferences have reported additional data in a total of 17 participants.  Across studies.  Some of which already received bilateral gene therapy.  
	So in summary, these are early.  But certainly encouraging data that warrant further investigation of AAV-based otoferlin gene therapy in other children and infants of various ages.  And we have currently 5 studies that are actively enrolling participants in the U.S. and Europe and in China.  Thank you very much for your attention.  
	>> DR. TERESA BLANKMEYER BURKE:  Hello.  Well, I would like to start with a communication check, can everyone see me okay?  
	I would also like to add that my signing style is more oriented toward English.  
	So we will have the two ASL interpreters to make sure we have clear and accessible communication.  
	The topic of mine discussion is Ethics, Language and Community, The Importance of Genetics and Gene Therapy for Early Hearing Detection and Intervention.  
	Next slide, please.  
	I would like to pause for a moment to let Deaf eyes take a moment to read the slide.  
	I would like to introduce myself, my background and then explain the ethical integrative of language access for all Deaf and hard of hearing children, rather hard of hearing children.  Informed consent and some ethical considerations involved with that, regarding gene therapy.  
	And the existential question coming out of this is what does gene therapy and heritable human genome editing mean for the Signing Deaf Community's continued existence.  And that is a heavy one.  
	This isn't easy to address.  But my hope is that we open this discussion and that is my goal for today.  We won't be completing or wrapping up this discussion today.  Because there will be no easy answers.  
	But I would like to open this dialogue.  
	I'm doing an interpreter check.  Are we doing well?  
	Excellent.  Next slide, please.  
	So my story begins with my mom noticing that I might be hard of hearing or Deaf.  So she took me for testing.  And found that I was hard of hearing.  
	At the age of 5 years old, I received hearing aids.  And I repeated kindergarten.  
	I grew up using speaking and speechreading.  
	But I was lucky because at the time, and this was really before we recognized hard of hearing as a category, so I had access to written English.  And I was thankful to have that linguistic access early on.  
	All of my education from kindergarten up through my PhD and doctoral work was in mainstream education.  
	I started off using Signed Exact English.  I didn't know what the difference was at the time.  But when I came to meet several Deaf people, in my older years, I realized that I felt that sense of absolute connection.  
	And learning ASL changed my life.  
	It doesn't mean that I disregarded my assigned exact English skills or got -- Signed Exact English skills or got rid of English altogether but I do value both and it's an imperative part of who I am I do know several languages my Spanish although a bit rusty I can read and write in Spanish.  
	But my primary language is English.  
	Next slide, please.  
	That was my Deaf introduction.  
	I now take you to my hearing introduction.  And you'll find my background listed on this slide.  
	You can see that with my Bachelor's Degree, I started off researching biology, ethics and society.  I was very interested early on in that convergence of those fields to see how exactly we use science in our everyday application.  
	At the time I hadn't made a connection with Deaf bioethics but I just found it fascinating in general.  
	When I started my doctoral work and wrote my dissertation, I wrote it about the question of what is ethical in gene therapy.  And can Deaf people make decisions to have Deaf children.  
	And have that support through ethical reasoning.  
	I am certified in mediation at the -- I also served on the bioEthics Committee on the UNM School of Medicine and at the Georgetown Kennedy Institute of Ethics.  
	I serve as a support.  I'm monitoring the language and the sign language at the same time so I'm sorry about that.  
	To give you an example on why mediation is important in bioethics, I called a hospital Ethics Committee and I went into a room with other people in the meeting.  I said suppose we have a family who has four adult children and you have a mother who is on life support.  Two of the children would like to remove the life support and two want to continue it.  
	How do you mediate this kind of discussion?  It does become challenging and complex but this topic now that we're facing today is perhaps more challenging.  I've also been involved with different policies and many, many groups over the years related to genetic therapy, gene editing, genetic technology and as it applies to the Deaf Community and you can see that here on this slide with my background.  Next slide, please.  
	So why am I here?  
	I'm here because I think people can have an open discussion about hard topics.  
	And I think we need to start with the disability model.  
	How many of you are aware of the medical model of disability?  Great.  And some of us are aware of the social model of disability.  
	But they really diverge.  
	My goal is to have them converge at some point.  So that we can have Deaf flourishing.  Next slide, please.  
	What do I mean when I say flourishing?  Well, what do you think when I say the word flourishing?  Next slide, please.  
	Reflecting on what flourishing means for the Deaf child is one aspect.  
	What does it mean for the family of the Deaf child.  
	Think about flourishing in the Deaf Community.  
	And also what it means for a democratic society.  
	We all have extremely different perspectives of what flourishing means and what it means to do so.  
	And that's perfectly fine.  
	Because what we're here to do is to have a discussion about what's important.  
	And that's not going to be simple.  
	Next slide, please.  
	I would like to emphasize three things in regards to Deaf flourishing the three areas of focus are language, identity and community.  
	We really want Deaf children to get appropriate language support.  And that must happen.  
	For example, with the boy from Morocco who had the ototherapy, he hadn't had any language exposure until he was eight years old.  So what his ability to communicate really would be after eight years old, he may get some access to sign language.  He does now have the ability to hear sounds.  But that's not necessarily language.  
	What this child receives in support is essential.  And that's essential to all of us here in this room I think all of us in this room agree that that child needed support early on.  
	Would anyone disagree with that?  I would say not.  
	So where do we start identifying that?  
	I would like to also say that there's some interesting philosophical discussions to come out of this and I'm a philosopher by nature so I will add some of that in.  
	There are vast differences between full access and partial access to language.  
	Let me give you an example.  
	My access to written English was full and complete.  I could read.  I could understand and communicate fully in English.  
	I never had to guess what a word was.  I wasn't missing anything in English.  
	In those forms.  
	But with spoken English, I do guess at some things that I'm seeing and hearing.  And sometimes I guess incorrectly.  
	Sometimes with captioning you'll see the same thing, the auto captioning is often wrong.  
	And sometimes interpreters need to repair those errors.  
	Because I didn't grow up with that, that is not -- with ASL, that is not my first language.  So oftentimes for me, most of the time I'm working with partial access to those languages.  
	My belief is that all children need to have complete and full access to language.  
	Because that is a human right.  
	It is my belief that if we want -- if you'd like to read more about that, you should read some of my articles.  But I'm not going to delve into that deep philosophical discussion of the nature of human rights and language.  
	But next let's address identity.  
	I think it's important to acknowledge the intersectionality that emerges for each one of us, including Deaf children.  
	And then we need to provide choices for those identities.  
	And how they intersect.  
	For example, I identify myself as an Arab American woman who grew up hard of hearing and Deaf and sign now.  But I also use Spanish and I have so many other aspects to my personhood.  
	And that comprise my identity.  
	And I'm sure all of you have multiple sections of your identity, as well.  
	So talking about identity and the potential and possibility for us to change that identity is water that we need to tread in very lightly.  
	If we make a decision about identity for another person, we need to consider that.  
	Next I would like to address community.  
	When you really feel part of a group, that's very important.  
	I feel very connected to spoken English and Spanish.  I feel connected to those communities.  But when I finally met an ASL user and the Deaf community, I felt extremely connected in a different way.  
	What we want is to be sure that we are doing and acknowledging the sense of belonging and valuing who each person is and who they are depends on their choice of identity.  
	It depends on your upbringing.  It depends on the parents.  And it depends on that whole person and acknowledging that mutual respect.  
	Next slide, please.  
	I would like to delve into a little bit more of the philosophical side of this discussion.  
	Now, I'm sure you've all been aware of what happened to Socrates.  
	Right?  I see some giggles out there.  
	So this is water.  This is not Hemlock.  I'm just making sure.  Okay.  
	So the bioethical issues raised in gene therapy when we talk about that with regards to Deaf children, we need to look at the risks and benefits to the Deaf child.  
	I would also like to discuss the impact of the Deaf child's family unit.  And what that will result in.  
	Because the family does not have unlimited resources.  Families are often given limited resources, they are also limited on time and money.  
	And so we need to acknowledge that for each individual family unit.  And that every unit's decision is going to be different.  
	We need to take a look at what resources are available to the Deaf child and that family unit and what we can actually provide to them.  
	What we can provide to all Deaf children equally.  And that is an ethical issue, too.  
	Last but not least, the impact of gene therapy on the Signing Deaf Community.  
	Next slide, please.  
	You'll have to keep up with a I'm going to get really philosophical right now the OTOF gene can result in a change in that Field child's ability to hear but they are still considered Deaf and hard of hearing in the presentations before me you could see that.  What that means is we need to remember that language deprivation is harmful and what we really want is for overall all Deaf children, all Deaf and hard-of-hearing children to receive language and early access to it.  
	Now it's not just language because with language comes psychological and societal supports, as well, we need to give children the chance to flourish and develop their identity within the Deaf and hard-of-hearing community.  
	We're in very early days right now in gene therapy.  And we don't know what lies ahead.  But we do know that children need to have access to language.  Next slide, please.  
	Gene therapy also raises issues of informed consent.  
	For many of the hundreds of thousands of years that we've had parents making decisions for children, we have not seen a change in that.  
	Most parents will make decisions that they do think are best for their child.  
	Let's acknowledge that.  
	But then when we have decisions to make in the medical realm or the research realm, bioethicists use a standard called the best interest of the person.  
	Which in this case would be the Deaf child.  
	That child cannot make decisions for themself because they don't have that legal autonomy to do so.  
	They haven't reached major age.  
	And they may not even have the language ability or the cognitive ability to make those decisions.  
	But we do still know children can express their preferences regardless of all of that.  
	In an age-appropriate fashion.  
	So when we have a 1-year-old it may be hard for them to express a preference.  But if we have an 8-year-old or a 17-year-old, that's a very different expression.  
	And with age comes more responsibility.  And more weight to the preferences of that person's decision.  And we need to consider that.  
	And this is called ascent.  
	What we're now faced with is a bit of a quagmire.  
	Because the Deaf child is the subject of our concern.  But is anyone checking in with them.  We can other Deaf people.  We can ask the parents to figure out what's best for their family.  But I encourage all of us to also have a dialogue with each other.  
	So that we recognize that maybe my experience growing up as a Deaf and hard-of-hearing individual is different from a baby that's born today.  Times are different.  Technology is different.  And we still have a society that imposes barriers to Deaf people.  
	So what does that mean for us as a society when the system is -- has a barrier against us?  
	Some people would like to invest all their time in breaking down those barriers.  
	And children need some more support than that -- with those.  
	Maybe we need to be making different decisions.  
	Next slide, please.  
	I'll give you a moment to read this.  
	This slide is a bit heavy to digest.  
	I raise these issues, these existential issues, because I want to talk about what gene therapy means, what gene therapy editing implies for the future of our community.  
	Will we disappear?  And that's truly a fear that we face in the community now.  We need to first acknowledge that fear and concern any time we address these issues.  
	There's a real threat to Deaf people and there's a real fear that they will eventually be wiped away.  
	So the effort to keep fighting for their culture and community is completely validated and understood.  
	However, science is already moving forward.  
	So we need to have these discussions.  We need to be included in the room when things are happening.  
	At the same time we need to recognize that there is a history of eugenics that was very real in the Deaf Community.  
	The medical treatment and approaches historically to the Deaf Community has created generational trauma.  
	I want to be clear that the word eugenics does carry a lot of weight.  When people hear that word they will be completely closed to that discussion but I'm here to open that discussion.  I would like to ask you to please consider your word choice when you are having these conversations.  
	Especially when it comes to this topic of the otoferlin gene therapy.  
	Where do we draw the line?  
	These are concerns for many people.  Because we can start with one fairly innocuous treatment.  But then soon we advance to gene editing.  
	What is the right thing to do?  What is the ethical dilemma we face?  
	Next slide, please.  
	I'll give you a moment to read the slide.  
	Am I okay on time?  Great, thank you.  
	I always forget to start a timer for myself.  
	So regarding ethical and existential concerns and policies around gene therapy, we've been looking at these for about the past 10 or 15 years.  And this is serious conditions.  
	We need to distinguish these serious conditions.  And this is a very specific phrase.  
	This means serious condition in the world of biomedicine usually means a life-or-death situation.  
	But now, and I'm happy to share any references with you, there is discussion about Deafness in this realm.  
	Because to be Deaf and hard of hearing is not a serious condition.  It's -- and we're talking about this is separate from syndromic Deafness.  
	So when we were talking about where we draw the line and where we invest our resources with regards to gene therapy, because often there are business interests in this.  But we do also have Federal moneys tied to the science research.  When we're talking about where we're putting our influence.  Where we're putting our resources.  And where we're putting that money.  For most of our policy discussions, they do seem to center around the priorities of the serious conditions.  
	Those do seem to be prioritized.  
	So that is one ethical issue.  
	But the second ethical concern then becomes can we or will we change how we respond to Deaf people in society if and when gene therapy comes to -- or gene editing comes to being.  
	It's a bit of a different situation.  But for many years now, we've had the ability to screen for Down syndrome.  
	As an example.  
	And we've had the ability to do that during pregnancy in utero.  
	So the numbers of people actually birthed with Down syndrome have been on the decline.  
	And that is an impact of people having received that screening in utero.  
	So the number of people with Down syndrome in the community has decreased.  And then those resources to support those people will commensurately decrease.  
	And that's just a very practical consideration.  But it is something to consider.  What happens when people see parents with a child who has from?  -- Down syndrome?  Sometimes we see people judging the parent for even bringing that child into existence.  Because we have the technology for screening for that.  
	Some parents do decide to go ahead and see the pregnancy through.  
	But there is then societal shame associated with that.  We need to tread very lightly here.  
	When a family makes a decision to give a child a cochlear implant, or to focus on Listening and Spoken Language or perhaps gene therapy and don't include the child into the Deaf Community, what happens is twofold.Th decision is for the -- the decision is for the parents and the family and the decisions they make have a double effect.  
	And this is from a school  of thinking, DDE which means when you make one decision and you -- you can predict one result.  But you don't intend for that result to happen.  
	The goal was initially perhaps one decision.  But the outcome is something else.  
	Perhaps you have a mother who is pregnant and becomes very ill.  
	And for her own safety, the woman needs to be given treatment that may kill the fetus.  
	The goal then is to save the woman.  But the result is that you will lose the baby.  
	So that's the DDE result.  
	And here with this gene therapy in the Deaf Community we do have a double result, as well.  Parents make decisions that with one intention.  But what often happens is the second result, which is ASL goes by the wayside and goes on the decline.  I think that's not the intention when people make decisions for their children.  Because they do focus on the child.  Maybe they are making a decision for a cochlear implant.  Listening and Spoken Language.  
	The goal is not to intentionally impact the Deaf Community.  But that's a hard thing to accept, is that that is the very real result of that.  
	You're making the decision for one person and one family.  But then when you add a second family, a third family, a fourth family, that impact becomes far more wide reaching.  
	Than the original goal.  
	So what is the ethical responsibility to the language and community of the Deaf population?  That's not an easy question to answer.  
	We really need to have a very real critical mass of people in order to flourish.  
	Next slide, please.  
	So now it's time for this very difficult conversation.  We need to open this conversation and recognize all of our different perspectives.  We've got to always have Deaf people in the room.  At all times.  
	We've got to try to understand those first steps.  We've got to understand and not to convince.  So many people want to jump to convincing someone to do something.  But what first we need to do is to step back and really listen.  
	We need to figure out how we maintain and keep that conversation open, despite our own impassioned fears.  
	Sometimes it is too much to handle, but we can, I remind you, leave and come back to this discussion.  
	We need all of us in this room.  For this discussion.  
	It is very difficult when you feel like you've been asked to justify why you -- including myself, I include myself in this, why we deserve to continue to exist.  
	It's very difficult.  
	I've been doing this for many years.  And still some days I actually have to stop, take a breath, and come back to the discussion.  
	This is not easy work.  
	The conversation does not to remain open.  Next slide, please.  
	Coming back full circle to where we began, what does it mean to flourish?  
	Our community for our children for our society, what does it mean to flourish?  
	Indeed for our world, what does it mean to flourish.  
	I leave you with that question.  
	Thank you so much.  
	>> KARL WHITE:  Well, this has been an extraordinary session.  We want to express our appreciation again to Dr. Blankmeyer Burke, Dr. Tward, Dr. Vassili Valayannopoulos.  And we are unfortunately completely out of time for questions.  We had over 50 questions come in.  
	But to be fair to the speakers and the subsequent questions -- subsequent sessions to this one, we need to close this session now.  
	We will make a list of those questions available to the presenters and to -- we'll post it on our website just to continue the discussion.  We're not going to take time now to try to answer any of those questions just because we're out of time.  
	But if you can join me in one more round of applause for such excellent presentations.  
	(APPLAUSE).
	>> KARL WHITE:  I would also like to mention many of you were snapping pictures of the slides or even taking videos of the presentations.  
	We would ask you not to distribute those further.  
	So when you attend the conference, we indicate that some of these sessions aren't approved for further dissemination.  So I'm sure we'll have many more discussions.  I personally could have stayed here the rest of the afternoon discussing this important topic but we need to move on the other sessions now.  
	So thanks again for your time.  
	And thanks, all of you, for excellent preparation and presentation.