WEBVTT

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<v Will>Welcome, everybody.</v>

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My name is Will Eiserman,

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and I am the Associate Director

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of the National Center for Hearing Assessment and Management

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at Utah State University.

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NCHAM is our nickname.

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And we are funded by HASA

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as the EHDI National Technical Resource Center,

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or the ENTRC.

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And we are delighted to be sharing

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our webinar platform today with

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the Maryland Early Hearing Detection and Intervention

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2022 Virtual Conference,

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along with the sponsors

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of the Hearing and Speech Agency there.

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We're delighted to be hosting a series

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of three webinars as a part of this conference.

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And this is the second of the series.

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Today's topic is New Developments and Diagnosis

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and Treatment for Hearing Loss.

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And our presenter is Dr. Eliot Shearer.

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Just before we get started,

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I wanna let you know that this webinar is being recorded

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and will be posted on infanthearing.org

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as well as the Maryland's EHDI website

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in the next couple of days.

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So keep that in mind.

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If anything, disrupt your full attention

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or participation in today's webinar,

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you'll be able to go back and view it again

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in the next couple of days.

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And also think about folks

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that may not be attending live today,

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who may also benefit from today's presentation.

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You can direct them to that website as well.

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At the end of our presentation today,

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we'll open up Q and A for everybody

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to interact with our presenter.

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So jot down any questions you have.

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We won't be monitoring the QA field during the presentation,

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but we will open it up toward the end of the presentation

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to dialogue a bit with our presenter.

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At the end of our presentation today,

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you'll have the opportunity

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to give us feedback on today's webinar.

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And when you do that,

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it will generate a certificate of attendance for today

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for those of you who may need to document

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your attendance in today's webinar.

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I wanna give a shout out

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to our interpreters today and our captioner.

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We really appreciate the time and talents of these folks

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who are making it more accessible as possible.

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So, we're really appreciative of your time and skills

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in helping us make our webinars accessible

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to as many people as possible.

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So our presenter today is Dr. Eliot Shearer,

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who is a pediatric otolaryngologist

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at the Boston Children's Hospital

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and whose clinical practice focuses on evaluation

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and treatment of children with hearing loss,

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including cochlea implant surgery.

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He's also a scientist and leads

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the Translational Hearing Genomics Research Laboratory.

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His research focuses on genetic hearing loss in children,

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including new genetic diagnostic tools,

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hearing loss gene discovery,

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and using genetics to understand

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cochlear implant outcomes in children.

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So without any further delay, Dr. Shearer.

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<v ->Thank you all for having me.</v>

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I'm really excited to get to talk to this group today.

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I think there's just some really seismic changes

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that are happening in the hearing field

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that are going to be affecting everyone

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who's on this presentation today and listens to this.

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And so, I think I'm really excited about it.

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I also have some, a lot of questions myself and concerns.

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And so I'm happy to, you know, start the discussion

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and I'm really interested to hear any questions

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that you have at the end of the presentation.

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I prepared a little more than an hour of a talk

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and I'm happy to take questions after that.

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So, I am a pediatric otolaryngologist.

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I did my PhD on hearing loss genetics

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at the University of Iowa.

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And my clinical practice does focus

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on children with hearing loss.

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And here at Children's we have a very busy clinical practice

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caring for children with hearing loss.

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And so, I'm very lucky to be part of the group here.

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But I should say that we have no,

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or I have no conflicts of interest to disclose.

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So I always like to start

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by going over some take home points.

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You know, I heard somewhere

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that you only remember three things from many presentations.

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So I'd like to start with that

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and then we'll come back to it at the end.

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The first point I'd like to make is that I think we need

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to reframe how we're thinking about hearing loss in general,

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and I'll talk more about this.

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But hearing loss is a symptom of an underlying alteration

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in the peripheral auditory system

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and sometimes a central auditory system.

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But it really is a symptom

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of an underlying pathogenic mechanism, okay.

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And a diagnosis for hearing loss provides the patient

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and the clinician with valuable information

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and it guides management of hearing loss.

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And I'll show you several examples of this.

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And then this slide used to say,

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gene therapy for hearing loss

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is on our doorstep or coming soon,

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but as you'll see now,

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gene therapy for hearing loss is here.

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Clinical trials have started.

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And so we all need to join this conversation

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and understand what's happening.

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So, throughout the course of presentation,

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I'm gonna give you an example

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of four different patients that I've seen,

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and I wanna talk you through

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how a genetic diagnosis has altered their clinical care

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and helped to the clinicians who care for them.

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So, we have a seven month old

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that's otherwise nonsyndromic patient

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and with severe to profound hearing loss.

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And the family's on a diagnostic odyssey

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to understand why their child has hearing loss.

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Compare that to patient number two,

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that has more of a slight, a mild slight hearing loss,

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and they've just been looking for answers.

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They're 18 years old

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and wondering why they have hearing loss.

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The third patient is a patient with a normal sloping

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to severe hearing loss at 16 years old

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and wondering whether they should

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proceed with cochlear implantation.

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And then the fourth patient is a seven year old.

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And I'll talk more about

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whether we have a new wave forward

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in the coming years for that patient.

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So, I'll show you how genetic diagnosis

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influenced the care of all these patients.

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So as an overview, we're gonna talk about genetic testing.

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So it's kind of like that who, what, where format.

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So what is genetic testing for hearing loss?

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Why should we perform it?

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Who should receive genetic testing?

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And then how should a clinician order it?

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And then the second part,

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we're gonna talk about genetic newborn hearing screening.

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I know all of you are very familiar

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with newborn hearing screening in general.

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There's many proponents

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of adding a genetic portion to the screen

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and I'm happy to talk about that today.

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And then finally we'll talk about gene therapy

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for hearing loss, new developments with regards to that.

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So we're in a unique position

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caring for individuals that have hearing loss

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because we are often presented with a symptom

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and we treat that patient without knowing the diagnosis.

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So it's been several years

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since I've been to medical school,

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but as an analogy, if I was a evaluating a patient

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that came to the emergency room

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and they had chest pain and I immediately said,

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we should take them to the cardiac catheterization lab

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and we should perform a balloon angioplasty, you know.

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That doesn't make any sense

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because we don't have a diagnosis yet.

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It could be many different things.

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And so, there's many things that we would obtain

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before going to the cath lab.

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So we would get a history, we'd get a physical exam,

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do vitals, labs,

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we'd certainly get an EKG,

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and we'd ideally come up with a diagnosis like a STEMI

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or a heart attack before taking them to the cath lab.

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And this is because you wanna prevent going to the cath lab

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when you think it's a heart attack,

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when really all they need have is

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some acid reflux and they just need some omeprazole.

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So on a very regular basis,

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I take patients to the operating room

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who have a hearing loss like this.

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So, you know, mild sloping to severe hearing loss,

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and I perform cochlear implantation for these patients.

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And around the country, around the world,

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people do this and people have done this for years.

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But really, when you take a step back

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and you think about it,

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we actually don't have a diagnosis

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for this patient in a lot of cases.

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And this is very, very important,

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particularly when you think of all the advances

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that we've come up with in diagnosis recently.

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So if I could tell you that this patient

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had a genetic variant in the gene MYH14

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that causes a stable hearing loss.

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So this hearing was going to stay the same

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for the rest of their life,

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I think that would change my discussion

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that I had with the patient

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about whether we should pursue cochlear implantation

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or whether we should just go ahead with hearing aids.

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Conversely, if I told you that they had

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a form of genetic hearing loss caused by a ACTG1,

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that's a fairly rapidly progressive form of hearing loss.

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That would change again,

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the conversation that I would have with them

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surrounding cochlear implantation.

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I also have seen patients that have a similar form of

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hearing loss as their symptom,

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but their underlying diagnosis is CMV

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or congenital cytomegalovirus.

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And in these patients you aren't doing your due diligence

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if you're not speaking to them about Valganciclovir,

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which is an oral medication that we use to treat

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congenital CMV in symptomatic patients in young children.

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We do this regularly,

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so, for several patients

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who are currently on Valganciclovir.

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In a similar fashion,

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if we knew that this patient had pathogenic variants

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in the gene otoferlin,

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you'd be remiss if you didn't talk to them

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about gene therapy because as I'll talk to you later,

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there's currently phase one clinical trials

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that are starting for gene therapy

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for this form of hearing loss.

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So clearly the diagnosis for this patient

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with this symptom of hearing loss

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changes depending on, you know,

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the treatment changes depending on the diagnosis.

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So, all of our ability to provide an improved diagnosis

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has relied on improved technological advances

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that we've had in the past 10 or 20 years.

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So we've had a much better improvement

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in the imaging resolution that we have.

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So now we have high resolution CTs and MRIs.

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So this is an MRI showing a cochlear nerve hypoplasia.

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So you can see the cochlear nerve is missing here.

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We also routinely have CMV testing and CMV screening.

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There's several states that are mandating this now.

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And then we have genetic testing,

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which I'll focus a lot on today.

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But the point is there's many different ways to do this.

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But in my opinion, every individual that has a hearing loss

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should undergo genetic evaluation.

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And then we have things that are really exciting,

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like electrocochleography,

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which is typically performed in the operating room,

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but can also be performed outside the operating room.

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And this provides a physiologic view

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of the peripheral auditory system.

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And so this was a nice publication

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that recently came out from South Korea.

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And if you perform all these evaluations

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in children with severe to profound hearing loss,

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this study looked at 119 children.

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They were able to come up with an etiologic diagnosis

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in greater than two thirds of children.

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So in 74% of children,

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they were able to come up with a diagnosis,

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00:12:37.500 --> 00:12:39.870
only 26%, they were not.

269
00:12:39.870 --> 00:12:41.850
You can see here, there's a mix of genetic,

270
00:12:41.850 --> 00:12:44.037
radiologic and CMV causes.

271
00:12:44.037 --> 00:12:46.920
And this varies based on your patient population,

272
00:12:46.920 --> 00:12:49.530
the severity of the hearing loss as we'll talk about.

273
00:12:49.530 --> 00:12:51.270
But the point is that we're providing

274
00:12:51.270 --> 00:12:53.310
a diagnosis for two thirds of these children,

275
00:12:53.310 --> 00:12:55.833
which as we'll talk about is hugely important.

276
00:12:56.850 --> 00:12:58.890
And what's really interesting is that

277
00:12:58.890 --> 00:13:00.810
we've suspected for a long time

278
00:13:00.810 --> 00:13:04.050
that the causes of congenital hearing loss in particular,

279
00:13:04.050 --> 00:13:05.070
look something like this.

280
00:13:05.070 --> 00:13:10.070
So genetics seems to account for probably about 65% of it.

281
00:13:11.340 --> 00:13:16.110
Anatomic causes about 10%, congenital CMV is up to 20%.

282
00:13:16.110 --> 00:13:17.850
But really we haven't had the tools

283
00:13:17.850 --> 00:13:21.193
up until recently to identify these causes.

284
00:13:21.193 --> 00:13:23.580
And as I showed on the previous slide,

285
00:13:23.580 --> 00:13:27.003
now we're able to do this with a lot of success.

286
00:13:28.830 --> 00:13:31.650
So, what is genetic testing for hearing loss?

287
00:13:31.650 --> 00:13:35.250
So, I know I'm not speaking to a group of geneticists here,

288
00:13:35.250 --> 00:13:38.640
so I'll take a take a step back with a introduction

289
00:13:38.640 --> 00:13:41.730
to human genetics just briefly.

290
00:13:41.730 --> 00:13:43.680
You all may remember from biology

291
00:13:43.680 --> 00:13:46.870
that we all have 23 pairs of chromosomes

292
00:13:47.910 --> 00:13:49.293
and the sex chromosomes.

293
00:13:50.160 --> 00:13:53.340
And within those chromosomes we have our genes.

294
00:13:53.340 --> 00:13:56.433
And there's about 20,000 of those in the human genome.

295
00:13:57.690 --> 00:14:02.100
And each of us has about 3 billion base pairs of DNA

296
00:14:02.100 --> 00:14:05.760
that comprise the genes and everything outside the genes.

297
00:14:05.760 --> 00:14:07.410
What's been really amazing that we've found

298
00:14:07.410 --> 00:14:09.420
since the completion of the Human Genome Project

299
00:14:09.420 --> 00:14:11.550
in the early 2000s is that

300
00:14:11.550 --> 00:14:15.813
each of us has about 20,000 differences that makes us,

301
00:14:16.824 --> 00:14:18.630
they're called variants,

302
00:14:18.630 --> 00:14:20.640
and those are what make us different from our parents.

303
00:14:20.640 --> 00:14:22.350
So that's why we're not all

304
00:14:22.350 --> 00:14:23.940
clones of each other essentially.

305
00:14:23.940 --> 00:14:27.003
So each person has about 20,000 variants.

306
00:14:28.290 --> 00:14:32.100
And because we have two sets of chromosomes,

307
00:14:32.100 --> 00:14:35.220
these variants can be in inherited in different fashion.

308
00:14:35.220 --> 00:14:37.980
So if you have a disease or a disorder

309
00:14:37.980 --> 00:14:41.310
that's inherited in an autosomal dominant fashion,

310
00:14:41.310 --> 00:14:44.520
that means carrying just one variant

311
00:14:44.520 --> 00:14:48.603
will lead to the disease or disorder phenotype.

312
00:14:49.980 --> 00:14:53.940
Conversely, if you have an autosomal recessive disorder,

313
00:14:53.940 --> 00:14:56.340
you will not have the phenotype

314
00:14:56.340 --> 00:14:57.840
unless you have two copies

315
00:14:57.840 --> 00:15:01.473
of the affected gene or two variants.

316
00:15:03.660 --> 00:15:04.860
So when you look specifically

317
00:15:04.860 --> 00:15:06.490
at the genetics of hearing loss

318
00:15:08.129 --> 00:15:11.370
and more specifically at congenital hearing loss,

319
00:15:11.370 --> 00:15:15.630
which is found at about one in 500 births,

320
00:15:15.630 --> 00:15:19.440
in the US, about 20% of causes are environmental.

321
00:15:19.440 --> 00:15:23.460
And the vast majority we're finding are congenital CMV.

322
00:15:23.460 --> 00:15:26.217
There's also some that are things like ototoxicity

323
00:15:26.217 --> 00:15:30.450
and hyperbilirubinemia, which is like severe jaundice.

324
00:15:30.450 --> 00:15:31.590
But the vast majority,

325
00:15:31.590 --> 00:15:35.640
probably 80% is due to a genetic cause.

326
00:15:35.640 --> 00:15:37.290
And if you separate this,

327
00:15:37.290 --> 00:15:39.660
most people categorize genetic hearing loss

328
00:15:39.660 --> 00:15:44.077
into what's called syndromic and nonsyndromic hearing loss.

329
00:15:44.077 --> 00:15:46.620
Syndromic hearing loss is any type of hearing loss

330
00:15:46.620 --> 00:15:49.440
that has another associated clinical feature.

331
00:15:49.440 --> 00:15:52.410
So some of the most common ones I've listed here.

332
00:15:52.410 --> 00:15:56.010
There's actually more than 400 reported

333
00:15:56.010 --> 00:15:57.360
forms of syndrome hearing loss.

334
00:15:57.360 --> 00:15:59.850
But things that you all know of like Usher Syndrome,

335
00:15:59.850 --> 00:16:01.710
which is hearing loss and vision loss,

336
00:16:01.710 --> 00:16:04.620
Pendred Syndrome, which is hearing loss and thyroid goiter,

337
00:16:04.620 --> 00:16:07.143
Waardenburg Syndrome, Branchiootorenal Syndrome.

338
00:16:08.790 --> 00:16:12.240
And about 70% of genetic hearing loss is non-syndromic.

339
00:16:12.240 --> 00:16:13.230
Now, what's important,

340
00:16:13.230 --> 00:16:16.050
and what I'll talk about later is that there's this

341
00:16:16.050 --> 00:16:19.380
other category or another way of thinking about this.

342
00:16:19.380 --> 00:16:20.910
In many young children,

343
00:16:20.910 --> 00:16:24.510
they don't yet have any of the other clinical phenotypes.

344
00:16:24.510 --> 00:16:26.283
So for instance, usher syndrome,

345
00:16:27.510 --> 00:16:29.820
most often these children will present

346
00:16:29.820 --> 00:16:30.780
just with hearing loss.

347
00:16:30.780 --> 00:16:32.907
They have not yet developed any vision loss.

348
00:16:32.907 --> 00:16:34.950
And so for this reason,

349
00:16:34.950 --> 00:16:37.590
we've started calling some of these patients at a young age,

350
00:16:37.590 --> 00:16:40.440
non-syndromic hearing loss mimics in that,

351
00:16:40.440 --> 00:16:43.110
it mimics a nonsyndromic form of hearing loss

352
00:16:43.110 --> 00:16:46.893
until the syndromic portion is manifested.

353
00:16:47.880 --> 00:16:49.650
So, when you look at nonsyndromic hearing loss,

354
00:16:49.650 --> 00:16:51.630
it's inherited in all different forms.

355
00:16:51.630 --> 00:16:54.330
So there's recessive in the majority of cases,

356
00:16:54.330 --> 00:16:58.350
but also dominant mitochondrial microRNA and X-Linked.

357
00:16:58.350 --> 00:17:00.930
And hearing loss is extraordinarily

358
00:17:00.930 --> 00:17:02.280
genetically heterogeneous.

359
00:17:02.280 --> 00:17:07.280
So to date, we've identified 124 total hearing loss genes.

360
00:17:07.860 --> 00:17:09.960
And you know, this is what I think

361
00:17:09.960 --> 00:17:12.720
makes studying genetic hearing loss so interesting is

362
00:17:12.720 --> 00:17:14.580
there are so many di different genes.

363
00:17:14.580 --> 00:17:16.620
But it's also what makes

364
00:17:16.620 --> 00:17:19.710
studying genetic hearing loss so difficult, you know.

365
00:17:19.710 --> 00:17:21.780
Sometimes I wish that I studied

366
00:17:21.780 --> 00:17:24.300
something like cystic fibrosis where there's just one gene

367
00:17:24.300 --> 00:17:26.460
and there's pretty much just one variant

368
00:17:26.460 --> 00:17:29.100
causing the vast majority cases,

369
00:17:29.100 --> 00:17:31.890
but hearing loss is very complex

370
00:17:31.890 --> 00:17:33.450
and there's a lot of genes involved.

371
00:17:33.450 --> 00:17:34.980
And this is important implications

372
00:17:34.980 --> 00:17:37.383
for genetic evaluation in particular.

373
00:17:38.640 --> 00:17:40.320
So another way to look at this is,

374
00:17:40.320 --> 00:17:44.460
we have all these non-syndromic hearing loss genes, 124.

375
00:17:44.460 --> 00:17:48.750
we have 48 different non-syndromic hearing loss mimic genes.

376
00:17:48.750 --> 00:17:51.120
And then there's all different types of genetic variants.

377
00:17:51.120 --> 00:17:54.000
So there's missense variants,

378
00:17:54.000 --> 00:17:57.060
which is just a change in the genetic code.

379
00:17:57.060 --> 00:18:00.090
There's a nonsense where the gene is actually stopped,

380
00:18:00.090 --> 00:18:02.040
all different types.

381
00:18:02.040 --> 00:18:03.390
And so the short of it is,

382
00:18:03.390 --> 00:18:05.190
genetic hearing loss is complicated.

383
00:18:06.210 --> 00:18:07.650
Another way to look at this,

384
00:18:07.650 --> 00:18:09.060
we published just a few years ago,

385
00:18:09.060 --> 00:18:13.127
if you look at 2,460 patients with hearing loss,

386
00:18:13.127 --> 00:18:15.990
you can see all these different genes are affected.

387
00:18:15.990 --> 00:18:20.990
So GJB2 is the gene also known as Connexin 26.

388
00:18:21.120 --> 00:18:23.700
And this is typically in most populations,

389
00:18:23.700 --> 00:18:26.373
the most common cause of genetic hearing loss.

390
00:18:27.240 --> 00:18:29.640
Stereocilin is typically the second most common cause.

391
00:18:29.640 --> 00:18:31.800
But then there's many other genes

392
00:18:31.800 --> 00:18:35.370
found to be causative in this group of patients

393
00:18:35.370 --> 00:18:38.010
and any group of patients you look at.

394
00:18:38.010 --> 00:18:40.350
And so, what this means is that,

395
00:18:40.350 --> 00:18:42.810
you can't really just test for one form

396
00:18:42.810 --> 00:18:44.490
of genetic hearing loss,

397
00:18:44.490 --> 00:18:47.190
you really need to test for all of them.

398
00:18:47.190 --> 00:18:50.100
And that's why comprehensive genetic testing

399
00:18:50.100 --> 00:18:52.680
using massively paralleled sequencing is the key.

400
00:18:52.680 --> 00:18:54.693
And I'll explain what that means.

401
00:18:56.880 --> 00:18:59.340
So, the human Genome project, as I told you,

402
00:18:59.340 --> 00:19:02.640
was completed in the early 2000s in 2003,

403
00:19:02.640 --> 00:19:04.740
and they used things like this.

404
00:19:04.740 --> 00:19:07.470
So I'm old enough to remember

405
00:19:07.470 --> 00:19:10.110
when our computer looked like this,

406
00:19:10.110 --> 00:19:12.580
but this is when the DNA sequencers

407
00:19:14.400 --> 00:19:16.980
were as big as a refrigerator essentially,

408
00:19:16.980 --> 00:19:19.410
and they used many of them simultaneously

409
00:19:19.410 --> 00:19:21.450
to complete the human genome project

410
00:19:21.450 --> 00:19:24.900
using something called Chain Termination Sequencing.

411
00:19:24.900 --> 00:19:26.643
This is a type of DNA sequencing

412
00:19:26.643 --> 00:19:28.860
that is invented in the 1970s.

413
00:19:28.860 --> 00:19:30.330
And it's very reliable

414
00:19:30.330 --> 00:19:32.910
and we actually still use it today.

415
00:19:32.910 --> 00:19:33.990
But it's very expensive

416
00:19:33.990 --> 00:19:36.573
when you're trying to sequence a lot of genes.

417
00:19:37.800 --> 00:19:40.803
In the mid 2000s, around 2008,

418
00:19:41.940 --> 00:19:44.940
a new category of sequencers, DNA sequencers,

419
00:19:44.940 --> 00:19:46.200
started coming around.

420
00:19:46.200 --> 00:19:51.000
The most common or the most widely used brand

421
00:19:51.000 --> 00:19:52.680
is called Illumina.

422
00:19:52.680 --> 00:19:54.540
This is one of the Illumina sequencers.

423
00:19:54.540 --> 00:19:57.423
And this is what's called a massively parallel sequencer.

424
00:19:58.590 --> 00:20:00.540
Essentially, I won't get into all the details,

425
00:20:00.540 --> 00:20:02.610
but on this slide,

426
00:20:02.610 --> 00:20:05.250
you can see each of these little fluorescent dots.

427
00:20:05.250 --> 00:20:09.720
Each of those is a group of DNA molecules

428
00:20:09.720 --> 00:20:12.000
being sequenced simultaneously.

429
00:20:12.000 --> 00:20:15.540
So it performs what the Sanger Sequencer was doing.

430
00:20:15.540 --> 00:20:18.840
It performs that on a massively parallel scale

431
00:20:18.840 --> 00:20:21.657
and it decreases the cost drastically.

432
00:20:21.657 --> 00:20:23.850
And so, we're easily able to sequence

433
00:20:23.850 --> 00:20:26.250
80 billion base pairs in less than 24 hours.

434
00:20:26.250 --> 00:20:29.520
So we can do many different genomes

435
00:20:29.520 --> 00:20:33.333
or many genomes very quickly using this technology.

436
00:20:34.710 --> 00:20:37.350
And I have this DNA sequencer in my lab.

437
00:20:37.350 --> 00:20:41.490
So this is the size of a big USB thumb drive.

438
00:20:41.490 --> 00:20:43.110
There's several different versions of this,

439
00:20:43.110 --> 00:20:45.870
but this is called the Oxford Nanopore Sequencer.

440
00:20:45.870 --> 00:20:48.000
And this is really amazing technology.

441
00:20:48.000 --> 00:20:49.800
There's several different of these,

442
00:20:49.800 --> 00:20:52.410
the Long-Read Single Strand DNA sequencing technology

443
00:20:52.410 --> 00:20:54.990
is where it pulls a single DNA molecule

444
00:20:54.990 --> 00:20:59.990
and sequences it each strand rapidly one at a time.

445
00:21:00.270 --> 00:21:03.060
So it's just amazing to see the advances in the technology

446
00:21:03.060 --> 00:21:04.833
just in the past 15 years.

447
00:21:05.760 --> 00:21:07.260
And this has been really important

448
00:21:07.260 --> 00:21:09.660
to the study of hearing loss because hearing loss

449
00:21:09.660 --> 00:21:11.793
is so genetically heterogeneous.

450
00:21:12.840 --> 00:21:14.100
So what this has meant is,

451
00:21:14.100 --> 00:21:18.210
when you look at the cost per genome in the early 2000s

452
00:21:18.210 --> 00:21:20.580
it was more than $100 million per genome.

453
00:21:20.580 --> 00:21:23.590
And this has fallen drastically so that now

454
00:21:24.450 --> 00:21:27.543
for less than $1,000 you can have your genome sequenced.

455
00:21:29.610 --> 00:21:34.610
And so in 2010, we published the first article looking at,

456
00:21:35.658 --> 00:21:38.100
the first study using this technology

457
00:21:38.100 --> 00:21:41.520
to evaluate hearing loss genes.

458
00:21:41.520 --> 00:21:44.400
And this was just the second use of this technology

459
00:21:44.400 --> 00:21:47.809
for humans for any form of genetic diagnosis.

460
00:21:47.809 --> 00:21:51.270
And we just had a small number of patients at that point.

461
00:21:51.270 --> 00:21:53.730
It was just 10 total patients in that study.

462
00:21:53.730 --> 00:21:57.720
But people quickly realized the importance of this technique

463
00:21:57.720 --> 00:22:00.030
for evaluating genetic hearing loss.

464
00:22:00.030 --> 00:22:03.600
And so very rapidly, many other groups came forward

465
00:22:03.600 --> 00:22:07.230
and used the same technology to perform genetic diagnosis

466
00:22:07.230 --> 00:22:11.613
for hearing loss in 2015.

467
00:22:13.660 --> 00:22:18.390
In 2016, we published the first 1,119 patients

468
00:22:18.390 --> 00:22:21.750
with hearing loss that we evaluated with this technology.

469
00:22:21.750 --> 00:22:24.930
And very quickly after a Japanese group

470
00:22:24.930 --> 00:22:27.930
published 1,120 just to make sure they had more than us,

471
00:22:27.930 --> 00:22:30.000
which I think is fantastic.

472
00:22:30.000 --> 00:22:32.700
But the point is that there's been dozens of studies

473
00:22:32.700 --> 00:22:34.830
and thousands of patients that this technology

474
00:22:34.830 --> 00:22:36.540
has been used for.

475
00:22:36.540 --> 00:22:37.650
And I'll show you later,

476
00:22:37.650 --> 00:22:39.810
but it really has become the new standard of care

477
00:22:39.810 --> 00:22:41.703
for evaluation of hearing loss.

478
00:22:42.810 --> 00:22:45.760
So, there's many different panels and many different

479
00:22:46.704 --> 00:22:49.530
companies around the country that perform

480
00:22:49.530 --> 00:22:51.933
a similar form of testing.

481
00:22:52.890 --> 00:22:55.920
They've all been developed around the same timeframe,

482
00:22:55.920 --> 00:22:58.110
and they have a very similar approach.

483
00:22:58.110 --> 00:22:59.970
They differ in the number of genes

484
00:22:59.970 --> 00:23:01.473
that are included essentially.

485
00:23:02.640 --> 00:23:05.100
OtoScope is the platform at University of Iowa

486
00:23:05.100 --> 00:23:08.160
that I helped develop but there's many other ones.

487
00:23:08.160 --> 00:23:09.570
So the point is,

488
00:23:09.570 --> 00:23:12.420
they all are comprehensive genetic testing methods

489
00:23:12.420 --> 00:23:13.723
for hearing loss using these massively

490
00:23:13.723 --> 00:23:16.080
paralleled sequencing techniques.

491
00:23:16.080 --> 00:23:17.790
And all these panels evaluate

492
00:23:17.790 --> 00:23:20.130
all the non-syndromic hearing loss genes,

493
00:23:20.130 --> 00:23:22.410
plus many syndromic forms of hearing loss

494
00:23:22.410 --> 00:23:23.460
like we talked about.

495
00:23:25.230 --> 00:23:27.390
So genetic testing for hearing loss

496
00:23:27.390 --> 00:23:29.814
really is the single most effective test.

497
00:23:29.814 --> 00:23:32.250
And what I mean by that is,

498
00:23:32.250 --> 00:23:34.920
there's been many studies showing that overall,

499
00:23:34.920 --> 00:23:38.460
if you take any individual that has hearing loss,

500
00:23:38.460 --> 00:23:41.430
the diagnostic rate is about 40%.

501
00:23:41.430 --> 00:23:45.120
So in 40% of individuals, you come up with a genetic cause.

502
00:23:45.120 --> 00:23:48.210
And when you compare that to things like getting a CT

503
00:23:48.210 --> 00:23:53.210
or an MRI, the diagnostic rate for those is about 25 or 30%.

504
00:23:54.060 --> 00:23:55.320
Even when I started training,

505
00:23:55.320 --> 00:23:59.310
there was kind of a whole host of other tests we would order

506
00:23:59.310 --> 00:24:03.180
like a thyroid ultrasound or kidney ultrasound, blood tests.

507
00:24:03.180 --> 00:24:05.940
All those other tests are really not very helpful

508
00:24:05.940 --> 00:24:07.692
in evaluating for hearing loss.

509
00:24:07.692 --> 00:24:11.553
They contribute about 10% of diagnostic evaluation.

510
00:24:12.870 --> 00:24:15.270
And genetic testing for hearing loss is really important

511
00:24:15.270 --> 00:24:17.430
because it provides information for families.

512
00:24:17.430 --> 00:24:20.940
So prognostic information for instance,

513
00:24:20.940 --> 00:24:24.240
so this is often when I see parents

514
00:24:24.240 --> 00:24:27.630
that have a young child with hearing loss,

515
00:24:27.630 --> 00:24:29.370
these are the sort of questions that they wanna know.

516
00:24:29.370 --> 00:24:32.010
So they wanna know whether the hearing loss

517
00:24:32.010 --> 00:24:33.450
is going to get worse over time

518
00:24:33.450 --> 00:24:35.790
or whether it's gonna stay the same?

519
00:24:35.790 --> 00:24:38.730
They also wanna know what the risk of recurrence is?

520
00:24:38.730 --> 00:24:40.560
So if they were going to have another child,

521
00:24:40.560 --> 00:24:42.180
what the chance would be that that child

522
00:24:42.180 --> 00:24:44.040
would also have hearing loss?

523
00:24:44.040 --> 00:24:45.750
And then, when their child goes on

524
00:24:45.750 --> 00:24:47.130
to have children of their own,

525
00:24:47.130 --> 00:24:50.010
what the chance would be that they would have hearing loss?

526
00:24:50.010 --> 00:24:53.040
This is very important information for some families.

527
00:24:53.040 --> 00:24:54.720
And then really importantly,

528
00:24:54.720 --> 00:24:57.510
we're finding that this form of genetic testing

529
00:24:57.510 --> 00:25:00.300
evaluates for syndromic causes of hearing loss.

530
00:25:00.300 --> 00:25:04.620
As we talked about the syndromic forms of hearing loss

531
00:25:04.620 --> 00:25:07.260
are things like Usher Syndrome and Pendred Syndrome,

532
00:25:07.260 --> 00:25:10.220
it turns out that these comprise about 20%

533
00:25:10.220 --> 00:25:13.230
of all the diagnoses that we make in children.

534
00:25:13.230 --> 00:25:17.790
And so this is really helps us guide therapy

535
00:25:17.790 --> 00:25:20.220
as we'll talk about and helps us

536
00:25:20.220 --> 00:25:23.403
have a informed conversation with families.

537
00:25:24.270 --> 00:25:25.980
Another thing I'll say is that

538
00:25:25.980 --> 00:25:30.870
providing a diagnosis for families really empowers patients.

539
00:25:30.870 --> 00:25:34.200
It it empowers the family and the individuals

540
00:25:34.200 --> 00:25:36.510
to do what they want with their diagnosis.

541
00:25:36.510 --> 00:25:41.340
So as an example with that, I have a family that I see.

542
00:25:41.340 --> 00:25:42.630
And they started

543
00:25:42.630 --> 00:25:46.740
the Stereocilin gene mutation hearing loss Facebook group.

544
00:25:46.740 --> 00:25:48.180
And you know, I think they have

545
00:25:48.180 --> 00:25:49.800
a few dozen members at this point.

546
00:25:49.800 --> 00:25:52.050
And this is hugely important for them

547
00:25:52.050 --> 00:25:53.460
to actually have a diagnosis

548
00:25:53.460 --> 00:25:55.320
and connect with other individuals

549
00:25:55.320 --> 00:25:57.783
that may have the same form of hearing loss.

550
00:25:59.010 --> 00:26:01.470
It also empowers patients and families

551
00:26:01.470 --> 00:26:05.043
to think about clinical trials as we'll be talking about.

552
00:26:06.600 --> 00:26:08.790
So some of you may be thinking, you know,

553
00:26:08.790 --> 00:26:10.710
the diagnostic rate is only 40%.

554
00:26:10.710 --> 00:26:12.540
That's not so great.

555
00:26:12.540 --> 00:26:16.680
I also had felt that way for many years.

556
00:26:16.680 --> 00:26:19.110
And I always look for ways

557
00:26:19.110 --> 00:26:21.210
that we can improve that diagnostic rate.

558
00:26:21.210 --> 00:26:22.650
I was talking to one of my colleagues

559
00:26:22.650 --> 00:26:25.920
here at Boston Children's who's in the Neurology Department

560
00:26:25.920 --> 00:26:27.870
about our diagnostic rate being 40%.

561
00:26:27.870 --> 00:26:30.570
And she said, "Are you kidding? That's amazing."

562
00:26:30.570 --> 00:26:32.820
And so I started looking into that.

563
00:26:32.820 --> 00:26:36.178
And when you look at other sort of,

564
00:26:36.178 --> 00:26:40.110
when you look at neurologic disorders where

565
00:26:40.110 --> 00:26:43.260
genetic testing is routinely ordered, so things like autism,

566
00:26:43.260 --> 00:26:45.060
it's pretty routine now that people

567
00:26:45.060 --> 00:26:47.220
will order genetic evaluation.

568
00:26:47.220 --> 00:26:50.670
The diagnostic rate for that is 17%.

569
00:26:50.670 --> 00:26:54.540
For epilepsy, where it's very routine and standard of care

570
00:26:54.540 --> 00:26:58.260
to order genetic testing, the diagnostic rate is 24%.

571
00:26:58.260 --> 00:27:01.830
Things like intellectual disability, it's 28%.

572
00:27:01.830 --> 00:27:04.530
And now it's quickly becoming standard of care.

573
00:27:04.530 --> 00:27:09.000
If you have a critically ill baby in the NICU,

574
00:27:09.000 --> 00:27:12.120
we'll order rapid genome sequencing on that baby

575
00:27:12.120 --> 00:27:14.100
to get a result back very quickly.

576
00:27:14.100 --> 00:27:17.010
That diagnostic rate is only 36%.

577
00:27:17.010 --> 00:27:18.090
And so when you compare that

578
00:27:18.090 --> 00:27:20.460
for the diagnostic rate for hearing loss,

579
00:27:20.460 --> 00:27:25.110
it's really, we're doing very well comparatively.

580
00:27:25.110 --> 00:27:28.260
And so, what I would say is that one of you

581
00:27:28.260 --> 00:27:32.550
that takes care of or helps any individuals

582
00:27:32.550 --> 00:27:33.960
that have hearing loss,

583
00:27:33.960 --> 00:27:37.140
you are involved with genetics

584
00:27:37.140 --> 00:27:40.380
and you are a geneticist yourself,

585
00:27:40.380 --> 00:27:41.430
whether you like it or not,

586
00:27:41.430 --> 00:27:44.223
because hearing loss is clearly a genetic disorder.

587
00:27:45.900 --> 00:27:47.280
So let's talk about the patient.

588
00:27:47.280 --> 00:27:50.670
So this is patient number one.

589
00:27:50.670 --> 00:27:52.650
This is a seven month old

590
00:27:52.650 --> 00:27:55.830
who referred on newborn hearing screen bilaterally.

591
00:27:55.830 --> 00:27:59.280
The family's been really adamant about it,

592
00:27:59.280 --> 00:28:02.250
making sure that the child had hearing aids very young,

593
00:28:02.250 --> 00:28:03.930
so three months old.

594
00:28:03.930 --> 00:28:07.140
Otherwise has normal developmental milestones.

595
00:28:07.140 --> 00:28:11.283
When we had genetic testing and genetic evaluation done,

596
00:28:12.390 --> 00:28:13.740
you know, the parents had the questions

597
00:28:13.740 --> 00:28:14.640
that we were talking about.

598
00:28:14.640 --> 00:28:18.060
So what is the cause of hearing loss? What's the prognosis?

599
00:28:18.060 --> 00:28:19.473
What's the recurrence risk?

600
00:28:20.370 --> 00:28:22.170
The genetic testing result for this patient

601
00:28:22.170 --> 00:28:26.340
showed two pathogenic mutations in the gene, Cadherin 23.

602
00:28:26.340 --> 00:28:28.830
And so we were able to provide a diagnosis

603
00:28:28.830 --> 00:28:31.860
of Usher Syndrome Type 1 for this patient.

604
00:28:31.860 --> 00:28:36.860
So this child will have onset of retinitis pigmentosa,

605
00:28:37.590 --> 00:28:42.590
which typically begins with a vision loss at night

606
00:28:42.952 --> 00:28:44.370
in the first decade.

607
00:28:44.370 --> 00:28:46.440
And then that'll be a progressive vision loss

608
00:28:46.440 --> 00:28:48.393
through their second and third decades.

609
00:28:49.860 --> 00:28:54.120
Actually, in our first cohort of patients in 2010

610
00:28:54.120 --> 00:28:57.000
that we tested, we identified an individual

611
00:28:57.000 --> 00:28:59.010
with Usher Syndrome Type 1.

612
00:28:59.010 --> 00:29:02.640
And this is a really difficult conversation

613
00:29:02.640 --> 00:29:04.110
to have with parents.

614
00:29:04.110 --> 00:29:05.730
And it's a really difficult conversation

615
00:29:05.730 --> 00:29:08.310
to have with such a young child.

616
00:29:08.310 --> 00:29:09.750
But I've found,

617
00:29:09.750 --> 00:29:11.596
after having many of these conversations,

618
00:29:11.596 --> 00:29:14.190
it's very, very crucially important

619
00:29:14.190 --> 00:29:17.280
that these families get this diagnosis.

620
00:29:17.280 --> 00:29:21.060
Although they may be upset and have some difficulty

621
00:29:21.060 --> 00:29:23.670
dealing with the diagnosis at first,

622
00:29:23.670 --> 00:29:25.920
everyone that I've spoken to,

623
00:29:25.920 --> 00:29:28.290
they've been thankful to have the diagnosis.

624
00:29:28.290 --> 00:29:30.880
So what they're able to do is

625
00:29:32.190 --> 00:29:35.430
pay more attention to vision, get the vision checked early,

626
00:29:35.430 --> 00:29:39.480
they can do things like take Vitamin A and wear sunglasses.

627
00:29:39.480 --> 00:29:41.684
They're teaching braille very early

628
00:29:41.684 --> 00:29:44.473
before the vision is affected.

629
00:29:44.473 --> 00:29:46.410
And then it really actually changes

630
00:29:46.410 --> 00:29:49.110
our discussion about cochlear implants,

631
00:29:49.110 --> 00:29:52.140
in particular, not as much for Usher Syndrome Type 1,

632
00:29:52.140 --> 00:29:53.820
but usher syndrome type two,

633
00:29:53.820 --> 00:29:56.193
which is more of a progressive hearing loss.

634
00:29:58.354 --> 00:30:01.050
I've had some very important conversations with families

635
00:30:01.050 --> 00:30:02.850
about when to consider cochlear implants

636
00:30:02.850 --> 00:30:05.430
and some patients or families,

637
00:30:05.430 --> 00:30:07.500
they would consider waiting a little bit longer,

638
00:30:07.500 --> 00:30:09.300
but this sort of diagnosis may move them

639
00:30:09.300 --> 00:30:11.400
to earlier cochlear implant patients.

640
00:30:11.400 --> 00:30:14.733
So very important, though very difficult diagnosis.

641
00:30:16.500 --> 00:30:20.310
This next patient is sort of in a way

642
00:30:20.310 --> 00:30:21.240
opposite of the last one.

643
00:30:21.240 --> 00:30:24.000
So this is an 18 year old who,

644
00:30:24.000 --> 00:30:26.460
although they had congenital hearing loss,

645
00:30:26.460 --> 00:30:29.430
as you can see, it's mild,

646
00:30:29.430 --> 00:30:32.550
really slight to mild, it's bilateral.

647
00:30:32.550 --> 00:30:34.980
And they've also had eustachian tube dysfunction

648
00:30:34.980 --> 00:30:36.900
and some hearing aids

649
00:30:36.900 --> 00:30:39.660
that they've worn on and off throughout the years.

650
00:30:39.660 --> 00:30:43.053
And then some difficulty with the ADHD as well.

651
00:30:44.070 --> 00:30:46.410
We've performed genetic evaluation for this patient

652
00:30:46.410 --> 00:30:48.510
because they really wanted to know

653
00:30:48.510 --> 00:30:49.800
what the cause of hearing loss was.

654
00:30:49.800 --> 00:30:51.330
They've just always kind of wondered, you know,

655
00:30:51.330 --> 00:30:52.620
why they had this hearing loss.

656
00:30:52.620 --> 00:30:54.330
And they also wanted to know, you know,

657
00:30:54.330 --> 00:30:55.380
they're 18 years old,

658
00:30:55.380 --> 00:30:57.750
whether it would get more severe over time

659
00:30:57.750 --> 00:31:00.240
or whether it would stay the same?

660
00:31:00.240 --> 00:31:01.230
And so in this patient,

661
00:31:01.230 --> 00:31:02.880
we identified a pathogenic

662
00:31:02.880 --> 00:31:06.420
or causative mutation in the gene FGFR3.

663
00:31:06.420 --> 00:31:10.290
And this is a syndrome called Muenke syndrome.

664
00:31:10.290 --> 00:31:12.450
It's very rare, but essentially,

665
00:31:12.450 --> 00:31:14.790
it's a form of craniosynostosis

666
00:31:14.790 --> 00:31:19.790
where there's premature fusion of the cranial skeleton.

667
00:31:21.900 --> 00:31:24.630
And what we're finding as we test more individuals

668
00:31:24.630 --> 00:31:27.120
with hearing loss is that a lot of these syndromes

669
00:31:27.120 --> 00:31:28.740
are actually on a spectrum.

670
00:31:28.740 --> 00:31:30.480
So what I mean by that is,

671
00:31:30.480 --> 00:31:33.750
when this syndrome was first identified,

672
00:31:33.750 --> 00:31:37.350
the patient maybe had all the most severe sort of symptoms

673
00:31:37.350 --> 00:31:42.150
and that's why they presented to the doctor initially.

674
00:31:42.150 --> 00:31:45.240
But in reality, a lot of these are variable.

675
00:31:45.240 --> 00:31:49.410
So, some people may have very mild expression

676
00:31:49.410 --> 00:31:53.340
or a very mild phenotype compared to other individuals.

677
00:31:53.340 --> 00:31:55.200
And that's what we're finding a lot.

678
00:31:55.200 --> 00:31:58.200
And so, this patient was very thankful

679
00:31:58.200 --> 00:31:59.580
to have a diagnosis finally,

680
00:31:59.580 --> 00:32:02.400
to kind of just answer the question of what's going on?

681
00:32:02.400 --> 00:32:03.990
But we noticed that they didn't have

682
00:32:03.990 --> 00:32:07.590
all the typical features of a patient with Muenke syndrome.

683
00:32:07.590 --> 00:32:10.080
And I think this shows us how important it is

684
00:32:10.080 --> 00:32:12.360
to evaluate all patients with hearing loss,

685
00:32:12.360 --> 00:32:15.003
not just those with severe to profound hearing loss.

686
00:32:16.950 --> 00:32:19.950
So why should we perform genetic testing for hearing loss?

687
00:32:19.950 --> 00:32:23.250
Well, I already gave you some examples and some reasons.

688
00:32:23.250 --> 00:32:25.860
A reason why is because now we have consensus guidelines.

689
00:32:25.860 --> 00:32:27.120
So there's groups like

690
00:32:27.120 --> 00:32:29.220
the International Pediatric Otolaryngology Group

691
00:32:29.220 --> 00:32:30.450
that recommends it,

692
00:32:30.450 --> 00:32:31.890
and then also the American College

693
00:32:31.890 --> 00:32:34.260
of Medical Genetics and Genomics.

694
00:32:34.260 --> 00:32:37.470
And the another reason why,

695
00:32:37.470 --> 00:32:39.660
as I talked about is prognosis and management.

696
00:32:39.660 --> 00:32:42.720
So if you look at two different forms

697
00:32:42.720 --> 00:32:47.720
of genetic hearing loss, so this is Alpha-tectorin or TECTA.

698
00:32:47.910 --> 00:32:50.880
And you can see if you look over time,

699
00:32:50.880 --> 00:32:52.320
this form of genetic hearing loss

700
00:32:52.320 --> 00:32:54.678
really doesn't have very much progression,

701
00:32:54.678 --> 00:32:58.410
whereas when you contrast that to individuals

702
00:32:58.410 --> 00:33:02.400
with genetic variants in KCNQ4 causing their hearing loss,

703
00:33:02.400 --> 00:33:04.680
you can see that it does progress over time

704
00:33:04.680 --> 00:33:07.110
at a fairly regular interval.

705
00:33:07.110 --> 00:33:11.040
And so, we're able to provide this prognosis to families.

706
00:33:11.040 --> 00:33:14.700
And the way I use this is starting a discussion

707
00:33:14.700 --> 00:33:18.270
about cochlear implants to see if they're interested earlier

708
00:33:18.270 --> 00:33:20.100
and those that have progressive hearing loss

709
00:33:20.100 --> 00:33:22.050
just to kind of put it on the table

710
00:33:22.050 --> 00:33:23.850
as something to think about.

711
00:33:23.850 --> 00:33:27.180
And then also, frequency of audiometric evaluation.

712
00:33:27.180 --> 00:33:28.890
So, I have several patients who I know

713
00:33:28.890 --> 00:33:30.600
have a stable form of hearing loss.

714
00:33:30.600 --> 00:33:32.700
And I'm more comfortable pushing out

715
00:33:32.700 --> 00:33:34.710
their audiometric evaluation to longer

716
00:33:34.710 --> 00:33:38.550
because I don't suspect that it'll get worse

717
00:33:38.550 --> 00:33:41.193
or more severe as quickly as others.

718
00:33:42.960 --> 00:33:45.300
So another reason is to think about

719
00:33:45.300 --> 00:33:46.560
cochlear implant outcomes.

720
00:33:46.560 --> 00:33:50.520
And this is still a very active area of research.

721
00:33:50.520 --> 00:33:52.470
But many people have shown that

722
00:33:52.470 --> 00:33:54.780
if you look at cochlear implant users

723
00:33:54.780 --> 00:33:57.060
and you look at things like the CNC word test

724
00:33:57.060 --> 00:33:59.040
or the AzBio test,

725
00:33:59.040 --> 00:34:01.320
you can see that there's a wide variability

726
00:34:01.320 --> 00:34:04.260
in sort of outcomes after cochlear implants.

727
00:34:04.260 --> 00:34:06.510
So this is every individual from this study

728
00:34:06.510 --> 00:34:07.440
plotted along here.

729
00:34:07.440 --> 00:34:08.910
And you can see that there's some

730
00:34:08.910 --> 00:34:11.130
very excellent performers with a cochlear implant

731
00:34:11.130 --> 00:34:12.750
and there's some that did not do as well

732
00:34:12.750 --> 00:34:14.340
with the cochlear implant.

733
00:34:14.340 --> 00:34:15.870
And although a lot of people,

734
00:34:15.870 --> 00:34:18.300
a lot of surgeons especially don't like

735
00:34:18.300 --> 00:34:21.300
to talk about poor outcomes with cochlear implants,

736
00:34:21.300 --> 00:34:23.010
I think it's incredibly important

737
00:34:23.010 --> 00:34:25.770
that we focus on ways to improve cochlear implants.

738
00:34:25.770 --> 00:34:27.900
And we have the appropriate discussion

739
00:34:27.900 --> 00:34:31.830
with patients prior to surgery about expected outcomes.

740
00:34:31.830 --> 00:34:33.210
And so that's why I and others

741
00:34:33.210 --> 00:34:37.410
have pushed to use genetics to improve our understanding

742
00:34:37.410 --> 00:34:39.480
of cochlear implant outcomes.

743
00:34:39.480 --> 00:34:41.430
And so the outcomes are variable.

744
00:34:41.430 --> 00:34:42.263
And so the question is,

745
00:34:42.263 --> 00:34:43.710
whether we can improve the outcomes

746
00:34:43.710 --> 00:34:45.273
using genetic evaluation?

747
00:34:46.620 --> 00:34:49.410
But clearly cochlear implant outcomes are multifactorial.

748
00:34:49.410 --> 00:34:51.630
So we know there's things like that environment,

749
00:34:51.630 --> 00:34:53.130
like socioeconomic status,

750
00:34:53.130 --> 00:34:55.650
time without hearing and social interactions.

751
00:34:55.650 --> 00:34:57.630
There's clinical variables like the device

752
00:34:57.630 --> 00:34:59.220
that was implanted, the surgeon,

753
00:34:59.220 --> 00:35:03.750
any complications afterwards, activation and training.

754
00:35:03.750 --> 00:35:06.690
And then I and others think that genes

755
00:35:06.690 --> 00:35:08.400
also play an important role in this.

756
00:35:08.400 --> 00:35:10.590
So genes that affect the peripheral pathway

757
00:35:10.590 --> 00:35:12.273
as well as the central pathway.

758
00:35:13.200 --> 00:35:15.510
And so a better understanding of cochlear implant genetics

759
00:35:15.510 --> 00:35:18.488
would allow identification of possible

760
00:35:18.488 --> 00:35:21.120
poor performers preoperatively.

761
00:35:21.120 --> 00:35:22.590
So I'm not necessarily saying that

762
00:35:22.590 --> 00:35:25.140
we wanna do a cochlear implant for these patients

763
00:35:25.140 --> 00:35:26.790
if they were interested in it,

764
00:35:26.790 --> 00:35:29.878
but I would argue that we need to be able

765
00:35:29.878 --> 00:35:32.070
to effectively counsel all patients

766
00:35:32.070 --> 00:35:34.590
with their expected outcomes.

767
00:35:34.590 --> 00:35:37.080
And then for those who are at risk

768
00:35:37.080 --> 00:35:38.640
for poorer outcomes than others,

769
00:35:38.640 --> 00:35:40.110
we could focus our activation

770
00:35:40.110 --> 00:35:43.350
and training for those individuals.

771
00:35:43.350 --> 00:35:45.210
And then ultimately this could pave the way

772
00:35:45.210 --> 00:35:47.210
to precision tailored cochlear implants.

773
00:35:48.390 --> 00:35:50.700
So the hypothesis looks something like this.

774
00:35:50.700 --> 00:35:51.960
So if you have your hair cell

775
00:35:51.960 --> 00:35:54.990
and your spiral ganglion neuron and your brainstem,

776
00:35:54.990 --> 00:35:58.950
the cochlear implant electrode bypasses the inner hair cell

777
00:35:58.950 --> 00:36:01.500
and directly stimulates the spiral ganglion neuron.

778
00:36:02.683 --> 00:36:05.010
And the hypothesis is that individuals

779
00:36:05.010 --> 00:36:08.310
with damaging genetic variants affecting the spiral ganglion

780
00:36:08.310 --> 00:36:11.280
will have significantly worse cochlear implant outcomes.

781
00:36:11.280 --> 00:36:13.800
And this is not something that I came up with.

782
00:36:13.800 --> 00:36:15.690
This has been around for a long time.

783
00:36:15.690 --> 00:36:17.970
But essentially, if you have a dysfunction

784
00:36:17.970 --> 00:36:20.850
of the sensory portion of your auditory system,

785
00:36:20.850 --> 00:36:21.870
you would've a good outcome.

786
00:36:21.870 --> 00:36:23.613
And if you have a neural dysfunction,

787
00:36:23.613 --> 00:36:26.190
you could have a poor outcome.

788
00:36:26.190 --> 00:36:29.130
And so there's 92 different known hearing loss genes

789
00:36:29.130 --> 00:36:31.650
that affect the organ of corti,

790
00:36:31.650 --> 00:36:34.440
and there's six or so that affect the spiral ganglion

791
00:36:34.440 --> 00:36:37.293
and three with an unknown function.

792
00:36:38.700 --> 00:36:42.750
So in 2017, we did show that individuals

793
00:36:42.750 --> 00:36:47.130
that had genetic variants that specifically

794
00:36:47.130 --> 00:36:51.690
negatively impacted the spiral ganglion neurons

795
00:36:51.690 --> 00:36:54.330
performed significantly worse than individuals

796
00:36:54.330 --> 00:36:59.330
who had genetic variants that affected the sensory portion.

797
00:37:00.660 --> 00:37:05.160
And these neural genetic individuals did statistically worse

798
00:37:05.160 --> 00:37:08.490
than individuals with bilateral sudden hearing loss

799
00:37:08.490 --> 00:37:09.753
and Otosclerosis.

800
00:37:10.950 --> 00:37:15.950
And so I think that, we and others have shown that

801
00:37:16.170 --> 00:37:19.050
some genetic variants do affect the auditory nerve

802
00:37:19.050 --> 00:37:21.780
and are associated with worse cochlear implant outcomes.

803
00:37:21.780 --> 00:37:22.890
But this is early data.

804
00:37:22.890 --> 00:37:24.780
And clearly there's a lot of variability

805
00:37:24.780 --> 00:37:29.780
that we need to look into more to tease this out further.

806
00:37:31.290 --> 00:37:33.370
So in particular,

807
00:37:33.370 --> 00:37:35.460
this individual going back to this individual,

808
00:37:35.460 --> 00:37:39.240
this is a 16 year old who has this form of hearing loss.

809
00:37:39.240 --> 00:37:41.304
It's been relatively stable,

810
00:37:41.304 --> 00:37:43.890
but the word recognition score has been decreasing

811
00:37:43.890 --> 00:37:45.840
significantly over time.

812
00:37:45.840 --> 00:37:47.717
And so, they're wondering what the causes

813
00:37:47.717 --> 00:37:51.060
of the hearing loss and whether they should undergo

814
00:37:51.060 --> 00:37:53.520
a cochlear implant or not?

815
00:37:53.520 --> 00:37:54.810
This patient was found to have

816
00:37:54.810 --> 00:37:58.170
pathogenic mutations in the gene TMPRSS3.

817
00:37:58.170 --> 00:38:00.371
This is a form of non-syndromic hearing loss.

818
00:38:00.371 --> 00:38:04.170
And we and others have reported that these individuals

819
00:38:04.170 --> 00:38:06.390
don't seem to do as well with a cochlear implant

820
00:38:06.390 --> 00:38:08.310
when you compare them to individuals

821
00:38:08.310 --> 00:38:10.860
with other genetic forms of hearing loss

822
00:38:10.860 --> 00:38:13.290
that don't seem to affect the nerve.

823
00:38:13.290 --> 00:38:16.140
And so the discussion I had with this patient,

824
00:38:16.140 --> 00:38:17.430
and I have it with any patient

825
00:38:17.430 --> 00:38:20.162
that has TMPRSS3 hearing loss is that

826
00:38:20.162 --> 00:38:24.128
a cochlear implant is still the best treatment

827
00:38:24.128 --> 00:38:27.180
to restore auditory function for individuals

828
00:38:27.180 --> 00:38:30.360
that have severe to profound sensory neural hearing loss,

829
00:38:30.360 --> 00:38:35.360
but they may be at risk for worse outcomes postoperatively.

830
00:38:35.700 --> 00:38:39.570
And you know, I think that most of these individuals

831
00:38:39.570 --> 00:38:41.100
go on to have a cochlear implant,

832
00:38:41.100 --> 00:38:43.830
but I'm all about full disclosure with patients

833
00:38:43.830 --> 00:38:45.810
and I wanna make sure that we're providing them

834
00:38:45.810 --> 00:38:49.023
the best counseling that we can preoperatively.

835
00:38:50.160 --> 00:38:51.810
So as I said, cochlear implants

836
00:38:51.810 --> 00:38:53.760
are the most effective available treatment

837
00:38:53.760 --> 00:38:55.560
for severe to profound hearing loss.

838
00:38:56.850 --> 00:38:58.560
So I'm gonna talk more about this,

839
00:38:58.560 --> 00:39:01.290
but another reason why to perform genetic testing

840
00:39:01.290 --> 00:39:05.010
for hearing loss is because of gene therapy.

841
00:39:05.010 --> 00:39:09.780
And so this is a picture showing

842
00:39:09.780 --> 00:39:12.450
all the different routes for gene therapy.

843
00:39:12.450 --> 00:39:15.030
And I'm gonna talk more about this later

844
00:39:15.030 --> 00:39:17.040
and also about different models

845
00:39:17.040 --> 00:39:19.350
for gene therapy for hearing loss.

846
00:39:19.350 --> 00:39:20.880
These are several of the companies

847
00:39:20.880 --> 00:39:25.020
that are moving forward with gene therapy.

848
00:39:25.020 --> 00:39:27.780
I'm not associated with these companies.

849
00:39:27.780 --> 00:39:31.170
But I'll show you that for Akouos,

850
00:39:31.170 --> 00:39:34.470
they have recently, Akouos and Decibel,

851
00:39:34.470 --> 00:39:37.350
have recently started phase one clinical trials

852
00:39:37.350 --> 00:39:41.040
for gene therapy for hearing loss for otoferlin.

853
00:39:41.040 --> 00:39:43.830
And I'm gonna give you more details later about

854
00:39:43.830 --> 00:39:46.050
why this is and what this gene does.

855
00:39:46.050 --> 00:39:48.870
But they're also looking at Usher Syndrome 3A,

856
00:39:48.870 --> 00:39:51.150
a different autosomal dominant form of hearing loss

857
00:39:51.150 --> 00:39:53.610
and then GJB2 hearing loss.

858
00:39:53.610 --> 00:39:54.900
And so all of these companies,

859
00:39:54.900 --> 00:39:56.610
there's many gene therapy companies

860
00:39:56.610 --> 00:39:59.220
and there's a lot happening in the field right now.

861
00:39:59.220 --> 00:40:02.160
And essentially the trials have started.

862
00:40:02.160 --> 00:40:07.160
And so before you can move forward with a genetic therapy,

863
00:40:07.740 --> 00:40:09.393
you need a genetic diagnosis.

864
00:40:10.740 --> 00:40:14.520
So the fourth patient I wanted to talk to you about,

865
00:40:14.520 --> 00:40:19.520
so this individual had a mild to moderate

866
00:40:19.770 --> 00:40:22.620
sort of flat sensory neural hearing loss

867
00:40:22.620 --> 00:40:24.480
that was congenital.

868
00:40:24.480 --> 00:40:25.530
This is a seven year old

869
00:40:25.530 --> 00:40:26.811
that didn't pass newborn hearing screening

870
00:40:26.811 --> 00:40:29.943
and was otherwise healthy and wears hearing aids?

871
00:40:30.811 --> 00:40:33.270
So this family really wanted to know

872
00:40:33.270 --> 00:40:34.860
what the cause of hearing loss was?

873
00:40:34.860 --> 00:40:36.330
What the prognosis was?

874
00:40:36.330 --> 00:40:38.100
And this family was really queued

875
00:40:38.100 --> 00:40:41.435
into all the gene therapy information.

876
00:40:41.435 --> 00:40:44.580
And they actually asked about gene therapy

877
00:40:44.580 --> 00:40:46.023
when I first met them.

878
00:40:46.920 --> 00:40:49.800
We actually showed that they had a deletion

879
00:40:49.800 --> 00:40:51.270
of the Stereocilin gene.

880
00:40:51.270 --> 00:40:54.240
This gene causes mild to moderate hearing loss,

881
00:40:54.240 --> 00:40:58.650
which is maybe very slowly progressive,

882
00:40:58.650 --> 00:41:00.213
but relatively stable.

883
00:41:01.170 --> 00:41:04.470
And we recently published at Boston Children's Hospital

884
00:41:04.470 --> 00:41:08.280
a paper last December showing a gene therapy

885
00:41:08.280 --> 00:41:10.050
for this form of hearing loss.

886
00:41:10.050 --> 00:41:12.420
And I'm gonna talk a little bit more about this later,

887
00:41:12.420 --> 00:41:15.660
but I just wanted to show you and get you thinking about

888
00:41:15.660 --> 00:41:17.640
whether this is a patient population

889
00:41:17.640 --> 00:41:19.590
that we should perform gene therapy for?

890
00:41:19.590 --> 00:41:22.710
So it's an open-ended question at this point.

891
00:41:22.710 --> 00:41:25.260
But this family was really interested to hear

892
00:41:25.260 --> 00:41:28.830
about the work that we had done in mice

893
00:41:28.830 --> 00:41:30.720
at Boston Children's Hospital.

894
00:41:30.720 --> 00:41:34.680
And it really empowered them

895
00:41:34.680 --> 00:41:37.773
in thinking about their child that had hearing loss.

896
00:41:39.120 --> 00:41:41.070
So who should we perform genetic testing

897
00:41:41.070 --> 00:41:42.123
for hearing loss on?

898
00:41:42.960 --> 00:41:45.060
So overall, I told you the diagnostic rate

899
00:41:45.060 --> 00:41:48.900
is about 40% for all comers.

900
00:41:48.900 --> 00:41:52.350
But it varies based on different clinical characteristics.

901
00:41:52.350 --> 00:41:53.520
So if you have a family history

902
00:41:53.520 --> 00:41:56.790
of hearing loss, for instance, it's typically higher.

903
00:41:56.790 --> 00:41:58.800
If the age of onset is earlier,

904
00:41:58.800 --> 00:42:02.040
it's a typically a higher diagnostic rate.

905
00:42:02.040 --> 00:42:04.560
And then if the hearing loss is symmetric,

906
00:42:04.560 --> 00:42:06.990
it's typically a higher diagnostic rate.

907
00:42:06.990 --> 00:42:09.660
This is data from six years ago now,

908
00:42:09.660 --> 00:42:12.450
and I'll show you some more recent data in a minute.

909
00:42:12.450 --> 00:42:14.010
But we found pretty early

910
00:42:14.010 --> 00:42:16.500
that individuals with asymmetric hearing loss

911
00:42:16.500 --> 00:42:19.830
had a decreased diagnostic yield

912
00:42:19.830 --> 00:42:21.990
or diagnostic rate with genetic testing.

913
00:42:21.990 --> 00:42:23.280
We think that's likely because

914
00:42:23.280 --> 00:42:26.340
these patients have more anatomic causes

915
00:42:26.340 --> 00:42:27.600
for their hearing loss.

916
00:42:27.600 --> 00:42:30.603
So abnormalities of the cochlea or the vestibule.

917
00:42:31.830 --> 00:42:34.620
But if I see a child in clinic that has

918
00:42:34.620 --> 00:42:37.800
congenital profound sensory neural hearing loss

919
00:42:37.800 --> 00:42:40.320
with a normal physical exam,

920
00:42:40.320 --> 00:42:43.110
I tell that family there's about a 60% chance

921
00:42:43.110 --> 00:42:47.400
that we will identify a cause if we do genetic testing.

922
00:42:47.400 --> 00:42:50.580
So it really is a very effective test,

923
00:42:50.580 --> 00:42:52.593
particularly for those individuals.

924
00:42:53.430 --> 00:42:56.430
But we do know that genetic diagnosis varies by age.

925
00:42:56.430 --> 00:42:58.950
So this was a study we published last year

926
00:42:58.950 --> 00:43:01.140
using data from University of Iowa,

927
00:43:01.140 --> 00:43:03.570
and we looked at cochlear implant patients.

928
00:43:03.570 --> 00:43:05.160
So these are all patients that have severe

929
00:43:05.160 --> 00:43:07.020
to profound hearing loss.

930
00:43:07.020 --> 00:43:12.020
For pediatric patients, the diagnostic rate was about 48%.

931
00:43:12.900 --> 00:43:15.630
And you can see the different genes affected here

932
00:43:15.630 --> 00:43:18.510
were GJB2, SLC26A4.

933
00:43:18.510 --> 00:43:20.970
There were 17 different genes.

934
00:43:20.970 --> 00:43:24.780
In the 359 cochlear implant patients that were adults,

935
00:43:24.780 --> 00:43:27.600
the diagnostic rate was about 22%.

936
00:43:27.600 --> 00:43:30.840
And the most commonly affected genes were very different.

937
00:43:30.840 --> 00:43:32.670
So things like TMPRSS3,

938
00:43:32.670 --> 00:43:34.743
some mitochondrial genes, for instance,

939
00:43:35.850 --> 00:43:38.680
the genetic diagnosis really does vary by age

940
00:43:39.690 --> 00:43:41.160
because these individuals

941
00:43:41.160 --> 00:43:43.080
or all these individuals had cochlear implants,

942
00:43:43.080 --> 00:43:45.333
so they had similar degrees of hearing loss.

943
00:43:47.310 --> 00:43:49.170
We also know that the genetic diagnosis

944
00:43:49.170 --> 00:43:51.829
varies significantly by race and ethnicity.

945
00:43:51.829 --> 00:43:55.650
And so this is some work again from a few years ago

946
00:43:55.650 --> 00:44:00.093
showing that if we look in individuals who are Caucasian,

947
00:44:01.500 --> 00:44:03.013
pathogenic variants in GJB2

948
00:44:03.013 --> 00:44:05.910
and Stereocilin are most common.

949
00:44:05.910 --> 00:44:09.213
But if you look in individuals who are African American,

950
00:44:10.410 --> 00:44:13.830
or Hispanic, the contribution of GJB2

951
00:44:13.830 --> 00:44:15.687
is very, very low for those patients.

952
00:44:15.687 --> 00:44:19.440
And so clearly, we need to consider ethnicity

953
00:44:19.440 --> 00:44:21.582
when we're thinking about diagnostic yield.

954
00:44:21.582 --> 00:44:25.890
And Dylan Chan's group from UC San Francisco

955
00:44:25.890 --> 00:44:29.880
has published some really nice work recently

956
00:44:29.880 --> 00:44:31.230
showing how important this is.

957
00:44:31.230 --> 00:44:34.350
So they looked at the diagnostic rate

958
00:44:34.350 --> 00:44:36.450
based on race and ethnicity.

959
00:44:36.450 --> 00:44:38.370
What they showed is that children

960
00:44:38.370 --> 00:44:39.720
who were Hispanic and Black

961
00:44:39.720 --> 00:44:42.360
had five times decreased chance

962
00:44:42.360 --> 00:44:46.110
of having a genetic diagnosis.

963
00:44:46.110 --> 00:44:48.750
And so clearly we have a lot of work to do

964
00:44:48.750 --> 00:44:52.440
to uncover genetic forms of hearing loss

965
00:44:52.440 --> 00:44:55.050
in individuals who are not Asian and white.

966
00:44:55.050 --> 00:44:57.120
And this is something that my lab is studying

967
00:44:57.120 --> 00:45:00.003
and I think it's hugely important work.

968
00:45:01.470 --> 00:45:04.800
So, how's this looking in my clinic overall?

969
00:45:04.800 --> 00:45:09.800
So if I have a patient that has congenital hearing loss

970
00:45:11.310 --> 00:45:14.980
that's newly diagnosed, I'll take a history physical exam

971
00:45:15.840 --> 00:45:18.750
and then, you know, we'll have audiometric evaluation.

972
00:45:18.750 --> 00:45:20.970
And if they're less than three weeks old,

973
00:45:20.970 --> 00:45:25.950
we get CMV testing via saliva swab.

974
00:45:25.950 --> 00:45:28.230
And if it's negative, we proceed.

975
00:45:28.230 --> 00:45:30.420
If there's specific physical exam findings,

976
00:45:30.420 --> 00:45:33.180
then we really should get genetic testing

977
00:45:33.180 --> 00:45:35.100
based on our suspected diagnosis.

978
00:45:35.100 --> 00:45:38.220
That's what insurance companies will almost always cover.

979
00:45:38.220 --> 00:45:40.920
And I'll talk more about insurance shortly.

980
00:45:40.920 --> 00:45:44.730
If they have no apparent physical exam findings,

981
00:45:44.730 --> 00:45:47.515
then we consider it non-syndromic hearing loss.

982
00:45:47.515 --> 00:45:50.730
And in my clinic, if it's unilateral

983
00:45:50.730 --> 00:45:52.830
and it's sensory neural hearing loss,

984
00:45:52.830 --> 00:45:56.640
in those cases the families are often

985
00:45:56.640 --> 00:45:58.110
asking me about cochlear implants.

986
00:45:58.110 --> 00:45:59.823
And so we'll proceed with imaging.

987
00:46:00.810 --> 00:46:01.920
And if it's more mild,

988
00:46:01.920 --> 00:46:04.380
then we will just go ahead with close follow ups

989
00:46:04.380 --> 00:46:07.440
or repeat audios and then consider imaging.

990
00:46:07.440 --> 00:46:10.773
But if we have bilateral hearing loss including any form

991
00:46:13.080 --> 00:46:15.480
of asymmetric hearing loss for all these patients,

992
00:46:15.480 --> 00:46:17.793
we start with comprehensive genetic testing.

993
00:46:18.780 --> 00:46:21.420
We also get an ophthalmology evaluation

994
00:46:21.420 --> 00:46:25.560
because we wanna make sure that their visual input

995
00:46:25.560 --> 00:46:27.945
is where it needs to be.

996
00:46:27.945 --> 00:46:30.360
And then we'll get an EKG for these patients

997
00:46:30.360 --> 00:46:34.633
because we don't wanna miss a hearing loss

998
00:46:35.910 --> 00:46:37.950
that's associated with a cardiac phenotype

999
00:46:37.950 --> 00:46:40.050
that could be life-threatening.

1000
00:46:40.050 --> 00:46:43.050
And then depending on the patient and the age,

1001
00:46:43.050 --> 00:46:44.580
and I'm happy to talk about this later,

1002
00:46:44.580 --> 00:46:46.890
we'll consider imaging for those

1003
00:46:46.890 --> 00:46:48.490
in a discussion with the family.

1004
00:46:50.820 --> 00:46:53.460
So some more recent data that we have

1005
00:46:53.460 --> 00:46:55.230
that's submitted that's in publication

1006
00:46:55.230 --> 00:46:56.280
goes back to this question

1007
00:46:56.280 --> 00:46:57.900
of whether we should do genetic testing

1008
00:46:57.900 --> 00:46:59.220
for asymmetric hearing loss?

1009
00:46:59.220 --> 00:47:04.220
So in our cohort of a couple hundred children that have

1010
00:47:04.710 --> 00:47:07.710
hearing loss that we performed exome sequencing on

1011
00:47:07.710 --> 00:47:09.000
our diagnostic rate, again,

1012
00:47:09.000 --> 00:47:12.780
for the bilateral symmetric individuals was about 40%.

1013
00:47:12.780 --> 00:47:17.250
It was 23% for asymmetric and it was 18% for unilateral.

1014
00:47:17.250 --> 00:47:19.890
So that's much higher than what we had seen

1015
00:47:19.890 --> 00:47:21.567
previously just a few years ago.

1016
00:47:21.567 --> 00:47:23.460
And I think that has something to do

1017
00:47:23.460 --> 00:47:27.033
with the new advances in sequencing techniques that we have.

1018
00:47:27.900 --> 00:47:30.480
And again, you may be thinking 18% diagnostic rate

1019
00:47:30.480 --> 00:47:31.740
is not very high.

1020
00:47:31.740 --> 00:47:33.870
I'll take you back to the diagnostic rate

1021
00:47:33.870 --> 00:47:38.100
for those neurologic disorders that was a similar level.

1022
00:47:38.100 --> 00:47:40.415
And I'll also point out what we found is that

1023
00:47:40.415 --> 00:47:43.500
our syndromic diagnoses did vary by symmetry.

1024
00:47:43.500 --> 00:47:47.343
So in individuals that had bilateral symmetric hearing loss,

1025
00:47:48.180 --> 00:47:50.610
20% had a syndromic diagnosis.

1026
00:47:50.610 --> 00:47:52.707
So again, this is Usher Syndrome

1027
00:47:52.707 --> 00:47:55.350
and Pendred syndrome most commonly.

1028
00:47:55.350 --> 00:48:00.150
In the individuals with bilateral asymmetric hearing loss,

1029
00:48:00.150 --> 00:48:03.480
33% or a third had a syndromic diagnosis.

1030
00:48:03.480 --> 00:48:06.240
And we were very surprised to find that

1031
00:48:06.240 --> 00:48:10.110
55% of our unilateral hearing loss with a diagnosis,

1032
00:48:10.110 --> 00:48:12.570
actually it was a syndromic form of hearing loss.

1033
00:48:12.570 --> 00:48:14.067
So these are things like CHARGE Syndrome

1034
00:48:14.067 --> 00:48:16.200
and Waardenburg Syndrome.

1035
00:48:16.200 --> 00:48:19.440
These are really important diagnoses to make.

1036
00:48:19.440 --> 00:48:23.040
And the ones that often families are most worried about

1037
00:48:23.040 --> 00:48:25.650
or most interested to hear the result from.

1038
00:48:25.650 --> 00:48:27.870
And so, some people would argue that maybe

1039
00:48:27.870 --> 00:48:30.780
it's even more important that we perform genetic evaluation

1040
00:48:30.780 --> 00:48:33.033
for unilateral hearing loss.

1041
00:48:34.440 --> 00:48:37.650
So, how do we perform genetic testing for hearing loss?

1042
00:48:37.650 --> 00:48:38.730
I told you,

1043
00:48:38.730 --> 00:48:40.710
there's all these different companies that offer it.

1044
00:48:40.710 --> 00:48:43.890
They're typically a one to three month turnaround time

1045
00:48:43.890 --> 00:48:45.660
for the test and it costs

1046
00:48:45.660 --> 00:48:49.200
somewhere between $1,000 and $4,000 depending on the test.

1047
00:48:49.200 --> 00:48:53.793
So it's actually more expensive than a CT or often an MRI.

1048
00:48:54.780 --> 00:48:57.415
But they're really complicated tests.

1049
00:48:57.415 --> 00:49:01.650
And so in back in 2014, we noticed that,

1050
00:49:01.650 --> 00:49:02.970
and I'm pointing out Aetna

1051
00:49:02.970 --> 00:49:05.310
just because it was on their website,

1052
00:49:05.310 --> 00:49:07.890
they specifically said that, there was limited published

1053
00:49:07.890 --> 00:49:12.870
evidence for the importance of these multi-gene panels.

1054
00:49:12.870 --> 00:49:15.210
And specifically they talk about our panel at Iowa,

1055
00:49:15.210 --> 00:49:17.310
which is the otoscope genetic testing.

1056
00:49:17.310 --> 00:49:19.620
At that time, they said it's considered investigational

1057
00:49:19.620 --> 00:49:21.480
and experimental.

1058
00:49:21.480 --> 00:49:25.020
And so Richard Smith and I put together this article

1059
00:49:25.020 --> 00:49:25.860
and we published it.

1060
00:49:25.860 --> 00:49:27.870
It says, "Massively Parallel Sequencing

1061
00:49:27.870 --> 00:49:29.280
for Genetic Diagnosis of Hearing Loss:

1062
00:49:29.280 --> 00:49:31.440
The New Standard of Care."

1063
00:49:31.440 --> 00:49:34.530
And we sent this to Aetna in 2015,

1064
00:49:34.530 --> 00:49:37.050
and we showed that there were 20 studies,

1065
00:49:37.050 --> 00:49:40.860
400 some controls, 600 some patients

1066
00:49:40.860 --> 00:49:43.443
that had a very high specificity and sensitivity.

1067
00:49:44.610 --> 00:49:47.370
And by 2019, there's been thousands of patients

1068
00:49:47.370 --> 00:49:49.830
that have undergone this evaluation.

1069
00:49:49.830 --> 00:49:53.070
And now I'm happy to say that several companies,

1070
00:49:53.070 --> 00:49:55.170
again, I just picked a couple different ones,

1071
00:49:55.170 --> 00:49:58.530
but Cigna deems that it's medically necessary

1072
00:49:58.530 --> 00:50:00.900
in evaluation of individuals that have hearing loss.

1073
00:50:00.900 --> 00:50:04.380
And this is Blue Cross Blue Shield said that

1074
00:50:04.380 --> 00:50:05.920
if you suspect that they have

1075
00:50:07.899 --> 00:50:09.060
a form of genetic hearing loss,

1076
00:50:09.060 --> 00:50:10.923
you should obtain a multi-gene panel.

1077
00:50:12.150 --> 00:50:14.160
And so, what this looks like at our hospital,

1078
00:50:14.160 --> 00:50:17.250
so we looked at our last 100 patients

1079
00:50:17.250 --> 00:50:22.250
that we evaluated for genetic hearing loss

1080
00:50:24.420 --> 00:50:28.110
and insurance covered overall 64% of these individuals

1081
00:50:28.110 --> 00:50:31.590
for a comprehensive genetic testing panel.

1082
00:50:31.590 --> 00:50:34.260
It was about 80% for private insurance

1083
00:50:34.260 --> 00:50:37.590
and about 50% for the public healthcare system

1084
00:50:37.590 --> 00:50:40.530
in Massachusetts, it was 0% for TRICARE

1085
00:50:40.530 --> 00:50:42.450
for the military for right now.

1086
00:50:42.450 --> 00:50:44.610
But so now we're able to say that

1087
00:50:44.610 --> 00:50:45.507
in the majority of patients,

1088
00:50:45.507 --> 00:50:48.093
the genetic evaluation is actually covered.

1089
00:50:49.050 --> 00:50:51.240
There's several research studies around the country.

1090
00:50:51.240 --> 00:50:53.520
We have one, so if individuals,

1091
00:50:53.520 --> 00:50:56.610
the insurance doesn't cover it,

1092
00:50:56.610 --> 00:50:59.220
we're able to provide essentially the same form of testing

1093
00:50:59.220 --> 00:51:00.450
as part of our research study.

1094
00:51:00.450 --> 00:51:02.400
So any individual that I see,

1095
00:51:02.400 --> 00:51:05.040
if the family wants to undergo genetic evaluation,

1096
00:51:05.040 --> 00:51:06.590
we're able to do that for them.

1097
00:51:08.070 --> 00:51:11.880
So that was kind of the who, what, where, when, why?

1098
00:51:11.880 --> 00:51:15.000
I wanna take a step back and think about

1099
00:51:15.000 --> 00:51:16.920
something called the therapeutic window.

1100
00:51:16.920 --> 00:51:20.550
And so, we think about this often

1101
00:51:20.550 --> 00:51:22.140
when we're thinking about cochlear implants.

1102
00:51:22.140 --> 00:51:25.590
And so there's something called the therapeutic efficacy.

1103
00:51:25.590 --> 00:51:27.300
And we know that for cochlear implants,

1104
00:51:27.300 --> 00:51:29.220
this decreases over time.

1105
00:51:29.220 --> 00:51:32.220
And we think that most likely what's going on

1106
00:51:32.220 --> 00:51:34.590
is there's a decrease in spinal ganglia neurons.

1107
00:51:34.590 --> 00:51:37.140
And this makes it so that the cochlear implant

1108
00:51:37.140 --> 00:51:39.360
won't work as effectively.

1109
00:51:39.360 --> 00:51:42.240
We also think about this with perspective

1110
00:51:42.240 --> 00:51:44.220
of single-sided hearing loss.

1111
00:51:44.220 --> 00:51:46.560
And so, we know that over time

1112
00:51:46.560 --> 00:51:48.450
there's a side preference that develops.

1113
00:51:48.450 --> 00:51:51.570
So if you place a cochlear implant after several years

1114
00:51:51.570 --> 00:51:53.460
of single-sided hearing loss,

1115
00:51:53.460 --> 00:51:55.380
the outcomes with that cochlear implant

1116
00:51:55.380 --> 00:51:58.113
are generally not as good for that single-sided ear.

1117
00:52:01.447 --> 00:52:03.420
You know, I just told you about all the resources

1118
00:52:03.420 --> 00:52:05.790
that we have at Boston Children's Hospital.

1119
00:52:05.790 --> 00:52:07.890
Our average age of genetic diagnosis,

1120
00:52:07.890 --> 00:52:09.480
still even with all that

1121
00:52:09.480 --> 00:52:11.913
in the current system is 13 1/2 months.

1122
00:52:13.290 --> 00:52:15.390
So that means our therapeutic window

1123
00:52:15.390 --> 00:52:18.483
is somewhere from the child to a adulthood range.

1124
00:52:19.560 --> 00:52:22.080
I'm gonna talk to you about gene therapy later.

1125
00:52:22.080 --> 00:52:24.600
But essentially, what's really important

1126
00:52:24.600 --> 00:52:25.770
for some of these discussions

1127
00:52:25.770 --> 00:52:27.610
is that we think about how we can

1128
00:52:28.800 --> 00:52:31.500
move the therapeutic window to earlier.

1129
00:52:31.500 --> 00:52:34.380
And so what I mean by that is we need to come up

1130
00:52:34.380 --> 00:52:36.180
with a genetic diagnosis earlier

1131
00:52:36.180 --> 00:52:38.550
before you have this side preference

1132
00:52:38.550 --> 00:52:41.010
and decrease in spiral ganglion neurons.

1133
00:52:41.010 --> 00:52:42.360
And this is particularly important

1134
00:52:42.360 --> 00:52:45.210
for certain types of genetic hearing loss

1135
00:52:45.210 --> 00:52:47.110
when we're talking about gene therapy.

1136
00:52:48.270 --> 00:52:51.172
So the way to think about moving

1137
00:52:51.172 --> 00:52:54.300
the therapeutic window earlier

1138
00:52:54.300 --> 00:52:57.510
is by improving the newborn hearing screening.

1139
00:52:57.510 --> 00:53:01.470
And we and others have proposed adding genetics to this.

1140
00:53:01.470 --> 00:53:04.290
I don't need to stress too much

1141
00:53:04.290 --> 00:53:07.440
the importance of newborn screening to this group,

1142
00:53:07.440 --> 00:53:09.480
except just to give some background,

1143
00:53:09.480 --> 00:53:11.100
and I like to give some context to this.

1144
00:53:11.100 --> 00:53:15.120
So if we think overall about newborn screening,

1145
00:53:15.120 --> 00:53:18.850
the goal overall is to achieve pre-symptomatic

1146
00:53:19.800 --> 00:53:23.280
and rapid diagnosis of treatable disorders

1147
00:53:23.280 --> 00:53:27.390
for which you're able to provide timely intervention, okay.

1148
00:53:27.390 --> 00:53:29.490
And these are conditions that are taught typically

1149
00:53:29.490 --> 00:53:32.340
not evident at birth and if not diagnosed

1150
00:53:32.340 --> 00:53:34.890
could result in disability or death.

1151
00:53:34.890 --> 00:53:37.050
And the goal of newborn screening is to prevent

1152
00:53:37.050 --> 00:53:39.543
or reduce significant morbidity and mortality.

1153
00:53:40.380 --> 00:53:42.240
So as many of you know,

1154
00:53:42.240 --> 00:53:45.510
newborn screening started in the 1960s

1155
00:53:45.510 --> 00:53:50.510
with this method for detection of PKU in newborn infants.

1156
00:53:52.410 --> 00:53:55.410
And this was put forth by Dr. Guthrie.

1157
00:53:55.410 --> 00:53:58.500
So he and his team were the first ones

1158
00:53:58.500 --> 00:54:01.680
to actually use dried blood spots on,

1159
00:54:01.680 --> 00:54:04.380
or obtain blood or urine on filter paper discs

1160
00:54:04.380 --> 00:54:06.393
and tests for phenylalanine.

1161
00:54:07.500 --> 00:54:09.720
And they published this in 1963

1162
00:54:09.720 --> 00:54:11.097
using this as a screening method.

1163
00:54:11.097 --> 00:54:15.660
And so this really launched the newborn screening era

1164
00:54:15.660 --> 00:54:16.653
that we're in now.

1165
00:54:17.670 --> 00:54:20.010
And so newborn screening development has started,

1166
00:54:20.010 --> 00:54:22.590
as I told you in 1963.

1167
00:54:22.590 --> 00:54:24.187
And then by 1970s,

1168
00:54:24.187 --> 00:54:28.200
PKU screening was implemented in all 50 states.

1169
00:54:28.200 --> 00:54:31.830
And over time, there's been many different

1170
00:54:31.830 --> 00:54:33.663
iterations of newborn screening.

1171
00:54:34.590 --> 00:54:37.590
There is a recommended uniform screening panel

1172
00:54:37.590 --> 00:54:39.150
that contains 35 conditions,

1173
00:54:39.150 --> 00:54:42.000
but then there's 29 other secondary conditions.

1174
00:54:42.000 --> 00:54:43.770
And when I just looked in New England,

1175
00:54:43.770 --> 00:54:45.510
it's hugely variable in New England,

1176
00:54:45.510 --> 00:54:46.890
which of these disorders

1177
00:54:46.890 --> 00:54:48.753
is screened on the newborn screening.

1178
00:54:50.670 --> 00:54:52.920
When thinking about newborn hearing screening,

1179
00:54:52.920 --> 00:54:55.830
we know that this has been immensely successful

1180
00:54:55.830 --> 00:54:59.010
in identifying children that have hearing loss early.

1181
00:54:59.010 --> 00:55:02.430
So this is just one figure from the CDC

1182
00:55:02.430 --> 00:55:05.330
talking about the number of individuals with hearing loss,

1183
00:55:06.330 --> 00:55:08.910
number of babies who are deaf or hard of hearing,

1184
00:55:08.910 --> 00:55:12.660
who were identified in 2005 versus 2019.

1185
00:55:12.660 --> 00:55:15.450
And I don't need to go into this,

1186
00:55:15.450 --> 00:55:18.420
in too much detail with this group but as you know in 94,

1187
00:55:18.420 --> 00:55:22.200
the JCIH endorsed Universal Newborn Hearing screening.

1188
00:55:22.200 --> 00:55:24.498
And based on data like this showing that

1189
00:55:24.498 --> 00:55:27.750
early identification of hearing loss

1190
00:55:27.750 --> 00:55:31.230
was important for receptive and expressive language scores.

1191
00:55:31.230 --> 00:55:33.690
By 1999, the AAP endorsed

1192
00:55:33.690 --> 00:55:35.730
the Universal Newborn Hearing Screening,

1193
00:55:35.730 --> 00:55:38.700
and by 2000, the guidelines were developed.

1194
00:55:38.700 --> 00:55:43.213
And by 2010 98% of newborns in the US

1195
00:55:45.330 --> 00:55:47.030
undergo newborn hearing screening.

1196
00:55:48.570 --> 00:55:51.300
So, when you take a big picture

1197
00:55:51.300 --> 00:55:53.100
on newborn screening and look at this,

1198
00:55:53.100 --> 00:55:58.100
so this is one study of 11.7 million newborns

1199
00:55:58.440 --> 00:56:00.300
from 2015 to 2017.

1200
00:56:00.300 --> 00:56:04.710
And if you look at the most commonly identified disorders

1201
00:56:04.710 --> 00:56:07.890
on the newborn screen, the most common

1202
00:56:07.890 --> 00:56:10.680
are things like primary congenital hypothyroidism

1203
00:56:10.680 --> 00:56:13.830
and sickle cell disease, as well as cystic fibrosis.

1204
00:56:13.830 --> 00:56:16.140
There's things that I unfortunately

1205
00:56:16.140 --> 00:56:17.460
don't remember from medical school

1206
00:56:17.460 --> 00:56:21.180
like isovaleric acidaemia.

1207
00:56:21.180 --> 00:56:24.270
But really when you look at it,

1208
00:56:24.270 --> 00:56:26.730
the by far the most common condition

1209
00:56:26.730 --> 00:56:30.270
identified on the newborn screen is hearing loss.

1210
00:56:30.270 --> 00:56:32.760
And a different way to look at this is

1211
00:56:32.760 --> 00:56:35.880
in these 11.7 million newborns,

1212
00:56:35.880 --> 00:56:39.633
hearing loss comprised 50% of the disorders

1213
00:56:41.580 --> 00:56:45.420
identified on the entire newborn screen.

1214
00:56:45.420 --> 00:56:48.840
So as hearing professionals and individuals

1215
00:56:48.840 --> 00:56:52.713
who take care of individuals that have hearing loss,

1216
00:56:53.640 --> 00:56:55.950
this is hugely important for us that we make sure

1217
00:56:55.950 --> 00:56:58.710
that the newborn screen is working to our advantage

1218
00:56:58.710 --> 00:56:59.910
and the best that it can

1219
00:57:01.170 --> 00:57:03.360
because hearing loss really is the primary condition

1220
00:57:03.360 --> 00:57:05.510
that's identified during newborn screening.

1221
00:57:07.410 --> 00:57:10.800
So another way to think about how newborn screening

1222
00:57:10.800 --> 00:57:13.410
is going is that this really nice study

1223
00:57:13.410 --> 00:57:14.860
from Nancy Young's group,

1224
00:57:14.860 --> 00:57:16.980
and it just looked at individuals

1225
00:57:16.980 --> 00:57:19.290
who were on average two years of age

1226
00:57:19.290 --> 00:57:21.780
and undergoing cochlear implantation.

1227
00:57:21.780 --> 00:57:24.840
30% of those children actually passed

1228
00:57:24.840 --> 00:57:26.070
their newborn hearing screen.

1229
00:57:26.070 --> 00:57:28.020
So they passed their newborn hearing screen

1230
00:57:28.020 --> 00:57:29.430
and they were getting cochlear implants

1231
00:57:29.430 --> 00:57:31.350
by the time they were two years old.

1232
00:57:31.350 --> 00:57:35.520
So to me, that tells me that we're clearly missing

1233
00:57:35.520 --> 00:57:37.533
people with the newborn hearing screen.

1234
00:57:38.820 --> 00:57:40.650
And if you look at overall how we're doing

1235
00:57:40.650 --> 00:57:43.713
on the JCIH, the 1-3-6 guidelines,

1236
00:57:45.360 --> 00:57:48.480
about 86% complete screening by one month,

1237
00:57:48.480 --> 00:57:50.670
which gives us about a B.

1238
00:57:50.670 --> 00:57:54.071
69% have a diagnosis by three months.

1239
00:57:54.071 --> 00:57:58.980
I have an issue with the word diagnosis in this context

1240
00:57:58.980 --> 00:58:02.880
just because it really is not an etiologic diagnosis,

1241
00:58:02.880 --> 00:58:06.870
but a diagnosis of hearing loss,

1242
00:58:06.870 --> 00:58:08.820
which is, as we talked about, is a symptom.

1243
00:58:08.820 --> 00:58:11.250
So about 69% of those undergo

1244
00:58:11.250 --> 00:58:15.270
or actually have a diagnosis by three months,

1245
00:58:15.270 --> 00:58:19.110
and then 67% have an intervention by six months.

1246
00:58:19.110 --> 00:58:22.710
So I would say we're doing fair to okay overall

1247
00:58:22.710 --> 00:58:25.230
on the 1-3-6 guidelines.

1248
00:58:25.230 --> 00:58:28.410
And when you really drill down and look at the data,

1249
00:58:28.410 --> 00:58:30.720
this is the most recent data we have from the CDC

1250
00:58:30.720 --> 00:58:34.302
looking at 3.8 million newborns in the US.

1251
00:58:34.302 --> 00:58:36.840
We we're really successful at screening

1252
00:58:36.840 --> 00:58:38.580
using the current protocols.

1253
00:58:38.580 --> 00:58:42.300
So 98.3% had newborn screening,

1254
00:58:42.300 --> 00:58:47.300
and 62,859 actually failed or referred.

1255
00:58:48.300 --> 00:58:51.330
Of those 21,000 were lost to follow up.

1256
00:58:51.330 --> 00:58:54.450
34,000 were found to have normal hearing,

1257
00:58:54.450 --> 00:58:56.817
and then 6,500 actually had hearing loss.

1258
00:58:56.817 --> 00:59:01.650
And so 35% were lost to follow up, 55% of normal hearing

1259
00:59:01.650 --> 00:59:03.841
and 10% were ultimately diagnosed

1260
00:59:03.841 --> 00:59:06.060
with a permanent hearing loss.

1261
00:59:06.060 --> 00:59:07.860
And so this was, you know,

1262
00:59:07.860 --> 00:59:10.380
when I first started looking into this several years ago,

1263
00:59:10.380 --> 00:59:12.750
I was surprised by this.

1264
00:59:12.750 --> 00:59:15.900
I think that when you talk to patients and their families

1265
00:59:15.900 --> 00:59:17.730
about the loss to follow up rate,

1266
00:59:17.730 --> 00:59:20.670
I think a big part of this is because screeners

1267
00:59:20.670 --> 00:59:24.630
very correctly tell families that

1268
00:59:24.630 --> 00:59:27.300
in the vast majority of cases it's normal.

1269
00:59:27.300 --> 00:59:29.550
They don't actually have hearing loss.

1270
00:59:29.550 --> 00:59:32.733
It's a very hard situation that screeners are put in.

1271
00:59:33.810 --> 00:59:37.020
My daughter failed her newborn hearing screen,

1272
00:59:37.020 --> 00:59:38.880
and that's very difficult to go into

1273
00:59:38.880 --> 00:59:41.663
a room with a newborn baby and tell them

1274
00:59:41.663 --> 00:59:44.310
that they failed or referred on something.

1275
00:59:44.310 --> 00:59:48.570
And so I think probably some of this loss to follow up

1276
00:59:48.570 --> 00:59:51.900
is because the result is downplayed somewhat,

1277
00:59:51.900 --> 00:59:54.660
but rightly so, because only 10% of individuals

1278
00:59:54.660 --> 00:59:58.080
are actually diagnosed with hearing loss.

1279
00:59:58.080 --> 00:59:59.910
And so the way to think about

1280
00:59:59.910 --> 01:00:02.790
the current physiologic newborn hearing screen

1281
01:00:02.790 --> 01:00:04.950
with regards to strengths and weaknesses,

1282
01:00:04.950 --> 01:00:07.470
clearly there's a universal adoption rate.

1283
01:00:07.470 --> 01:00:09.450
It's low cost overall.

1284
01:00:09.450 --> 01:00:11.760
And there's an immediate answer that's provided

1285
01:00:11.760 --> 01:00:14.160
as far as pass and refer.

1286
01:00:14.160 --> 01:00:15.840
It's easily administered.

1287
01:00:15.840 --> 01:00:17.880
And it is very highly sensitive

1288
01:00:17.880 --> 01:00:20.823
for moderate to severe hearing loss.

1289
01:00:22.320 --> 01:00:24.510
The weaknesses are that it does have

1290
01:00:24.510 --> 01:00:26.520
a low positive predictive value.

1291
01:00:26.520 --> 01:00:29.040
And so this means that it has a high false positive rate.

1292
01:00:29.040 --> 01:00:30.450
So as I told you,

1293
01:00:30.450 --> 01:00:33.513
only 90% are actually diagnosed with hearing loss.

1294
01:00:34.440 --> 01:00:37.050
And it also may not identify more mild

1295
01:00:37.050 --> 01:00:38.130
to moderate hearing loss

1296
01:00:38.130 --> 01:00:40.080
depending on the screening method used.

1297
01:00:41.490 --> 01:00:43.800
It won't identify forms of hearing loss that occur

1298
01:00:43.800 --> 01:00:45.690
outside the newborn period.

1299
01:00:45.690 --> 01:00:48.210
It's not designed to do that.

1300
01:00:48.210 --> 01:00:50.130
There's several forms of genetic hearing loss

1301
01:00:50.130 --> 01:00:53.580
that have very rapidly progressive hearing loss

1302
01:00:53.580 --> 01:00:55.710
within a couple months after birth.

1303
01:00:55.710 --> 01:00:58.320
And those forms of hearing loss will be missed

1304
01:00:58.320 --> 01:01:00.150
using physiologic screening.

1305
01:01:00.150 --> 01:01:02.550
Those are probably the patients that ended up with,

1306
01:01:02.550 --> 01:01:04.200
or a large number of the patients

1307
01:01:04.200 --> 01:01:05.520
that ended up with cochlear implants,

1308
01:01:05.520 --> 01:01:07.920
even though they passed their newborn screening.

1309
01:01:09.300 --> 01:01:14.300
Because it also misses a lot of congenital CMV

1310
01:01:14.700 --> 01:01:17.550
because that often is rapidly progressive hearing loss

1311
01:01:17.550 --> 01:01:19.110
outside the newborn period.

1312
01:01:19.110 --> 01:01:21.600
Again, that's not what the screening method

1313
01:01:21.600 --> 01:01:22.890
is designed to do.

1314
01:01:22.890 --> 01:01:24.420
And then depending on the method you use,

1315
01:01:24.420 --> 01:01:27.300
auditory neuropathy may be missed as well.

1316
01:01:27.300 --> 01:01:28.970
And then another weakness is that

1317
01:01:28.970 --> 01:01:31.200
if you don't provide etiologic information.

1318
01:01:31.200 --> 01:01:33.960
And I think this might be another reason

1319
01:01:33.960 --> 01:01:36.780
that we have such a high loss to follow up rate,

1320
01:01:36.780 --> 01:01:38.430
because you're not really saying

1321
01:01:38.430 --> 01:01:42.333
what the underlying cause of the fail or refer is.

1322
01:01:44.370 --> 01:01:45.480
So the question is,

1323
01:01:45.480 --> 01:01:48.810
can we use genetics to improve the newborn hearing screen?

1324
01:01:48.810 --> 01:01:53.810
And so several years ago, a large group of us got together.

1325
01:01:54.570 --> 01:01:56.870
Some of you on the call may have been involved with this.

1326
01:01:56.870 --> 01:02:00.690
It was a really enlightening series of discussions.

1327
01:02:00.690 --> 01:02:01.833
I learned a lot.

1328
01:02:02.768 --> 01:02:06.450
The idea was to bring a group that includes

1329
01:02:06.450 --> 01:02:10.320
stakeholders and clinicians and really discuss

1330
01:02:10.320 --> 01:02:12.963
how we could improve the newborn hearing screen.

1331
01:02:13.920 --> 01:02:16.200
And essentially what we proposed is,

1332
01:02:16.200 --> 01:02:19.530
as opposed to the current method where we have

1333
01:02:19.530 --> 01:02:22.920
all newborns undergo a physiologic screen, if they fail,

1334
01:02:22.920 --> 01:02:26.700
then we do genetic testing or CMV or another evaluation,

1335
01:02:26.700 --> 01:02:30.180
we proposed a comprehensive newborn hearing screening

1336
01:02:30.180 --> 01:02:33.300
where we perform physiologic genetic and CMV screening

1337
01:02:33.300 --> 01:02:36.810
on all individuals all at once with the goal to be,

1338
01:02:36.810 --> 01:02:39.120
to provide ideological information,

1339
01:02:39.120 --> 01:02:41.370
reduce the time to diagnosis,

1340
01:02:41.370 --> 01:02:44.583
and then hopefully reduce the loss to follow up rate.

1341
01:02:46.380 --> 01:02:49.350
So this gets really difficult because as I told you,

1342
01:02:49.350 --> 01:02:51.570
genetic hearing loss is really complicated.

1343
01:02:51.570 --> 01:02:55.230
I told you about the 1.2 million base pairs of DNA

1344
01:02:55.230 --> 01:02:58.290
and there's more than 8,000 reported hearing loss mutations.

1345
01:02:58.290 --> 01:03:01.170
So how do we perform this genetic screening?

1346
01:03:01.170 --> 01:03:03.750
And this is where we're kind of stuck right now,

1347
01:03:03.750 --> 01:03:07.380
and several groups are working on this including my lab.

1348
01:03:07.380 --> 01:03:08.730
The two different ways to look at this

1349
01:03:08.730 --> 01:03:10.470
is a more limited screen.

1350
01:03:10.470 --> 01:03:14.310
So you screen just the most common genetic variants,

1351
01:03:14.310 --> 01:03:16.260
or you do something like genome sequencing

1352
01:03:16.260 --> 01:03:20.490
or a test very similar to the diagnostic test

1353
01:03:20.490 --> 01:03:23.090
where you screen all the hearing loss genes at once.

1354
01:03:24.450 --> 01:03:25.590
The issue is that,

1355
01:03:25.590 --> 01:03:27.417
what are the most common genetic causes of hearing loss?

1356
01:03:27.417 --> 01:03:30.810
And I told you that it really varies

1357
01:03:30.810 --> 01:03:31.950
based on your ethnicity.

1358
01:03:31.950 --> 01:03:36.950
So for instance, if you were just to screen GJB2 variants,

1359
01:03:37.470 --> 01:03:38.817
you detect about, you know,

1360
01:03:38.817 --> 01:03:43.080
15, 20% of Caucasian individuals would have that.

1361
01:03:43.080 --> 01:03:47.850
But that's essentially cause of and 0% of African Americans.

1362
01:03:47.850 --> 01:03:49.290
And so it's really not helpful

1363
01:03:49.290 --> 01:03:53.313
for specific races or ethnicities.

1364
01:03:54.240 --> 01:03:55.440
And so what we looked at is,

1365
01:03:55.440 --> 01:03:59.550
if you screen only the 10 most common genetic mutations

1366
01:03:59.550 --> 01:04:03.660
or genetic variants in a mixed population like the US,

1367
01:04:03.660 --> 01:04:05.130
you come up with a diagnosis

1368
01:04:05.130 --> 01:04:08.310
or a screen positive and only about 35%.

1369
01:04:08.310 --> 01:04:12.090
Whereas in a ethnically more mixed or sorry,

1370
01:04:12.090 --> 01:04:16.560
ethnically more homogeneous population like the Han Chinese,

1371
01:04:16.560 --> 01:04:21.560
you'll come up with a positive screening about 57%.

1372
01:04:22.020 --> 01:04:24.330
And so that's what they've actually been doing in China

1373
01:04:24.330 --> 01:04:26.370
for several years now.

1374
01:04:26.370 --> 01:04:30.600
So this was one study from 2019.

1375
01:04:30.600 --> 01:04:33.630
And this looked at 1.1 million newborns

1376
01:04:33.630 --> 01:04:35.520
between 2012 and 2017.

1377
01:04:35.520 --> 01:04:37.890
And they did the physiologic screen,

1378
01:04:37.890 --> 01:04:41.763
which was an OAE with a rescreen with AABR.

1379
01:04:42.840 --> 01:04:45.360
And then they did a genetic screen with the top 20 variants

1380
01:04:45.360 --> 01:04:49.102
in the most common hearing loss genes in China.

1381
01:04:49.102 --> 01:04:51.900
And they were able to provide a result in two weeks.

1382
01:04:51.900 --> 01:04:55.950
And the positive result was a clearly causative

1383
01:04:55.950 --> 01:04:59.610
set of variants in GJB2 or SLC26A4.

1384
01:04:59.610 --> 01:05:01.080
They had inconclusive results.

1385
01:05:01.080 --> 01:05:02.400
And then they included

1386
01:05:02.400 --> 01:05:04.380
the mitochondrial genes on here, you know.

1387
01:05:04.380 --> 01:05:06.753
I won't talk about this a bunch except to say that

1388
01:05:06.753 --> 01:05:11.753
some mitochondrial genetic variants are associated with

1389
01:05:14.520 --> 01:05:18.090
exquisite sensitivity to amino glycoside hearing loss.

1390
01:05:18.090 --> 01:05:21.330
And so if you know that you have a genetic variant

1391
01:05:21.330 --> 01:05:23.670
in these mitochondrial genes,

1392
01:05:23.670 --> 01:05:25.167
you can avoid those amino glycosides.

1393
01:05:25.167 --> 01:05:27.303
And so they included that on their screen.

1394
01:05:28.560 --> 01:05:29.880
So this is what their data looked like.

1395
01:05:29.880 --> 01:05:33.300
So they had 1.1 million newborns,

1396
01:05:33.300 --> 01:05:38.300
55,000 or about 56,000 screened non-negative.

1397
01:05:39.060 --> 01:05:44.060
And of those, about 0.25% had an actual actionable result,

1398
01:05:44.880 --> 01:05:47.700
and 360 had a positive genetic screen.

1399
01:05:47.700 --> 01:05:50.040
So the numbers weren't huge,

1400
01:05:50.040 --> 01:05:53.940
but they followed up on 112 of the positive patients

1401
01:05:53.940 --> 01:05:57.870
that individuals who screened genetic positive.

1402
01:05:57.870 --> 01:06:02.870
And of the a 112, 65 did fail the physiologic screen.

1403
01:06:03.357 --> 01:06:08.357
But 47 of those individuals actually had a genetic form

1404
01:06:09.090 --> 01:06:10.560
of hearing loss and they passed

1405
01:06:10.560 --> 01:06:12.180
their newborn hearing screen.

1406
01:06:12.180 --> 01:06:15.513
So 42% benefited from the genetic screen.

1407
01:06:16.590 --> 01:06:19.710
And they really felt like limited screening works well

1408
01:06:19.710 --> 01:06:22.923
for this ethnically homogeneous population.

1409
01:06:23.760 --> 01:06:25.230
They also felt like,

1410
01:06:25.230 --> 01:06:26.520
and there's other studies showing that

1411
01:06:26.520 --> 01:06:29.130
it does seem to decrease the loss to follow up.

1412
01:06:29.130 --> 01:06:31.350
And maybe that's because they perform

1413
01:06:31.350 --> 01:06:34.530
a callback in two weeks to provide results back

1414
01:06:34.530 --> 01:06:36.060
and the family knows that they're waiting

1415
01:06:36.060 --> 01:06:38.610
for a genetic result for the screen.

1416
01:06:38.610 --> 01:06:40.680
We still need to clarify that,

1417
01:06:40.680 --> 01:06:43.330
and we need a lot more work on the loss to follow up.

1418
01:06:44.370 --> 01:06:47.550
So I'm excited to say that in Ontario in Canada,

1419
01:06:47.550 --> 01:06:51.690
they've implemented a sort of similar genetic screen.

1420
01:06:51.690 --> 01:06:54.870
And this is a ethnically heterogeneous population.

1421
01:06:54.870 --> 01:06:58.620
This just started, I think the past year.

1422
01:06:58.620 --> 01:07:02.610
I'm really interested to see how this turns out for them.

1423
01:07:02.610 --> 01:07:07.020
So they're screening the genes, GJB2, GJB6 and SLC26A4

1424
01:07:09.450 --> 01:07:11.760
and they're also screening for CMB.

1425
01:07:11.760 --> 01:07:14.220
So they're performing a comprehensive

1426
01:07:14.220 --> 01:07:17.340
newborn hearing screening with genetics in CMB.

1427
01:07:17.340 --> 01:07:20.130
And I'll be interested to see how this turns out.

1428
01:07:20.130 --> 01:07:21.753
So it is happening already.

1429
01:07:23.100 --> 01:07:25.410
So we can also look at the strengths and weaknesses

1430
01:07:25.410 --> 01:07:26.910
of genetic newborn hearing screening.

1431
01:07:26.910 --> 01:07:31.140
So it should identify children missed by physiologic screen.

1432
01:07:31.140 --> 01:07:33.090
I think that's what the data shows from China,

1433
01:07:33.090 --> 01:07:34.490
and that's what we expected.

1434
01:07:35.340 --> 01:07:37.950
It does provide etiologic information

1435
01:07:37.950 --> 01:07:40.623
and it does allow you to screen for ototoxicity,

1436
01:07:41.460 --> 01:07:44.670
although, you know, the timeframe typically needed for that

1437
01:07:44.670 --> 01:07:48.240
is varied in very young children to be most helpful.

1438
01:07:48.240 --> 01:07:51.240
And then I would hypothesize or I would think that

1439
01:07:51.240 --> 01:07:55.620
it should shorten the time to diagnosis and intervention,

1440
01:07:55.620 --> 01:07:57.390
which is very important.

1441
01:07:57.390 --> 01:07:59.730
And then you have a single point of contact

1442
01:07:59.730 --> 01:08:01.830
where you obtain the genetic evaluation

1443
01:08:01.830 --> 01:08:04.353
and the physiologic evaluation at the same time.

1444
01:08:05.670 --> 01:08:08.430
The weaknesses is that it's a really complicated analysis.

1445
01:08:08.430 --> 01:08:10.380
So most of the time for genetic diagnosis,

1446
01:08:10.380 --> 01:08:14.250
the hardest part is interpreting all the genetic variants.

1447
01:08:14.250 --> 01:08:17.340
The approach that my lab is working on with this,

1448
01:08:17.340 --> 01:08:19.350
which I'll talk more about in a minute,

1449
01:08:19.350 --> 01:08:22.770
is trying to simplify this using everything we've learned

1450
01:08:22.770 --> 01:08:25.380
about genetic hearing loss over the past decade or so,

1451
01:08:25.380 --> 01:08:28.770
so that we're able to provide a pass inconclusive

1452
01:08:28.770 --> 01:08:31.560
or a fail or refer.

1453
01:08:31.560 --> 01:08:35.430
So the interpretation of the results is not difficult.

1454
01:08:35.430 --> 01:08:36.900
Another weakness is thinking about things

1455
01:08:36.900 --> 01:08:38.220
called secondary findings.

1456
01:08:38.220 --> 01:08:40.140
So this isn't something that I've talked about yet,

1457
01:08:40.140 --> 01:08:43.260
but anytime you perform a genetic evaluation,

1458
01:08:43.260 --> 01:08:46.170
you may identify genetic variants

1459
01:08:46.170 --> 01:08:49.080
that affect things that you didn't wanna look into.

1460
01:08:49.080 --> 01:08:52.200
So for instance, if you get to do,

1461
01:08:52.200 --> 01:08:54.660
some people are proposing doing genome sequencing

1462
01:08:54.660 --> 01:08:58.620
or sequencing the whole genome on babies very young age.

1463
01:08:58.620 --> 01:09:02.550
That's kind of like doing a whole body CT or MRI scan.

1464
01:09:02.550 --> 01:09:04.950
You may find things that you weren't really interested in.

1465
01:09:04.950 --> 01:09:08.280
And so we have to be really careful in diagnosing

1466
01:09:08.280 --> 01:09:11.700
or identifying conditions in very young children,

1467
01:09:11.700 --> 01:09:15.210
particularly if the family wasn't interested

1468
01:09:15.210 --> 01:09:16.920
in finding these things out.

1469
01:09:16.920 --> 01:09:19.740
And so one approach is just to ignore all of those

1470
01:09:19.740 --> 01:09:21.573
and not provide those findings back.

1471
01:09:22.860 --> 01:09:25.440
Also, the sequencing costs, which we need to think about.

1472
01:09:25.440 --> 01:09:28.410
In order to successfully be implemented,

1473
01:09:28.410 --> 01:09:30.450
costs have to be really low when you think about

1474
01:09:30.450 --> 01:09:32.430
doing things on a universal level.

1475
01:09:32.430 --> 01:09:33.660
I already showed you the chart

1476
01:09:33.660 --> 01:09:35.403
of the cost of genome sequencing.

1477
01:09:36.750 --> 01:09:40.737
My goal in my lab is to get the cost down below $100.

1478
01:09:40.737 --> 01:09:42.420
And I think we'll be able to do that

1479
01:09:42.420 --> 01:09:43.743
for the genetic screening.

1480
01:09:44.580 --> 01:09:46.890
And so this is what this looks like,

1481
01:09:46.890 --> 01:09:47.850
a different way to look at this.

1482
01:09:47.850 --> 01:09:49.230
So the current standard,

1483
01:09:49.230 --> 01:09:51.960
as we talked about is the physiologic screen.

1484
01:09:51.960 --> 01:09:53.760
When they fail that, we use saliva

1485
01:09:53.760 --> 01:09:55.800
or blood to do genetic screening.

1486
01:09:55.800 --> 01:09:56.700
And here at Children's,

1487
01:09:56.700 --> 01:09:59.550
we always get saliva on individuals that fail

1488
01:09:59.550 --> 01:10:02.130
newborn hearing screening and we do CMV screening.

1489
01:10:02.130 --> 01:10:04.740
I told you that this gives us an average age of diagnosis

1490
01:10:04.740 --> 01:10:07.080
about 13 1/2 months.

1491
01:10:07.080 --> 01:10:10.530
Our goal is to this proposed rapid comprehensive screen

1492
01:10:10.530 --> 01:10:12.450
where we have physiologic screening.

1493
01:10:12.450 --> 01:10:15.060
When they fail, that we obtain a dried blood spot,

1494
01:10:15.060 --> 01:10:16.950
and then we're able to do genetic screening

1495
01:10:16.950 --> 01:10:19.200
and CMV screening from that.

1496
01:10:19.200 --> 01:10:21.540
And as I told you, our goal is less than $100.

1497
01:10:21.540 --> 01:10:23.690
Hopefully we can get it much less than that

1498
01:10:26.267 --> 01:10:28.680
and a result with the actual

1499
01:10:28.680 --> 01:10:30.810
etiologic diagnosis by three months,

1500
01:10:30.810 --> 01:10:33.840
which I also think we should be able to do with this method.

1501
01:10:33.840 --> 01:10:35.520
So I'm really excited about working on this.

1502
01:10:35.520 --> 01:10:37.930
I think there's a lot of issues still

1503
01:10:39.300 --> 01:10:41.250
that we need to move forward with,

1504
01:10:41.250 --> 01:10:43.390
but, you know, I'm happy to see

1505
01:10:44.370 --> 01:10:46.320
that in Ontario they're going ahead with it

1506
01:10:46.320 --> 01:10:49.713
and as I told you, they've been doing it in China for years.

1507
01:10:50.580 --> 01:10:53.610
So the last section that I'll talk to you about

1508
01:10:53.610 --> 01:10:55.263
is gene therapy for hearing loss.

1509
01:10:57.295 --> 01:11:00.240
What I wanted to do here is, as I told you,

1510
01:11:00.240 --> 01:11:02.040
this is happening now.

1511
01:11:02.040 --> 01:11:04.860
Your patients are going to be talking to you about this

1512
01:11:04.860 --> 01:11:06.723
as they hear about this in the news,

1513
01:11:07.620 --> 01:11:09.000
as they hear about clinical trials.

1514
01:11:09.000 --> 01:11:11.370
And so I think it's helpful for you all

1515
01:11:11.370 --> 01:11:13.290
to be informed at least somewhat,

1516
01:11:13.290 --> 01:11:16.260
with why we're moving forward with gene therapy

1517
01:11:16.260 --> 01:11:19.350
for these specific forms of hearing loss.

1518
01:11:19.350 --> 01:11:21.210
The other point that I'll also say

1519
01:11:21.210 --> 01:11:25.762
before I even talk about this is I like to,

1520
01:11:25.762 --> 01:11:27.630
when I take care of any individual

1521
01:11:27.630 --> 01:11:29.250
that has hearing loss,

1522
01:11:29.250 --> 01:11:32.070
any individual who is deaf or hard of hearing,

1523
01:11:32.070 --> 01:11:33.750
I prioritize their goals.

1524
01:11:33.750 --> 01:11:36.400
And so, I have many patients that

1525
01:11:37.710 --> 01:11:40.110
sign language is their primary form of communication.

1526
01:11:40.110 --> 01:11:42.450
I have many patients that want

1527
01:11:42.450 --> 01:11:44.040
cochlear implants as soon as possible.

1528
01:11:44.040 --> 01:11:47.440
I try to treat all patients and all individuals

1529
01:11:49.500 --> 01:11:51.627
as how I would wanna be treated essentially

1530
01:11:51.627 --> 01:11:54.270
and if they were my family members.

1531
01:11:54.270 --> 01:11:57.270
What I'm gonna say is that these new clinical trials,

1532
01:11:57.270 --> 01:12:00.540
these gene therapy trials,

1533
01:12:00.540 --> 01:12:03.840
they're revisiting some issues with hearing loss

1534
01:12:03.840 --> 01:12:06.414
that started when cochlear implants

1535
01:12:06.414 --> 01:12:08.430
really became mainstream.

1536
01:12:08.430 --> 01:12:10.290
And what I mean by that is,

1537
01:12:10.290 --> 01:12:12.810
it's bringing up all these sort of questions

1538
01:12:12.810 --> 01:12:17.190
and ethical dilemmas about how we should treat hearing loss,

1539
01:12:17.190 --> 01:12:19.440
whether we should treat hearing loss at all.

1540
01:12:19.440 --> 01:12:24.030
And so again, I'd like to treat every individual

1541
01:12:24.030 --> 01:12:25.470
on an individual basis.

1542
01:12:25.470 --> 01:12:29.040
And so I'm not advocating specifically

1543
01:12:29.040 --> 01:12:33.000
for one form of therapy for a patient versus another.

1544
01:12:33.000 --> 01:12:35.430
But it does raise a lot of interesting questions.

1545
01:12:35.430 --> 01:12:38.193
And so, I'm happy to to discuss that going forward.

1546
01:12:39.360 --> 01:12:42.840
So I don't know if you've seen these press releases,

1547
01:12:42.840 --> 01:12:46.860
but just three months ago now, not even three months ago,

1548
01:12:46.860 --> 01:12:50.490
a company based in Boston, Akouos received FDA clearance

1549
01:12:50.490 --> 01:12:54.390
for phase one clinical trials for gene therapy

1550
01:12:54.390 --> 01:12:56.310
for otoferlin mediated hearing loss.

1551
01:12:56.310 --> 01:12:58.230
And so for years I've been saying,

1552
01:12:58.230 --> 01:13:01.290
gene therapy's coming soon, for hearing loss coming soon.

1553
01:13:01.290 --> 01:13:03.140
And then all of a sudden it happened.

1554
01:13:04.080 --> 01:13:06.660
This was followed about a month later by another company,

1555
01:13:06.660 --> 01:13:09.870
which is also based in Boston called Decibel Therapeutics.

1556
01:13:09.870 --> 01:13:14.070
They are also targeting otoferlin hearing loss.

1557
01:13:14.070 --> 01:13:16.080
And so the first question you may have is,

1558
01:13:16.080 --> 01:13:18.580
why are they talking about otoferlin hearing loss?

1559
01:13:19.470 --> 01:13:21.810
And, and that's what I wanna focus a bit on is,

1560
01:13:21.810 --> 01:13:24.153
why this form of hearing loss in particular.

1561
01:13:25.110 --> 01:13:28.410
But just a broader picture of gene therapy for hearing loss.

1562
01:13:28.410 --> 01:13:33.130
So anytime you think about a therapy

1563
01:13:34.290 --> 01:13:36.900
and a genetic therapy, you have to think about the method.

1564
01:13:36.900 --> 01:13:40.560
So whether you're going to actually replace the gene

1565
01:13:40.560 --> 01:13:43.350
that's non-functioning or not present,

1566
01:13:43.350 --> 01:13:46.740
whether you're going to suppress that gene

1567
01:13:46.740 --> 01:13:50.640
that's not working so that the sort of gene

1568
01:13:50.640 --> 01:13:53.910
that's working correctly can work in overdrive

1569
01:13:53.910 --> 01:13:58.083
and overcome that gene that's not appropriately working.

1570
01:13:59.010 --> 01:14:03.030
You can also perform therapy by actually editing the gene.

1571
01:14:03.030 --> 01:14:05.220
And then there's things like cell replacements,

1572
01:14:05.220 --> 01:14:06.780
which aren't really gene therapy at all,

1573
01:14:06.780 --> 01:14:09.600
but things like using stem cells

1574
01:14:09.600 --> 01:14:14.600
to correct hearing loss in the auditory system.

1575
01:14:15.990 --> 01:14:17.640
You also have to think about things like,

1576
01:14:17.640 --> 01:14:19.560
how efficacious is the therapy?

1577
01:14:19.560 --> 01:14:22.950
So is it going to be more helpful than things

1578
01:14:22.950 --> 01:14:25.320
like hearing aids or cochlear implants?

1579
01:14:25.320 --> 01:14:27.210
There's things like the systemic effects

1580
01:14:27.210 --> 01:14:29.640
of the vector that we use in the virus.

1581
01:14:29.640 --> 01:14:32.010
I mean, it's been incredible to hear

1582
01:14:32.010 --> 01:14:34.860
all the debates around and things like the COVID vaccine.

1583
01:14:34.860 --> 01:14:37.350
So we're going to be going through the same sort of things

1584
01:14:37.350 --> 01:14:38.610
and having the same sort of questions

1585
01:14:38.610 --> 01:14:41.640
in the hearing loss field over the next few years.

1586
01:14:41.640 --> 01:14:45.090
I'll tell you from a systemic effects perspective,

1587
01:14:45.090 --> 01:14:47.073
it's actually very helpful.

1588
01:14:48.390 --> 01:14:51.720
The cochlea is what's called an immune privileged space.

1589
01:14:51.720 --> 01:14:54.450
And so typically most things that you put into it

1590
01:14:54.450 --> 01:14:58.083
should not go systemic, go into the rest of the body.

1591
01:14:59.190 --> 01:15:00.930
But you also have to think about the safety of the approach.

1592
01:15:00.930 --> 01:15:04.680
So here this picture shows different injection techniques

1593
01:15:04.680 --> 01:15:08.223
that people have proposed to use for this gene therapy.

1594
01:15:09.510 --> 01:15:11.910
What is very helpful for me

1595
01:15:11.910 --> 01:15:13.650
when I'm thinking about my future personally,

1596
01:15:13.650 --> 01:15:16.260
is that any therapy we use

1597
01:15:16.260 --> 01:15:18.600
requires an accurate genetic diagnosis first.

1598
01:15:18.600 --> 01:15:21.090
So the baseline is before you can enroll

1599
01:15:21.090 --> 01:15:21.960
in a clinical trial,

1600
01:15:21.960 --> 01:15:24.840
before you can think about a different therapy,

1601
01:15:24.840 --> 01:15:27.027
you have to have an accurate genetic diagnosis first.

1602
01:15:27.027 --> 01:15:31.383
And so, I have a job safety from that perspective.

1603
01:15:32.820 --> 01:15:34.740
So whenever we talk about gene therapy,

1604
01:15:34.740 --> 01:15:37.110
we have to talk about the mouse

1605
01:15:37.110 --> 01:15:39.420
because the mouse has been used for decades

1606
01:15:39.420 --> 01:15:41.160
as a model for hearing loss research,

1607
01:15:41.160 --> 01:15:43.260
but there's some major weaknesses to it.

1608
01:15:43.260 --> 01:15:47.160
So the advantages are that it has a short lifespan.

1609
01:15:47.160 --> 01:15:49.860
It's about two years, and they quickly reproduce.

1610
01:15:49.860 --> 01:15:53.190
Has a low cost of housing and maintenance overall,

1611
01:15:53.190 --> 01:15:54.990
especially compared to other vertebrates

1612
01:15:54.990 --> 01:15:58.110
and other mammals like pigs for instance.

1613
01:15:58.110 --> 01:16:00.900
The ear anatomy closely approximates primates.

1614
01:16:00.900 --> 01:16:03.000
So it's not exactly the same as primates,

1615
01:16:03.000 --> 01:16:05.013
but it is very close.

1616
01:16:06.120 --> 01:16:08.370
And we can do similar measures of auditory functions.

1617
01:16:08.370 --> 01:16:12.120
So in my lab we do OAEs, we do ABRs on mice,

1618
01:16:12.120 --> 01:16:15.240
and then, you know, we also measure the vestibular system.

1619
01:16:15.240 --> 01:16:17.643
So we can do VSCPs in mice for instance.

1620
01:16:18.810 --> 01:16:20.580
Disadvantages are that

1621
01:16:20.580 --> 01:16:22.200
the hearing in mice is very different.

1622
01:16:22.200 --> 01:16:25.110
So it actually extends up to 100,000 hertz,

1623
01:16:25.110 --> 01:16:29.130
which is not really applicable in humans for instance.

1624
01:16:29.130 --> 01:16:30.600
They are very small size.

1625
01:16:30.600 --> 01:16:32.790
So that makes the surgery very difficult.

1626
01:16:32.790 --> 01:16:35.860
But I'm always impressed by what people are able to do

1627
01:16:36.726 --> 01:16:39.333
with a lot of practice.

1628
01:16:40.410 --> 01:16:42.720
And then importantly we have to think about for mice,

1629
01:16:42.720 --> 01:16:45.900
they do have what's called a, so the cochlear aqueduct,

1630
01:16:45.900 --> 01:16:48.930
which typically in humans it closes in mice.

1631
01:16:48.930 --> 01:16:49.830
It's patent.

1632
01:16:49.830 --> 01:16:52.470
So I told you how the cochlear in humans

1633
01:16:52.470 --> 01:16:54.180
it's kind of a closed system,

1634
01:16:54.180 --> 01:16:55.920
in mice it's more of an open system.

1635
01:16:55.920 --> 01:16:58.620
So you do have more systemic effects,

1636
01:16:58.620 --> 01:17:02.400
which doesn't exactly mirror humans.

1637
01:17:02.400 --> 01:17:04.620
And then the phenotypes can be very different.

1638
01:17:04.620 --> 01:17:07.260
So for instance, Usher Syndrome is very difficult

1639
01:17:07.260 --> 01:17:09.930
to model and mice because they actually don't have

1640
01:17:09.930 --> 01:17:13.743
the same vision loss that humans with Usher Syndrome do.

1641
01:17:15.210 --> 01:17:17.550
And then a really important thing

1642
01:17:17.550 --> 01:17:19.050
that's very different from humans,

1643
01:17:19.050 --> 01:17:21.420
particularly when talking about gene therapy,

1644
01:17:21.420 --> 01:17:24.320
is that mice actually can't hear until after they're born.

1645
01:17:26.130 --> 01:17:27.780
So from that perspective,

1646
01:17:27.780 --> 01:17:29.370
they're very different from humans.

1647
01:17:29.370 --> 01:17:31.860
It's actually been very helpful for hearing loss research

1648
01:17:31.860 --> 01:17:34.400
because we can actually inject gene therapy

1649
01:17:34.400 --> 01:17:36.990
in mice before they hear,

1650
01:17:36.990 --> 01:17:38.160
but that would be the equivalent

1651
01:17:38.160 --> 01:17:40.200
of doing an injection on a human

1652
01:17:40.200 --> 01:17:42.600
when they were still in utero.

1653
01:17:42.600 --> 01:17:45.453
So it's not as translatable as we would like.

1654
01:17:46.560 --> 01:17:49.290
So different ways to manipulate

1655
01:17:49.290 --> 01:17:51.480
or create a genetic mouse models.

1656
01:17:51.480 --> 01:17:53.250
There's things called reverse genetics.

1657
01:17:53.250 --> 01:17:56.460
So this is where you take a naturally occurring mutation

1658
01:17:56.460 --> 01:17:59.343
in mouse and then you identify the responsible gene,

1659
01:18:00.540 --> 01:18:03.259
or you can do things like ENU Mutagenesis

1660
01:18:03.259 --> 01:18:05.520
or DNA editing techniques.

1661
01:18:05.520 --> 01:18:08.070
This is where you actually change the mouse genome

1662
01:18:08.070 --> 01:18:11.857
and then identify the gene responsible for the phenotype.

1663
01:18:11.857 --> 01:18:14.820
Or now with new gene editing techniques,

1664
01:18:14.820 --> 01:18:17.070
which I'll talk more about on the next slide,

1665
01:18:17.070 --> 01:18:18.720
you can do things called forward genetics

1666
01:18:18.720 --> 01:18:21.660
where you take a mouse that does not have a hearing loss

1667
01:18:21.660 --> 01:18:23.880
and then you edit the gene so that

1668
01:18:23.880 --> 01:18:26.760
they do have hearing loss afterwards.

1669
01:18:26.760 --> 01:18:28.890
All of these methods are used regularly

1670
01:18:28.890 --> 01:18:30.903
studying hearing loss mice.

1671
01:18:31.770 --> 01:18:34.170
You may have heard about CRISPR Cas9.

1672
01:18:34.170 --> 01:18:38.290
So this is the technology that's really changed

1673
01:18:39.270 --> 01:18:42.180
gene editing and the whole field of genetics in general.

1674
01:18:42.180 --> 01:18:44.190
And for this reason,

1675
01:18:44.190 --> 01:18:46.440
Jennifer Doudna was awarded the Nobel Prize

1676
01:18:46.440 --> 01:18:48.540
just a couple years ago.

1677
01:18:48.540 --> 01:18:49.890
The short of it is that,

1678
01:18:49.890 --> 01:18:54.890
it's this method that's used where there's a protein

1679
01:18:55.140 --> 01:18:58.140
and it latches onto a DNA sequence

1680
01:18:58.140 --> 01:19:00.270
through something called a guide RNA.

1681
01:19:00.270 --> 01:19:03.750
And that actually allows the DNA to be sliced

1682
01:19:03.750 --> 01:19:06.330
and then the gene can actually be deleted

1683
01:19:06.330 --> 01:19:09.870
or you can insert a new gene or insert a change.

1684
01:19:09.870 --> 01:19:12.600
And so really, this technology means that

1685
01:19:12.600 --> 01:19:16.023
for the first time we can directly edit the genome.

1686
01:19:18.030 --> 01:19:21.136
So an overview of how I think about

1687
01:19:21.136 --> 01:19:23.100
gene therapy for hearing loss.

1688
01:19:23.100 --> 01:19:24.900
So first thing you have to do is,

1689
01:19:24.900 --> 01:19:27.540
you determine the molecular mechanism of the hearing loss.

1690
01:19:27.540 --> 01:19:30.030
So first, you have to figure out

1691
01:19:30.030 --> 01:19:31.827
what's actually causing the hearing loss.

1692
01:19:31.827 --> 01:19:33.300
And so in this example,

1693
01:19:33.300 --> 01:19:35.520
we'll say that this is an inner hair cell

1694
01:19:35.520 --> 01:19:39.930
that lacks expression of a critical protein.

1695
01:19:39.930 --> 01:19:42.910
So, there's a protein that's missing encoded by a gene

1696
01:19:43.800 --> 01:19:46.590
that causes the hearing loss.

1697
01:19:46.590 --> 01:19:50.070
You have to choose what virus you use and what promoter.

1698
01:19:50.070 --> 01:19:54.690
So a promoter is the thing that makes the gene transcribed.

1699
01:19:54.690 --> 01:19:57.210
And so, a very common approach is to use

1700
01:19:57.210 --> 01:20:00.330
something called an adeno-associated virus.

1701
01:20:00.330 --> 01:20:02.820
And this virus would actually include the gene

1702
01:20:02.820 --> 01:20:06.060
that's required as well as a promoter

1703
01:20:06.060 --> 01:20:08.880
that only works in the hair cells.

1704
01:20:08.880 --> 01:20:10.042
You can use the promoters

1705
01:20:10.042 --> 01:20:13.560
to say where the gene would be expressed.

1706
01:20:13.560 --> 01:20:15.990
And so here we'd say only the hair cells.

1707
01:20:15.990 --> 01:20:18.180
And then you'd need to choose your surgical approach.

1708
01:20:18.180 --> 01:20:21.870
And so one approach that's gaining favor

1709
01:20:21.870 --> 01:20:24.183
is to use a round window injection.

1710
01:20:25.050 --> 01:20:27.480
But when you inject fluid into the cochlea,

1711
01:20:27.480 --> 01:20:29.880
you need to think about the pressure in the cochlea.

1712
01:20:29.880 --> 01:20:32.040
And so you can't inject fluid

1713
01:20:32.040 --> 01:20:33.147
without causing extra pressure,

1714
01:20:33.147 --> 01:20:35.097
and that could cause more hearing loss.

1715
01:20:35.097 --> 01:20:36.630
And so what people have proposed

1716
01:20:36.630 --> 01:20:39.000
is to actually do a stapedectomy

1717
01:20:39.000 --> 01:20:42.690
or actually make a port for some of the fluid

1718
01:20:42.690 --> 01:20:45.180
to come out so that you don't cause further hearing loss.

1719
01:20:45.180 --> 01:20:47.380
And then you would close that up afterwards.

1720
01:20:48.420 --> 01:20:50.700
So specifically otoferlin hearing loss.

1721
01:20:50.700 --> 01:20:53.853
So otoferlin or OTOF,

1722
01:20:54.990 --> 01:20:59.160
this causes a type of auditory neuropathy spectrum disorder.

1723
01:20:59.160 --> 01:21:03.450
And so this is some representative physiologic data

1724
01:21:03.450 --> 01:21:07.560
from individuals with otoferlin hearing loss.

1725
01:21:07.560 --> 01:21:12.560
You can see the finding on the ABR with no response,

1726
01:21:12.600 --> 01:21:14.520
but then you see the OAEs,

1727
01:21:14.520 --> 01:21:17.040
there's a response which is similarly matched

1728
01:21:17.040 --> 01:21:19.833
with the cochlear microphonic, you can see.

1729
01:21:21.660 --> 01:21:26.527
And what we find and what makes the consideration

1730
01:21:28.050 --> 01:21:30.540
of otoferlin for gene therapy very difficult

1731
01:21:30.540 --> 01:21:32.820
is that these patients actually do very well

1732
01:21:32.820 --> 01:21:34.350
with cochlear implants.

1733
01:21:34.350 --> 01:21:36.000
And we think that's probably because,

1734
01:21:36.000 --> 01:21:40.470
as I'll show on the next slide, the physiology of otoferlin,

1735
01:21:40.470 --> 01:21:41.880
it affects the hair cell

1736
01:21:41.880 --> 01:21:44.160
and that's bypassed by the cochlear implant.

1737
01:21:44.160 --> 01:21:45.210
And so these patients actually

1738
01:21:45.210 --> 01:21:47.130
do very well with cochlear implants.

1739
01:21:47.130 --> 01:21:50.790
And so that actually sets a very high bar for gene therapy

1740
01:21:50.790 --> 01:21:51.960
because you would need to say,

1741
01:21:51.960 --> 01:21:54.630
well, they need to do better than cochlear implant,

1742
01:21:54.630 --> 01:21:56.930
which again, I think is going to be difficult.

1743
01:21:57.840 --> 01:21:59.790
This is the physiology of otoferlin.

1744
01:21:59.790 --> 01:22:03.436
So otoferlin encodes for this protein,

1745
01:22:03.436 --> 01:22:05.820
and this protein actually is found

1746
01:22:05.820 --> 01:22:07.860
at the base of the inner hair cell.

1747
01:22:07.860 --> 01:22:11.940
And it actually helps with the fusion of the vesicle

1748
01:22:11.940 --> 01:22:15.750
that allows release of the glutamate out of the hair cell.

1749
01:22:15.750 --> 01:22:20.640
And this helps explain why otoferlin was picked

1750
01:22:20.640 --> 01:22:24.630
as the first gene to use for gene therapy for hearing loss

1751
01:22:24.630 --> 01:22:27.060
because the hair cells developed normally,

1752
01:22:27.060 --> 01:22:29.130
the neurons developed normally.

1753
01:22:29.130 --> 01:22:33.030
It's just this one little protein that forms a latch

1754
01:22:33.030 --> 01:22:34.710
essentially that's missing.

1755
01:22:34.710 --> 01:22:38.310
And so some very smart people a few years ago realized,

1756
01:22:38.310 --> 01:22:40.380
this would be a great candidate for gene therapy

1757
01:22:40.380 --> 01:22:42.840
because the hair cells haven't all died

1758
01:22:42.840 --> 01:22:44.250
and the neurons haven't all died yet.

1759
01:22:44.250 --> 01:22:46.590
And if they could just fix this one little latch,

1760
01:22:46.590 --> 01:22:48.483
then they could restore hearing.

1761
01:22:49.740 --> 01:22:53.820
And so this is what the results look like in mice.

1762
01:22:53.820 --> 01:22:58.350
So they use a viral vector to inject a mouse

1763
01:22:58.350 --> 01:23:01.380
that has no otoferlin.

1764
01:23:01.380 --> 01:23:03.660
And you can see they can express otoferlin.

1765
01:23:03.660 --> 01:23:04.590
That's the green,

1766
01:23:04.590 --> 01:23:07.533
the bright green here in hair cells very easily.

1767
01:23:08.730 --> 01:23:10.683
It's very readily expressed.

1768
01:23:11.610 --> 01:23:15.180
And I have to apologize for the whole

1769
01:23:15.180 --> 01:23:17.250
auditory science field.

1770
01:23:17.250 --> 01:23:20.400
Someone decided a long time ago that mouse hearing tests

1771
01:23:20.400 --> 01:23:22.170
are flipped the other way around.

1772
01:23:22.170 --> 01:23:26.880
So zero decibels is at the bottom for mice

1773
01:23:26.880 --> 01:23:30.300
and 90 decibels SPL is up at the top.

1774
01:23:30.300 --> 01:23:32.130
And so, what you can see here is mice

1775
01:23:32.130 --> 01:23:33.960
with otoferlin hearing loss

1776
01:23:33.960 --> 01:23:36.000
have severe to profound hearing loss.

1777
01:23:36.000 --> 01:23:38.370
And if you treat the mice with gene therapy,

1778
01:23:38.370 --> 01:23:41.910
it essentially completely restores their hearing.

1779
01:23:41.910 --> 01:23:44.430
What's really interesting and this is the ABR

1780
01:23:44.430 --> 01:23:47.460
showing a similar improvement after,

1781
01:23:47.460 --> 01:23:50.700
what's really interesting is that you can see,

1782
01:23:50.700 --> 01:23:52.980
not every single one of the hair cells

1783
01:23:52.980 --> 01:23:56.460
was treated with otoferlin,

1784
01:23:56.460 --> 01:23:58.920
but you had essentially a normalization of the hearing.

1785
01:23:58.920 --> 01:24:01.530
So you don't need 100% transduction

1786
01:24:01.530 --> 01:24:03.483
to get improvement in hearing.

1787
01:24:05.670 --> 01:24:07.800
I wanna briefly talk about that gene

1788
01:24:07.800 --> 01:24:10.830
that I talked about earlier, Stereocilin.

1789
01:24:10.830 --> 01:24:12.300
This is as I told you,

1790
01:24:12.300 --> 01:24:14.037
the second most common cause of hearing loss

1791
01:24:14.037 --> 01:24:17.430
and this causes a more mild to moderate hearing loss.

1792
01:24:17.430 --> 01:24:19.233
Here is several individuals.

1793
01:24:20.280 --> 01:24:22.530
The mechanism by which Stereocilin

1794
01:24:22.530 --> 01:24:24.210
causes hearing loss is very different.

1795
01:24:24.210 --> 01:24:26.190
So this shows the inner hair cells here.

1796
01:24:26.190 --> 01:24:30.840
And Stereocilin helps form this connection on the top.

1797
01:24:30.840 --> 01:24:33.270
You can see all these little bright dots.

1798
01:24:33.270 --> 01:24:35.070
The connection between the hair cells

1799
01:24:35.070 --> 01:24:37.893
and the tectorial membrane that lays on top of it.

1800
01:24:39.060 --> 01:24:42.123
And that's why it has a more mild to moderate hearing loss.

1801
01:24:43.050 --> 01:24:45.660
Now, what's interesting is that

1802
01:24:45.660 --> 01:24:48.420
there's some group of people who think that

1803
01:24:48.420 --> 01:24:50.490
hearing aids work great and you don't need

1804
01:24:50.490 --> 01:24:52.350
to perform gene therapy for hearing loss.

1805
01:24:52.350 --> 01:24:56.880
And there's another group of people who feel that, you know,

1806
01:24:56.880 --> 01:24:59.400
there's certainly patients that if they could have

1807
01:24:59.400 --> 01:25:02.793
one injection and never wear a hearing aid again,

1808
01:25:03.780 --> 01:25:05.190
would they go for that?

1809
01:25:05.190 --> 01:25:07.710
And I think there probably are some individuals

1810
01:25:07.710 --> 01:25:10.560
who'd want one injection over wearing hearing aids.

1811
01:25:10.560 --> 01:25:14.100
But I just wanted to bring this example up as something,

1812
01:25:14.100 --> 01:25:16.260
it's a very common cause of hearing loss

1813
01:25:16.260 --> 01:25:18.780
compared to otoferlin which I didn't mention,

1814
01:25:18.780 --> 01:25:19.770
but I should have.

1815
01:25:19.770 --> 01:25:21.450
Otoferlin is one of one

1816
01:25:21.450 --> 01:25:24.750
of the least common causes of genetic hearing loss.

1817
01:25:24.750 --> 01:25:28.140
But again, they picked it because they know the mechanism.

1818
01:25:28.140 --> 01:25:29.520
Stereocilin is one of the most

1819
01:25:29.520 --> 01:25:30.690
common causes of hearing loss,

1820
01:25:30.690 --> 01:25:32.070
but it causes more of a mild

1821
01:25:32.070 --> 01:25:33.300
to moderate form of hearing loss.

1822
01:25:33.300 --> 01:25:35.370
So it raises some really interesting questions

1823
01:25:35.370 --> 01:25:38.310
about whether we should pursue gene therapy for it.

1824
01:25:38.310 --> 01:25:41.400
This is data from the Holt Lab.

1825
01:25:41.400 --> 01:25:42.390
I helped with this paper,

1826
01:25:42.390 --> 01:25:45.150
but with the human genetics part of it.

1827
01:25:45.150 --> 01:25:48.180
You can see that in wild type mice

1828
01:25:48.180 --> 01:25:50.520
that have no hearing loss,

1829
01:25:50.520 --> 01:25:52.650
you can see Stereocilin expressed

1830
01:25:52.650 --> 01:25:54.480
in the outer hair cells here.

1831
01:25:54.480 --> 01:25:58.740
When you have mice with no Stereocilin, that green is lost.

1832
01:25:58.740 --> 01:26:02.850
And when they treat it with gene therapy, many of the cells,

1833
01:26:02.850 --> 01:26:05.910
but not all of them will express Stereocilin.

1834
01:26:05.910 --> 01:26:08.340
What you see here really nicely is that

1835
01:26:08.340 --> 01:26:12.210
these hair cells they look very disorganized

1836
01:26:12.210 --> 01:26:15.150
in the mice that have no Stereocilin

1837
01:26:15.150 --> 01:26:17.190
and they straighten right up when you treat them

1838
01:26:17.190 --> 01:26:19.443
with Stereocilin gene therapy.

1839
01:26:20.610 --> 01:26:22.740
And they had a really excellent result

1840
01:26:22.740 --> 01:26:27.740
with these individuals were in the five best mice

1841
01:26:28.050 --> 01:26:29.550
that were treated overall.

1842
01:26:29.550 --> 01:26:32.703
They had a close to normal hearing in those mice.

1843
01:26:36.265 --> 01:26:37.617
So it raises very interesting questions,

1844
01:26:37.617 --> 01:26:39.213
and is very exciting data.

1845
01:26:40.680 --> 01:26:45.680
So to conclude, I wanted to talk about

1846
01:26:46.020 --> 01:26:48.420
how we're viewing things at Boston Children's Hospital

1847
01:26:48.420 --> 01:26:49.530
and what's going on right now.

1848
01:26:49.530 --> 01:26:51.900
Because again, this is all happening

1849
01:26:51.900 --> 01:26:53.823
whether we like it or not right now.

1850
01:26:54.810 --> 01:26:57.360
I have a really great team to work with

1851
01:26:57.360 --> 01:26:58.440
at Boston Children's Hospital.

1852
01:26:58.440 --> 01:27:02.880
So I work closely with Dr. Kenna on the clinical side.

1853
01:27:02.880 --> 01:27:05.340
On the Basic Science side, we work with Karl Koehler,

1854
01:27:05.340 --> 01:27:08.070
who does, you know, your organoid research

1855
01:27:08.070 --> 01:27:09.777
where you actually take stem cells

1856
01:27:09.777 --> 01:27:12.420
and turn them into hair cells

1857
01:27:12.420 --> 01:27:15.270
and can evaluate them in the Petri dish.

1858
01:27:15.270 --> 01:27:16.710
And then Jeff and Gwen Geleoc

1859
01:27:16.710 --> 01:27:19.290
who are both experts in gene therapy.

1860
01:27:19.290 --> 01:27:22.080
And so this is a model that we're working on today

1861
01:27:22.080 --> 01:27:23.400
and we have patients that we're taking

1862
01:27:23.400 --> 01:27:24.450
through this model now.

1863
01:27:24.450 --> 01:27:27.480
So we have a patient that has hearing loss,

1864
01:27:27.480 --> 01:27:29.790
we obtained a genetic diagnosis,

1865
01:27:29.790 --> 01:27:32.430
we worked to uncover the molecular mechanism.

1866
01:27:32.430 --> 01:27:34.080
Within a matter of months,

1867
01:27:34.080 --> 01:27:37.440
so three to four months we can make a mouse model

1868
01:27:37.440 --> 01:27:40.440
of that patient's specific hearing loss.

1869
01:27:40.440 --> 01:27:42.900
We use that CRISPR technology and we're able

1870
01:27:42.900 --> 01:27:44.850
to make a mouse that has a hearing loss

1871
01:27:45.900 --> 01:27:47.940
very similar to the patient.

1872
01:27:47.940 --> 01:27:50.670
And then we can actually test a gene therapy

1873
01:27:50.670 --> 01:27:51.870
on that mouse that has

1874
01:27:51.870 --> 01:27:54.540
the same genetic variant as that patient.

1875
01:27:54.540 --> 01:27:57.330
We can also take that patient's blood

1876
01:27:57.330 --> 01:28:00.240
and make stem cells from the blood.

1877
01:28:00.240 --> 01:28:03.540
And we can test gene therapy in the Petri dish

1878
01:28:03.540 --> 01:28:07.200
on those patients own cells to see if it'll work

1879
01:28:07.200 --> 01:28:10.140
prior to performing gene therapy for that patient.

1880
01:28:10.140 --> 01:28:14.940
So this is really exciting time right now.

1881
01:28:14.940 --> 01:28:16.860
There's a lot of moving pieces,

1882
01:28:16.860 --> 01:28:19.424
but this is kind of how I view the field right now

1883
01:28:19.424 --> 01:28:22.380
and also why it's so important.

1884
01:28:22.380 --> 01:28:24.720
Genetic diagnosis is so important to all of this.

1885
01:28:24.720 --> 01:28:26.883
And early genetic diagnosis is important.

1886
01:28:28.410 --> 01:28:31.500
So just to summarize take home points.

1887
01:28:31.500 --> 01:28:33.270
Again, starting from the very beginning,

1888
01:28:33.270 --> 01:28:34.590
hearing loss is a symptom.

1889
01:28:34.590 --> 01:28:39.283
So it's a symptom of an underlying pathogenic perturbation

1890
01:28:40.830 --> 01:28:42.540
to the auditory system.

1891
01:28:42.540 --> 01:28:45.210
And we need to reframe how we think about this so that

1892
01:28:45.210 --> 01:28:48.160
we're able to best care for our patients.

1893
01:28:48.160 --> 01:28:49.530
And the diagnosis for hearing loss

1894
01:28:49.530 --> 01:28:50.850
provides the patient and clinician

1895
01:28:50.850 --> 01:28:52.770
with valuable information.

1896
01:28:52.770 --> 01:28:55.320
And it really, for me on a daily basis

1897
01:28:55.320 --> 01:28:57.150
when I work with individuals that have hearing loss,

1898
01:28:57.150 --> 01:29:00.033
it guides management in a lot of things that I do.

1899
01:29:00.930 --> 01:29:04.293
And as I said, gene therapy for hearing loss is here today.

1900
01:29:06.990 --> 01:29:08.400
So hopefully after all this,

1901
01:29:08.400 --> 01:29:12.870
you can understand now how we can shift our thinking

1902
01:29:12.870 --> 01:29:14.430
so that we come up with a diagnosis

1903
01:29:14.430 --> 01:29:16.800
so we can best provide the treatment

1904
01:29:16.800 --> 01:29:18.813
that's appropriate for that patient.

1905
01:29:19.800 --> 01:29:23.070
And with that, I'd like to thank everybody in my lab

1906
01:29:23.070 --> 01:29:27.540
and Dr. Kenna and Jeff and Gwen's lab and Karl Koehler.

1907
01:29:27.540 --> 01:29:30.090
And thank you very much for having me.

1908
01:29:30.090 --> 01:29:32.463
I'm very happy to take any questions.

1909
01:29:33.510 --> 01:29:35.933
<v Will>This is Will Eiserman again from NCHAM.</v>

1910
01:29:37.710 --> 01:29:42.127
Dr. Shearer, thank you for such a thorough presentation.

1911
01:29:42.990 --> 01:29:47.220
You took us through a lot of heavy content,

1912
01:29:47.220 --> 01:29:50.670
but made it accessible for those of us

1913
01:29:50.670 --> 01:29:53.250
who aren't scientists or physicians.

1914
01:29:53.250 --> 01:29:54.903
So thank you for that.

1915
01:29:56.940 --> 01:30:01.140
We've got the Q and A field open for questions

1916
01:30:01.140 --> 01:30:04.320
and I have several to start us off with.

1917
01:30:04.320 --> 01:30:08.730
So first of all, Dr. Shearer,

1918
01:30:08.730 --> 01:30:12.990
when you described the 40% diagnostic rate

1919
01:30:12.990 --> 01:30:17.990
early on in your presentation, just by way of clarification,

1920
01:30:18.000 --> 01:30:22.350
is the population you were doing genetic testing comprised

1921
01:30:22.350 --> 01:30:26.613
solely of children already identified with a hearing loss?

1922
01:30:27.750 --> 01:30:29.310
<v ->Yeah. That's a good question.</v>

1923
01:30:29.310 --> 01:30:32.280
The 40% overall diagnostic rate is if you just take

1924
01:30:32.280 --> 01:30:34.920
a population of individuals that have hearing loss,

1925
01:30:34.920 --> 01:30:38.013
so children and adults, if you take everyone.

1926
01:30:39.780 --> 01:30:40.650
<v Will>Yeah.</v>

1927
01:30:40.650 --> 01:30:41.910
So that's really different

1928
01:30:41.910 --> 01:30:43.650
than what you were proposing later

1929
01:30:43.650 --> 01:30:47.910
about universal screening of children as a compliment

1930
01:30:47.910 --> 01:30:50.520
to current newborn hearing screening.

1931
01:30:50.520 --> 01:30:54.507
We wouldn't expect to see a 40% diagnostic rate of them.

1932
01:30:54.507 --> 01:30:57.390
<v ->Yeah, it's very different for screening.</v>

1933
01:30:57.390 --> 01:30:58.290
It would be very different.

1934
01:30:58.290 --> 01:31:02.880
So the data from China, for instance showed 0.25%, right.

1935
01:31:02.880 --> 01:31:06.210
A screening test is very different than a diagnostic test.

1936
01:31:06.210 --> 01:31:07.800
<v Will>Sure, sure. Yeah.</v>

1937
01:31:07.800 --> 01:31:10.470
So here's another question.

1938
01:31:10.470 --> 01:31:15.210
Sometimes people equate a condition that is described

1939
01:31:15.210 --> 01:31:20.210
as a genetic disorder as one that is hereditary.

1940
01:31:20.760 --> 01:31:22.410
Can you describe the difference

1941
01:31:22.410 --> 01:31:25.290
and give us an idea of what percentage

1942
01:31:25.290 --> 01:31:29.133
of genetic hearing loss is hereditary?

1943
01:31:30.030 --> 01:31:31.530
<v ->That's a great question.</v>

1944
01:31:31.530 --> 01:31:32.370
I get that a lot.

1945
01:31:32.370 --> 01:31:36.000
So the first way that I help explain it is that

1946
01:31:36.000 --> 01:31:39.570
the majority of people that have hearing loss,

1947
01:31:39.570 --> 01:31:41.880
their parents do not have hearing loss.

1948
01:31:41.880 --> 01:31:44.970
And that's because, again,

1949
01:31:44.970 --> 01:31:46.860
each of us has 20,000 variants

1950
01:31:46.860 --> 01:31:48.017
that are different from our parents.

1951
01:31:48.017 --> 01:31:50.340
And so it's just a combination of our parents

1952
01:31:50.340 --> 01:31:51.780
that makes us different.

1953
01:31:51.780 --> 01:31:54.780
And most genetic hearing loss is recessive.

1954
01:31:54.780 --> 01:31:56.793
So, you need one copy from each parent.

1955
01:31:58.800 --> 01:32:02.130
There's also the issue that comes up.

1956
01:32:02.130 --> 01:32:03.360
When I talk to families

1957
01:32:03.360 --> 01:32:06.300
that I always ask about family history of hearing loss

1958
01:32:06.300 --> 01:32:07.290
and they'll talk about,

1959
01:32:07.290 --> 01:32:10.410
oh, you know, my grandmother or, you know,

1960
01:32:10.410 --> 01:32:12.930
my mom had hearing loss when they're in their 70s.

1961
01:32:12.930 --> 01:32:16.050
They started wearing hearing aids.

1962
01:32:16.050 --> 01:32:19.729
There's this idea of later onset hearing loss

1963
01:32:19.729 --> 01:32:21.597
or presbycusis.

1964
01:32:21.597 --> 01:32:24.150
And that certainly has a genetic contribution,

1965
01:32:24.150 --> 01:32:28.113
but we don't have a as good of an understanding of it yet.

1966
01:32:29.220 --> 01:32:32.290
There are specific instances called genetic

1967
01:32:33.290 --> 01:32:37.800
where essentially the genetic disorder

1968
01:32:37.800 --> 01:32:40.650
becomes more severe through generations.

1969
01:32:40.650 --> 01:32:42.120
And we do see that sometimes,

1970
01:32:42.120 --> 01:32:45.123
particularly with autosomal dominant forms of hearing loss.

1971
01:32:46.590 --> 01:32:51.540
So I think that not all genetic hearing loss

1972
01:32:51.540 --> 01:32:53.790
is hereditary or runs in families

1973
01:32:53.790 --> 01:32:56.490
because the majority of it is recessive.

1974
01:32:56.490 --> 01:32:58.050
I hope that makes sense.

1975
01:32:58.050 --> 01:32:59.250
<v Will>Yes, thank you.</v>

1976
01:33:00.720 --> 01:33:03.900
Here's another question, Dr. Shearer.

1977
01:33:03.900 --> 01:33:06.180
We commonly hear that the incidence

1978
01:33:06.180 --> 01:33:09.180
of permanent hearing loss more than doubles

1979
01:33:09.180 --> 01:33:13.320
between birth and the school age for a variety of reasons.

1980
01:33:13.320 --> 01:33:16.530
What would you predict would be the impact

1981
01:33:16.530 --> 01:33:21.150
on identifying late onset or progressive hearing loss

1982
01:33:21.150 --> 01:33:24.423
by doing universal genetic testing at birth?

1983
01:33:25.410 --> 01:33:26.610
<v ->Yeah, I think it would be huge</v>

1984
01:33:26.610 --> 01:33:28.920
because I think, like I said,

1985
01:33:28.920 --> 01:33:31.710
I think the majority of those forms of hearing loss

1986
01:33:31.710 --> 01:33:36.120
that occur outside the newborn newborn period are genetic.

1987
01:33:36.120 --> 01:33:39.600
There's some very good examples of things like MYO15A

1988
01:33:39.600 --> 01:33:43.478
is one gene were within the first few months of life

1989
01:33:43.478 --> 01:33:45.780
they'll go from essentially normal hearing

1990
01:33:45.780 --> 01:33:48.690
to very severe hearing loss very quickly.

1991
01:33:48.690 --> 01:33:51.750
And so if you have that single initial point of contact,

1992
01:33:51.750 --> 01:33:55.320
you'd be able to identify those individuals a lot earlier.

1993
01:33:55.320 --> 01:33:57.660
And as I said, that's really not the goal

1994
01:33:57.660 --> 01:33:59.610
of the current physiologic newborn screen

1995
01:33:59.610 --> 01:34:02.210
because it's not hearing loss in the newborn period.

1996
01:34:03.510 --> 01:34:07.200
It would also be helpful if we had universal CMV screening

1997
01:34:07.200 --> 01:34:08.220
for the same perspective,

1998
01:34:08.220 --> 01:34:10.860
because I think a lot of those later onset

1999
01:34:10.860 --> 01:34:12.990
hearing loss individuals are CMV

2000
01:34:12.990 --> 01:34:15.933
or rapidly progressive genetic hearing loss.

2001
01:34:17.940 --> 01:34:19.470
<v Will>Okay. This is William again.</v>

2002
01:34:19.470 --> 01:34:23.793
Here's another question from one of our attendees today.

2003
01:34:24.840 --> 01:34:28.260
Of the 55% of unilaterals

2004
01:34:28.260 --> 01:34:31.980
with syndromic hearing loss you discussed,

2005
01:34:31.980 --> 01:34:35.490
was there data analysis for microtia

2006
01:34:35.490 --> 01:34:40.110
or atresia versus sensory neural hearing loss?

2007
01:34:40.110 --> 01:34:41.710
<v ->Yeah. That's a great question.</v>

2008
01:34:43.080 --> 01:34:44.340
Almost all those patients

2009
01:34:44.340 --> 01:34:46.350
had sensory and neural hearing loss.

2010
01:34:46.350 --> 01:34:48.147
Our paper is under review,

2011
01:34:48.147 --> 01:34:50.850
and it should be coming outta in the next couple weeks,

2012
01:34:50.850 --> 01:34:52.770
I can't re recall the exact number,

2013
01:34:52.770 --> 01:34:54.975
but the majority were just sensory and neural.

2014
01:34:54.975 --> 01:34:57.780
Again, what we think is going on on I told you about that

2015
01:34:57.780 --> 01:35:01.380
phenotypic spectrum of syndromes

2016
01:35:01.380 --> 01:35:03.900
where some are more severe than others,

2017
01:35:03.900 --> 01:35:05.580
probably a similar thing is happening

2018
01:35:05.580 --> 01:35:07.470
with some forms of genetic hearing loss,

2019
01:35:07.470 --> 01:35:10.320
where some forms only affect one ear

2020
01:35:10.320 --> 01:35:13.533
for complex sort of embryologic reasons,

2021
01:35:14.700 --> 01:35:17.340
particularly in things like CHARGE or Waardenburg Syndrome,

2022
01:35:17.340 --> 01:35:20.460
only one ear may be affected than another.

2023
01:35:20.460 --> 01:35:21.860
But that's a great question.

2024
01:35:23.190 --> 01:35:25.203
<v Will>Thank you. Here's another.</v>

2025
01:35:26.130 --> 01:35:28.623
You can collect your thoughts for a second here.

2026
01:35:31.050 --> 01:35:32.820
We don't want you to feel grilled.

2027
01:35:32.820 --> 01:35:34.140
<v ->Oh, no. This is great.</v>

2028
01:35:34.140 --> 01:35:34.973
<v Will>Yep.</v>

2029
01:35:34.973 --> 01:35:39.710
So can you please describe a diagnosis of congenital CMV

2030
01:35:40.560 --> 01:35:45.480
if the baby was not tested in the first 21 days of life?

2031
01:35:45.480 --> 01:35:46.920
Would you also please comment

2032
01:35:46.920 --> 01:35:50.790
on the current incidents of congenital CMV?

2033
01:35:50.790 --> 01:35:53.070
Is it based only on testing within

2034
01:35:53.070 --> 01:35:57.303
the first 21 days of life or cases also considered?

2035
01:35:58.320 --> 01:36:00.286
<v ->Yeah, those are great questions.</v>

2036
01:36:00.286 --> 01:36:04.140
This is one of the most difficult

2037
01:36:04.140 --> 01:36:06.330
and I think interesting sort of,

2038
01:36:06.330 --> 01:36:08.410
diagnostic evaluations that I have

2039
01:36:09.330 --> 01:36:12.300
because we have some patients that were,

2040
01:36:12.300 --> 01:36:13.920
it really looks like CMV.

2041
01:36:13.920 --> 01:36:16.443
So, I'm talking about a asymmetric hearing loss.

2042
01:36:17.580 --> 01:36:19.530
And we have to work really hard to figure it out.

2043
01:36:19.530 --> 01:36:24.530
So first of all, our protocol at Children's,

2044
01:36:24.570 --> 01:36:26.160
I skimmed over it a little bit,

2045
01:36:26.160 --> 01:36:28.860
but essentially if we are referred a patient

2046
01:36:28.860 --> 01:36:33.860
for a confirmatory ABR or any time any of our audiologists

2047
01:36:34.320 --> 01:36:37.710
diagnose a hearing loss for the first time,

2048
01:36:37.710 --> 01:36:39.660
they will get a CMV swab.

2049
01:36:39.660 --> 01:36:42.180
And so sometimes we actually get a CMV swab

2050
01:36:42.180 --> 01:36:43.680
on a kid who's several months old

2051
01:36:43.680 --> 01:36:45.480
that'll end up being positive.

2052
01:36:45.480 --> 01:36:47.850
And then the question is, what to do with it?

2053
01:36:47.850 --> 01:36:49.680
You know, I could do a whole presentation

2054
01:36:49.680 --> 01:36:52.290
on CMV hearing loss but the short of it is that,

2055
01:36:52.290 --> 01:36:54.180
CMV is ubiquitous in the environment.

2056
01:36:54.180 --> 01:36:58.440
So the longer delay since birth that you have,

2057
01:36:58.440 --> 01:37:01.290
the more likely you are to come in contact with it.

2058
01:37:01.290 --> 01:37:02.310
I'll tell you what I do.

2059
01:37:02.310 --> 01:37:04.680
The first thing I do is I try to get a hold

2060
01:37:04.680 --> 01:37:07.650
of the dried blood spot from the kid.

2061
01:37:07.650 --> 01:37:10.980
In most states, they actually hold the dried blood spot

2062
01:37:10.980 --> 01:37:12.447
for a long period of time.

2063
01:37:12.447 --> 01:37:15.030
And in Massachusetts, it's five years.

2064
01:37:15.030 --> 01:37:16.983
Some states they hold it forever.

2065
01:37:18.330 --> 01:37:20.730
The patients are allowed to obtain the dried blood spot.

2066
01:37:20.730 --> 01:37:23.310
Usually they have to get it through the pediatrician,

2067
01:37:23.310 --> 01:37:25.560
and then you can send the dried blood spot for testing.

2068
01:37:25.560 --> 01:37:29.643
So we use ARUP labs, ARUP Labs in in Utah.

2069
01:37:30.840 --> 01:37:32.970
And I have several patients who we are able

2070
01:37:32.970 --> 01:37:36.801
to definitively diagnose CMV from that dried blood spot.

2071
01:37:36.801 --> 01:37:39.630
And that's very helpful for them.

2072
01:37:39.630 --> 01:37:41.520
Otherwise you're stuck with kind of a,

2073
01:37:41.520 --> 01:37:44.310
<v Will>Let me interject and to clarify,</v>

2074
01:37:44.310 --> 01:37:48.030
you would have to do that because the dried blood spot

2075
01:37:48.030 --> 01:37:51.510
is not currently looking at for CMV.

2076
01:37:51.510 --> 01:37:52.983
<v ->Right. Yeah.</v>

2077
01:37:54.480 --> 01:37:57.930
Typically we use saliva for CMV

2078
01:37:57.930 --> 01:37:59.550
because it has the highest sensitivity

2079
01:37:59.550 --> 01:38:01.833
and because it's not an extra test to order.

2080
01:38:03.870 --> 01:38:05.880
It's not perfect off dried blood spots,

2081
01:38:05.880 --> 01:38:07.620
but if it gives you a positive diagnosis,

2082
01:38:07.620 --> 01:38:08.770
then you have a result.

2083
01:38:10.140 --> 01:38:11.850
Then otherwise we're stuck.

2084
01:38:11.850 --> 01:38:15.540
If that's negative or we don't have a result after that,

2085
01:38:15.540 --> 01:38:20.310
then we will get antibody testing and we can come up,

2086
01:38:20.310 --> 01:38:22.500
we'll work with our colleagues with infectious disease

2087
01:38:22.500 --> 01:38:26.340
to kind of give a general idea of whether

2088
01:38:26.340 --> 01:38:29.280
we have a hunch that it's CMV or not.

2089
01:38:29.280 --> 01:38:31.350
I'll tell you the other thing that we do is

2090
01:38:31.350 --> 01:38:33.810
even no matter what,

2091
01:38:33.810 --> 01:38:36.480
if they have a diagnosis of congenital CMV,

2092
01:38:36.480 --> 01:38:38.220
I get genetic testing on the patients

2093
01:38:38.220 --> 01:38:40.770
because we and others have examples

2094
01:38:40.770 --> 01:38:44.160
of patients we're treating with Valganciclovir,

2095
01:38:44.160 --> 01:38:48.300
which has some side effects that you have to think about.

2096
01:38:48.300 --> 01:38:50.190
And we'll get a genetic diagnosis of something

2097
01:38:50.190 --> 01:38:52.530
like GJB2 hearing loss.

2098
01:38:52.530 --> 01:38:53.580
And so in those cases,

2099
01:38:53.580 --> 01:38:56.400
we will consider stopping the Valganciclovir

2100
01:38:56.400 --> 01:38:57.540
because they have an underlying

2101
01:38:57.540 --> 01:38:59.100
genetic form of hearing loss.

2102
01:38:59.100 --> 01:39:01.050
Both of those things are so common

2103
01:39:01.050 --> 01:39:02.187
that they can occur at the same time.

2104
01:39:02.187 --> 01:39:04.770
And so, in all kids,

2105
01:39:04.770 --> 01:39:06.480
even if we're trying to get the dry blood spot,

2106
01:39:06.480 --> 01:39:08.220
I'll get genetic testing.

2107
01:39:08.220 --> 01:39:09.390
And sometimes we come up with a

2108
01:39:09.390 --> 01:39:11.820
genetic diagnosis and then we have our answer.

2109
01:39:11.820 --> 01:39:13.740
Sometimes the genetic testing's negative

2110
01:39:13.740 --> 01:39:15.690
and we're leaning towards CMV

2111
01:39:15.690 --> 01:39:17.100
and then we're more likely to think

2112
01:39:17.100 --> 01:39:20.253
that it's CMV if the genetic testing is is negative.

2113
01:39:22.650 --> 01:39:23.700
<v Will>Thank you.</v>

2114
01:39:23.700 --> 01:39:25.113
This is William again.

2115
01:39:26.130 --> 01:39:29.283
Is there an age cutoff for gene therapy?

2116
01:39:30.270 --> 01:39:32.070
<v ->That's a great question.</v>

2117
01:39:32.070 --> 01:39:33.180
And that goes into a question of,

2118
01:39:33.180 --> 01:39:35.910
which patients are we focusing on.

2119
01:39:35.910 --> 01:39:40.910
So the two companies now are focusing on adolescents

2120
01:39:47.100 --> 01:39:50.130
or young adults for otoferlin.

2121
01:39:50.130 --> 01:39:52.140
And the reason for that is because

2122
01:39:52.140 --> 01:39:54.090
I didn't really specify or show you,

2123
01:39:54.090 --> 01:39:58.710
but in mice you can treat older mice with gene therapy

2124
01:39:58.710 --> 01:40:02.760
and they do very well with otoferlin hearing loss.

2125
01:40:02.760 --> 01:40:04.290
Again, that's because the hair cells

2126
01:40:04.290 --> 01:40:06.990
are still alive even at later ages.

2127
01:40:06.990 --> 01:40:08.760
And so if you can just, you know,

2128
01:40:08.760 --> 01:40:12.420
make that latch work even at later stages

2129
01:40:12.420 --> 01:40:13.710
should be treatable.

2130
01:40:13.710 --> 01:40:16.460
People are thinking the same thing for Stereocilin too.

2131
01:40:17.670 --> 01:40:20.580
If you think about things like GJB2

2132
01:40:20.580 --> 01:40:22.800
or other forms of genetic hearing loss,

2133
01:40:22.800 --> 01:40:25.800
you would need to treat very, very early.

2134
01:40:25.800 --> 01:40:29.640
So in mice we have to treat before they even hear at all.

2135
01:40:29.640 --> 01:40:33.060
So then you're talking about like a in utero gene therapy,

2136
01:40:33.060 --> 01:40:36.450
which raises all sorts of issues, you know,

2137
01:40:36.450 --> 01:40:38.283
medically and ethically.

2138
01:40:39.390 --> 01:40:43.200
So the short answer is it completely depends

2139
01:40:43.200 --> 01:40:45.930
on the form of genetic hearing loss

2140
01:40:45.930 --> 01:40:47.343
at what age you can treat.

2141
01:40:49.140 --> 01:40:52.410
<v Will>So this is an extension of that question.</v>

2142
01:40:52.410 --> 01:40:54.000
This is William again.

2143
01:40:54.000 --> 01:40:58.053
Have you actually done gene therapy on humans?

2144
01:41:00.300 --> 01:41:01.173
<v ->I have not.</v>

2145
01:41:02.250 --> 01:41:05.430
And the first trials are still recruiting.

2146
01:41:05.430 --> 01:41:09.120
So as far as I know they haven't performed it yet.

2147
01:41:09.120 --> 01:41:11.220
There's other targeted therapies

2148
01:41:11.220 --> 01:41:14.310
that have gone through phase one trials already

2149
01:41:14.310 --> 01:41:15.600
that aren't using gene therapy,

2150
01:41:15.600 --> 01:41:19.860
but are using small molecules to help with hearing loss.

2151
01:41:19.860 --> 01:41:21.240
But as far as I know,

2152
01:41:21.240 --> 01:41:25.323
no one's actually injected a gene therapy into a human yet.

2153
01:41:26.850 --> 01:41:28.530
<v Will>This is William again.</v>

2154
01:41:28.530 --> 01:41:32.970
So Dr. Eliot, or Dr. Shearer,

2155
01:41:32.970 --> 01:41:37.970
I noticed during your presentation you made a point

2156
01:41:39.030 --> 01:41:43.110
of saying that you really wanted to respect

2157
01:41:43.110 --> 01:41:45.990
the choices of individuals

2158
01:41:45.990 --> 01:41:49.980
and that you weren't promoting any kind of

2159
01:41:49.980 --> 01:41:53.460
one size fits all approach.

2160
01:41:53.460 --> 01:41:54.293
<v ->Yep.</v>

2161
01:41:54.293 --> 01:41:57.630
<v Will>And yet, you know that there are ethical</v>

2162
01:41:57.630 --> 01:42:02.010
and other sociological sensitivities about this area.

2163
01:42:02.010 --> 01:42:04.860
So here, I'm noticing several questions

2164
01:42:04.860 --> 01:42:08.190
that kind of fit under this category.

2165
01:42:08.190 --> 01:42:12.390
And the first is regarding the 70%

2166
01:42:12.390 --> 01:42:16.500
of identified individuals with hearing loss,

2167
01:42:16.500 --> 01:42:19.920
why is the primary focus geared toward

2168
01:42:19.920 --> 01:42:22.200
correcting the hearing loss

2169
01:42:22.200 --> 01:42:25.983
rather than acceptance with human diversity?

2170
01:42:27.870 --> 01:42:31.260
<v ->Yeah, I think it's the same question as cochlear implants.</v>

2171
01:42:31.260 --> 01:42:32.790
I think it's a great question.

2172
01:42:32.790 --> 01:42:36.900
I ultimately, as I said, I wanna treat every individual

2173
01:42:36.900 --> 01:42:38.190
as they would wanna be treated.

2174
01:42:38.190 --> 01:42:41.430
And so, I don't wanna make any judgements

2175
01:42:41.430 --> 01:42:46.430
about different goals and I wanna respect every individual

2176
01:42:47.670 --> 01:42:50.490
as they wanna be treated ultimately.

2177
01:42:50.490 --> 01:42:52.200
So, if that's their goal,

2178
01:42:52.200 --> 01:42:54.050
then I'm happy to go along with that.

2179
01:42:54.930 --> 01:42:57.390
But I think this sort of form is hugely important

2180
01:42:57.390 --> 01:43:00.390
just so everybody is informed about all these issues

2181
01:43:00.390 --> 01:43:05.390
as they come up because anyone who's deaf or hard of hearing

2182
01:43:07.592 --> 01:43:10.320
is going to be hearing about this sort of thing as well.

2183
01:43:10.320 --> 01:43:12.863
And so it's important for all of us to know about it.

2184
01:43:16.710 --> 01:43:17.543
<v Will>This is William.</v>

2185
01:43:17.543 --> 01:43:22.053
Perhaps you can comment on this individual's question.

2186
01:43:25.620 --> 01:43:28.440
Are you open to using different vocabularies

2187
01:43:28.440 --> 01:43:31.620
describing populations with hearing losses

2188
01:43:31.620 --> 01:43:33.473
such as deaf, hard of hearing,

2189
01:43:33.473 --> 01:43:36.243
which would be more culturally respectful?

2190
01:43:37.410 --> 01:43:38.637
<v ->Oh, sure. Yeah.</v>

2191
01:43:38.637 --> 01:43:41.370
And if I offended anyone, I'm sorry.

2192
01:43:41.370 --> 01:43:45.450
I think that many people use hearing loss

2193
01:43:45.450 --> 01:43:47.820
as shorthand and if that, you know,

2194
01:43:47.820 --> 01:43:50.130
it's difficult from a scientific perspective

2195
01:43:50.130 --> 01:43:53.130
to describe differences in hearing,

2196
01:43:53.130 --> 01:43:55.860
especially when we're talking about mice

2197
01:43:55.860 --> 01:43:58.593
and basic science and everything like that.

2198
01:43:59.520 --> 01:44:01.950
As we all know, the vocabulary can be very tricky.

2199
01:44:01.950 --> 01:44:04.263
So, I'm sorry if I offended anyone.

2200
01:44:06.420 --> 01:44:08.730
<v Will>Thank you for that Dr. Shearer.</v>

2201
01:44:08.730 --> 01:44:11.370
And we know that some of the population

2202
01:44:11.370 --> 01:44:13.830
that you are talking about does in fact

2203
01:44:13.830 --> 01:44:18.810
experience a change in hearing status over time.

2204
01:44:18.810 --> 01:44:20.400
And so for that group,

2205
01:44:20.400 --> 01:44:24.240
hearing loss does more technically

2206
01:44:24.240 --> 01:44:26.340
and accurately apply, right?

2207
01:44:26.340 --> 01:44:27.603
<v ->Sure, of course. Yep.</v>

2208
01:44:30.210 --> 01:44:32.970
<v Will>Well, I wanna thank you, Dr. Shearer.</v>

2209
01:44:32.970 --> 01:44:35.640
Those are all of the questions that we have today.

2210
01:44:35.640 --> 01:44:39.990
And that was a really informative

2211
01:44:39.990 --> 01:44:43.953
and well articulated presentation for us today.

2212
01:44:45.600 --> 01:44:50.600
For all of you who are on line with us,

2213
01:44:50.610 --> 01:44:54.750
remember that this presentation has been recorded

2214
01:44:54.750 --> 01:44:57.930
and it's going to be on infanthearing.org

2215
01:44:57.930 --> 01:45:01.860
and the Maryland EHDI website in the next couple of days.

2216
01:45:01.860 --> 01:45:06.030
So you can review it again or share it with others

2217
01:45:06.030 --> 01:45:09.060
that you think may benefit from this.

2218
01:45:09.060 --> 01:45:12.513
Before you head out, if you look in the chat field,

2219
01:45:13.380 --> 01:45:18.380
you'll see a link to a survey that will give us feedback

2220
01:45:18.930 --> 01:45:20.790
on today's presentation

2221
01:45:20.790 --> 01:45:24.090
and it will also generate a certificate of attendance

2222
01:45:24.090 --> 01:45:26.760
for today if you need to document

2223
01:45:26.760 --> 01:45:30.930
your participation in today's webinar.

2224
01:45:30.930 --> 01:45:35.220
A thank you to our interpreters and our captioner today

2225
01:45:35.220 --> 01:45:39.660
for helping make this presentation accessible

2226
01:45:39.660 --> 01:45:43.080
to as many people as possible

2227
01:45:43.080 --> 01:45:44.970
and all of our collaborators

2228
01:45:44.970 --> 01:45:47.043
in front end, behind the scenes.

2229
01:45:48.870 --> 01:45:50.430
Just a big thank you.

2230
01:45:50.430 --> 01:45:52.830
And of course, again, Dr. Shearer,

2231
01:45:52.830 --> 01:45:56.730
thank you for all the time you put into

2232
01:45:56.730 --> 01:45:58.230
preparing this presentation

2233
01:45:58.230 --> 01:46:01.260
and for your time delivering it to us today.

2234
01:46:01.260 --> 01:46:02.730
Thank you.

2235
01:46:02.730 --> 01:46:04.380
<v ->Thank you very much for having me.</v>

2236
01:46:04.380 --> 01:46:05.610
And I appreciate all the questions.

2237
01:46:05.610 --> 01:46:07.653
And please follow up if you have more.

2238
01:46:10.170 --> 01:46:11.634
<v Will>Go to that link, everybody,</v>

2239
01:46:11.634 --> 01:46:13.143
you see you in the chat field.