00:00:00 Welcome to the hearing circle. I'm Dr.

00:00:02 Shri Rao and today my guest is professor

00:00:06 Chi Yang Yun from Seol, South Korea. He

00:00:10 is an ear surgeon. He is a researcher.

00:00:13 He is a scientist and more than any of

00:00:16 this he is the CEO of Sensory Cure, a

00:00:19 gene therapy company which has found the

00:00:21 cure for hearing loss. We are very

00:00:23 fortunate to have him on this hearing

00:00:26 circle podcast. And in this podcast,

00:00:28 I'll be covering most of the commonly

00:00:31 asked questions about this gene therapy.

00:00:33 What is this gene gene therapy? What is

00:00:35 the eligibility criteria for this gene

00:00:37 therapy? What are the risks for this

00:00:39 gene therapy? What is the minimal age

00:00:41 group that a child can undergo this gene

00:00:43 therapy in case if this is available

00:00:46 India? What is the cost of it? And what

00:00:48 are the things that parents should look

00:00:50 for when they are suspecting any hearing

00:00:52 loss related for this gene therapy and

00:00:55 many more. Thank you, professor, for

00:00:57 accepting for our hearing circle

00:00:59 podcast. Thank you so much for coming

00:01:01 and

00:01:02 >> it's my great pleasure,

00:01:03 >> professor. Uh let me ask you the most

00:01:06 commonly asked question by our uh

00:01:08 viewersh.

00:01:09 >> Is gene therapy a cure for hearing loss?

00:01:13 >> It's very good questions. the um the

00:01:15 gene therapy is actually offers uh

00:01:18 biological cure of the hearing loss

00:01:21 while the coke implantation u actually

00:01:24 enable us to rehabilitate rehabilitate

00:01:27 the the hearing loss. So that's the main

00:01:28 difference. But here's a uh limitation

00:01:32 >> and the gene therapy is very fantastic,

00:01:34 but it's not a magic one

00:01:36 >> for all type of the hearing loss. Only a

00:01:39 very specific type of the hearing loss

00:01:41 can benefit from the genet the gene

00:01:43 therapy of the hearing loss.

00:01:45 >> You work with uh researchers and

00:01:46 scientists across regeneron the company

00:01:49 which has found the cure for auto

00:01:52 related uh hearing loss which is

00:01:54 completely US FDA approved. M

00:01:56 >> how far are we to call this as a cure

00:01:58 for deafness? I mean about the other

00:02:01 forms of hearing loss also. How far are

00:02:02 we?

00:02:03 >> But um I would like to focus that I

00:02:05 would like to stress the fact that the

00:02:07 autof

00:02:09 >> is as a very unique

00:02:11 >> and it actually uh was in the very

00:02:14 unique biological conditions. So not all

00:02:16 definite u genes can immediately benefit

00:02:19 from the gene therapy. So I would like

00:02:22 to mention that. So for example the art

00:02:26 >> um is um uh usually think about think of

00:02:29 the gene therapy as a kind of delivering

00:02:32 kind of software update

00:02:34 >> to the cellular machines.

00:02:36 >> So it does not cure

00:02:39 >> the hardware. So once hair cells

00:02:41 >> if the hair cells are already dead

00:02:44 >> and especially if it is reversibly dead

00:02:47 then there is no way to bring them back.

00:02:49 So even gene therapy cannot do that. M

00:02:52 >> so delivering the software software

00:02:54 update

00:02:55 >> for example auto

00:02:57 >> although the the parent the patients

00:02:59 with the auto the variants

00:03:02 >> show the profound deafness severe to

00:03:04 profound deafness as you already know

00:03:06 >> nonetheless the hair cells

00:03:10 >> such as the hardware so-called hardware

00:03:12 the software hair cells are intact

00:03:16 >> and healthy at least until their early

00:03:19 life

00:03:20 >> although the uh with age the hair cells

00:03:23 just go die but at least for the early

00:03:26 stages of the the life the hair cells

00:03:28 are intact in auto related deafness. So

00:03:31 think about that. So the only the gene

00:03:33 therapy just offers the just the

00:03:35 software updates. So if the the the uh

00:03:38 the hardware is gone then there's no way

00:03:40 for gene therapy there's no room for

00:03:42 gene therapy. So but in a tough cases

00:03:45 >> the hair cells are intact. the hardwares

00:03:47 are intact and healthy. And if we just

00:03:50 inject the uh the cDNA of the auto that

00:03:55 can produce the odor protein which the

00:03:58 uh DFNB9 patients

00:04:00 only lack

00:04:02 >> the the the auto related patients lack

00:04:05 the the protein autofillion that's all

00:04:08 >> while the all the other the cellular

00:04:11 structures are remain intact. So in this

00:04:14 type of the uh situations make the auto

00:04:17 is a very unique position and that's why

00:04:20 the auto uh has been remarked as the

00:04:23 first successful target of gene therapy

00:04:25 but but not all gene therapy uh not all

00:04:28 genetic definitions can benefit from the

00:04:30 gene therapy.

00:04:32 That's well said professor and the way

00:04:34 the analogy that you were using a

00:04:36 hardware and the software

00:04:38 >> you mean by the external year the middle

00:04:41 ear structures the inner ear structures

00:04:42 if we consider as a hardware

00:04:44 >> hardware is completely intact

00:04:46 >> and it's just a bug which is there

00:04:48 within the software and we are giving a

00:04:50 software update

00:04:51 >> exactly

00:04:51 >> out of gene therapy and the patient will

00:04:53 be able to hear well

00:04:55 >> if the hardware is not good some broken

00:04:57 things no hair cells it's useless so it

00:05:00 the gene therapy will not work even

00:05:02 though if we upgrade the software that's

00:05:04 what you mean.

00:05:05 >> Exactly. Exactly right.

00:05:06 >> Very well put uh professor.

00:05:08 >> You're exactly right. Right.

00:05:09 >> Uh before getting into this science

00:05:12 proper, we want to know something about

00:05:14 you professor. How can an ear surgeon

00:05:16 just like us build a cure for toughness?

00:05:20 Is there any particular patient that

00:05:22 triggered you? Oh no, this is not the

00:05:25 end. I think I have to go beyond this.

00:05:27 Is there any situation that you felt? uh

00:05:30 because before I become a US surgeons

00:05:33 actually I was trained as a geneticist

00:05:35 actually I just spent my uh the postoc

00:05:39 uh the four years in the United States

00:05:41 the national institute of health NIH in

00:05:44 United States uh and I worked in the um

00:05:46 genetic deafness lab

00:05:48 >> and my role was to uh find out the cost

00:05:52 gene of deafness at that point and then

00:05:55 I was um my effort was also focused to

00:05:59 delineate and clarify the topiology of

00:06:02 deafness genes

00:06:04 >> and and also at that point the auto one

00:06:06 of my interesting gene because as I

00:06:09 mentioned that is a very um auto the the

00:06:12 problems in the auto can lead to the

00:06:15 only the uh defect in the synaptic the

00:06:18 vesicle release while the all the other

00:06:21 hair cells looked intact. So uh that

00:06:24 kind of the experience in the as a

00:06:26 geneticist can make me get uh interested

00:06:29 and get interested in the uh the gene

00:06:31 therapy naturally. So that's the reason

00:06:34 actually I uh become interested in the

00:06:36 gene therapy and then I also had a

00:06:38 chance to uh work with the um decibel

00:06:42 company actually now actually it uh it

00:06:45 has been merged into the uh regenerant

00:06:48 the big pharmaceutical company

00:06:49 regenerant. So I we actually worked

00:06:52 together um to uh rescue the phenotype

00:06:55 of the autophilated mice and then we

00:06:58 were successful. So through that

00:07:00 experiences actually I just um I want to

00:07:03 just build up some some company that

00:07:06 invent new type of the gene therapy

00:07:09 material not only for the congenital

00:07:11 cost but also for adult the progress of

00:07:14 the hearing loss. That's the reason why

00:07:15 I just uh founded the the company the

00:07:19 sensory cure.

00:07:20 >> That's fantastic professor. You're doing

00:07:23 so much good for the entire world

00:07:25 especially people who are going through

00:07:26 this deafness.

00:07:29 So now let's get into the science proper

00:07:33 >> mainly the basics I can say.

00:07:36 >> Imagine I'm not here. Imagine a parent

00:07:39 is sitting here in front of you

00:07:41 >> who [clears throat] has not studied any

00:07:43 science who does not know anything about

00:07:45 science.

00:07:46 >> Can you explain what is this gene

00:07:48 therapy for a parent who has never

00:07:51 studied science in a very simple

00:07:53 possible manner because for them this is

00:07:55 just like a science fiction movie

00:07:57 unbelievable thing

00:07:59 >> and what is exactly happening in the

00:08:01 child when they do this gene therapy if

00:08:04 you could just

00:08:06 >> tell us. is [laughter] very difficult

00:08:08 task very difficult but okay so I just

00:08:12 um uh previously I mentioned that the

00:08:14 gene therapy is like a uh software

00:08:17 update uh while the there are intact the

00:08:20 the hardwares so that's the actually the

00:08:22 main main uh the explanation that

00:08:25 usually how I put the gene therapy in

00:08:27 the in the in the in the novice uh for

00:08:30 the u the gene therapy that that's the

00:08:33 uh main uh uh way of explaining the gene

00:08:36 therapy to the patients. But as I

00:08:39 mentioned the most important thing uh is

00:08:43 that so far

00:08:45 autogene is the only gene that can

00:08:48 benefit from the gene therapy. So uh

00:08:52 once the hair cells before the hair cell

00:08:55 die eventually the autorelated

00:08:57 definition can show the the definition

00:08:59 uh the degeneration of hair cells.

00:09:02 Before the hair cells degenerate, we can

00:09:06 inject

00:09:08 >> the um normal un um mutated nonmutated

00:09:13 auto gene um with the viral vectors

00:09:17 viral vehicles so-called AAV adeno

00:09:20 associated virus AAV into the coia that

00:09:24 that's all actually. So um so we just

00:09:30 usually generate the normal autog gene

00:09:35 encapsulated with the vital vectors

00:09:37 called the AAV but which has a lifespan

00:09:41 into the cookia. So and then then

00:09:44 injected the um uh normal autogene

00:09:48 can produce normal the protein product

00:09:52 odapurene and which

00:09:56 uh revive the uh impaired the neuro

00:10:01 transmitter release and then uh it can

00:10:04 elicit the the the the colear nerve and

00:10:08 then it can just revive the the normal

00:10:11 auditory pathway. Right.

00:10:12 >> So that's actually how it just the gene

00:10:15 therapy for the autorelate patients

00:10:16 works.

00:10:17 >> So you were telling about this

00:10:18 autofurlin protein professor

00:10:21 >> for the parents who are watching this

00:10:24 one.

00:10:24 >> What is this wordlinin? Why is it

00:10:27 required for the patients for the kids?

00:10:29 >> What role does this autofurlin has?

00:10:32 >> Okay, let me put this this way. So

00:10:34 there's the hair cells. Here's the most

00:10:37 uh peripheral the receptors

00:10:40 >> that convert the the sound into the

00:10:44 electrical signals.

00:10:46 >> So but to be to achieve that purpose the

00:10:49 hair cell should release the

00:10:52 neurotransmitters

00:10:54 to the the colear nerve.

00:10:57 >> But without the odorillain

00:11:00 >> the hair cell cannot release the

00:11:02 neurotransmitters.

00:11:04 So but once the new auto oto gene is

00:11:07 introduced and it just can if it can

00:11:10 produce the normal autofilling then the

00:11:14 neurotransmitter release can be

00:11:16 restarted and then it can uh produce it

00:11:20 can stimulate the auditory nerve so

00:11:22 people can hear and people can uh

00:11:24 recognize what other people say. That's

00:11:26 the pathway and that's what the oto gene

00:11:29 does

00:11:30 >> for parents. Uh to put this out

00:11:32 >> if you imagine the cell to be a mic like

00:11:35 this.

00:11:36 >> Okay. The mic

00:11:37 >> microphone.

00:11:38 >> Right. Right.

00:11:38 >> And the nerve it if it is nerve or the

00:11:41 brain that is a recording system.

00:11:44 >> Right. Recording system. Right.

00:11:45 >> The cable is missing. That cable is

00:11:48 something which is formed by this

00:11:50 autofolin protein.

00:11:51 >> Right. Right. Right.

00:11:52 >> Microphone is good.

00:11:53 >> The recording system is good. But but

00:11:55 without the cable the cable is

00:11:57 autoerlin.

00:11:58 >> So that's why you inject a genetically

00:12:01 modified virus

00:12:03 >> which codes for this auto gene and

00:12:06 finally produces this

00:12:09 autoferlin protein.

00:12:10 >> Wow. Fantastic way of put

00:12:13 >> right you're right

00:12:13 >> cable.

00:12:14 >> Exactly.

00:12:15 >> So is a cable right [laughter]

00:12:18 fantastic way of putting it. Okay.

00:12:20 That's uh that's something which is very

00:12:23 fascinating professor because uh for

00:12:26 normal people this just looks like a

00:12:27 science fiction movie to be very frank

00:12:30 with you. they they are not even

00:12:32 believing that really just with an

00:12:34 injection is this happening why can't it

00:12:37 cure our hearing loss as well I mean the

00:12:40 people who had normal hearing and later

00:12:42 they lost their hearing

00:12:44 >> right right

00:12:45 >> so I was trying to tell them that no

00:12:47 this is only for auto related genes

00:12:50 because for them the microphone is there

00:12:52 this is there but the cable is not there

00:12:55 >> and they were like no even this should

00:12:57 work so even that's a question Mark for

00:13:00 me professor there are many several

00:13:03 other causes for this congenital hearing

00:13:06 loss and sensory neural severe sensory

00:13:08 neural hearing loss

00:13:10 >> on top of this just contributes to 2% of

00:13:13 this congenital hearing loss

00:13:15 >> there are GJB2 mutations SLC26 A4

00:13:19 mutations myo 15A mutations which

00:13:21 contribute to almost 80 to 90% of this

00:13:24 hearing loss why only this what got this

00:13:27 special

00:13:28 >> attention Why only this? Yeah, the

00:13:32 that's what I already mentioned because

00:13:34 the auto is a only gene where the

00:13:37 hardware is and looks intact and and the

00:13:41 software update was was enough actually

00:13:43 to restore the whole new whole the

00:13:46 hearing the echo system for let's say

00:13:49 the the masin 15A you know the mass 15A

00:13:52 actually involved with the um sterilia

00:13:54 elongation there is a um the three rows

00:13:57 of the sterily has a different length of

00:13:59 the um uh the different length and to

00:14:02 but without the mas 15A the sterilia of

00:14:04 the hair cell doesn't grow after birth

00:14:06 you know in the animal models in the

00:14:09 mouse model uh having the the hearing

00:14:12 loss can be misleading because uh the

00:14:16 mouse coia kept developing after birth

00:14:19 but in humans the coia development

00:14:23 actually just finished way before birth

00:14:27 so for example you're right for example

00:14:30 SLC 26 6A4 and catering 23 and for GJB2

00:14:34 >> see the mouse models carrying that type

00:14:36 of mutations can benefit from the gene

00:14:40 therapy in the mouse models.

00:14:42 >> Oh

00:14:43 >> because their coia develops keep

00:14:45 developing after birth. we inject their

00:14:48 this normal gene into the the mouse coia

00:14:51 and then uh because the coia is still

00:14:54 developing but in humans for example

00:14:58 GJB2 mutation can affect the spiral

00:15:01 ligament and the the supporting uh

00:15:03 supporting cell the organ of cordi and

00:15:05 uh and which in turn affects the hair

00:15:08 cell. So the GJB2 kids was born is born

00:15:14 with the hair cell already damaged. So

00:15:17 as I mentioned so which the the hair

00:15:20 cell which were already damaged

00:15:22 irreversibly cannot be revived with the

00:15:25 gene therapy. Gene therapy just offer

00:15:27 only the software update not uh just

00:15:30 restoring the the hardware of the

00:15:32 impairment. So that's the reason why so

00:15:35 far only the G auto is can is a

00:15:38 beneficiary of the um the gene therapy

00:15:41 unfortunately but many companies uh

00:15:43 actually are working on the the other

00:15:46 genes. So think about that who would be

00:15:48 the next which genes would come next

00:15:51 after which could be the progressive

00:15:54 hearing loss

00:15:55 >> progress. So we can inject the gene

00:15:59 therapy materials before the hair cells

00:16:03 are largely irreversibly damaged. So

00:16:07 that's that's the uh situation and

00:16:10 that's the uh uh how we can think about

00:16:13 the next target for the hearing loss the

00:16:15 gene therapy.

00:16:16 >> So you're very clearly mentioning that

00:16:19 uh the mouse the laboratory mice where

00:16:22 many people all the scientists like you

00:16:25 work on. Mhm.

00:16:26 >> For them the coccia keeps developing

00:16:28 even after birth

00:16:29 >> and that's why it was completely

00:16:30 misleading. So you you would have

00:16:33 thought that okay because this is

00:16:34 working on mice this should also work on

00:16:37 human beings.

00:16:38 >> That was not

00:16:38 >> surprisingly

00:16:40 >> it's not possible because the human

00:16:41 coccia is not once again growing after

00:16:44 birth that's it. So professor if I could

00:16:48 ask you now after this regeneron company

00:16:52 got this USFDA approval for yes for

00:16:56 related hearing loss

00:16:57 >> right

00:16:57 >> the sensorion the other company

00:16:59 >> right

00:17:00 >> they have withdrew from the trials and

00:17:03 they started this GJB2 gene mutation

00:17:07 >> exactly

00:17:07 >> as their clinical trials

00:17:09 >> right right

00:17:10 >> immediately how do you square that

00:17:12 >> the the French this scientist the the

00:17:15 Christian who who is very f famous in

00:17:18 this field and is actually she is mainly

00:17:20 working on that in collaboration with

00:17:21 the sensorian and um you know you know

00:17:23 what GJB2 knockkin mice so the mut the

00:17:27 mice uh who which carries the mutation

00:17:29 GJB2

00:17:31 >> actually significantly benefited from

00:17:33 the gene therapy in the mouse model

00:17:35 actually the based on that they actually

00:17:37 the many scientists actually working on

00:17:39 that here's are some u unique uh point

00:17:42 of in in in GJB2 because the GJB2 main

00:17:45 expression is not in the hair cells but

00:17:49 in the supporting cells.

00:17:51 >> Yes.

00:17:51 >> So for example the myosin 15A is mainly

00:17:54 in the sterilia of the hair cells. So

00:17:57 actually initially attacks the hair

00:17:59 cells. So

00:18:00 >> but GJB2 initially attacks the

00:18:03 supporting cells

00:18:04 >> and then that insult in turn affects the

00:18:08 hair cell. So I think the their thought

00:18:10 that sensor censorian thought is that we

00:18:13 can intervene before the um the problems

00:18:17 in the supporting cell affect the hair

00:18:19 cell that's how they thinks but I I'm

00:18:22 not sure about that but I don't I'm not

00:18:24 100% positive effect of the gene gene

00:18:28 therapy in the GJB2 related deafness but

00:18:30 but let's see let's see how it goes

00:18:34 >> because GJB2's main expression is not in

00:18:36 the hair cell that's actually uh one of

00:18:39 the point that we can um think about for

00:18:42 the future possibility of although I'm

00:18:45 not 100% positive about that. No.

00:18:48 >> So [clears throat] it's it's very

00:18:49 clearly established as of now the gene

00:18:52 therapy for hearing loss is right now

00:18:54 available only for auto related

00:18:57 >> right

00:18:57 >> and we cannot expect the hearing loss

00:19:01 treatment with gene therapy for other

00:19:03 forms of congenital hearing loss like

00:19:05 GJB2 especially which contributes to

00:19:07 significant amount because of the

00:19:10 mechanism of action that it it does.

00:19:13 That's something which all the parents

00:19:14 should understand. Professor

00:19:17 >> right

00:19:18 >> uh professor uh if we look at the actual

00:19:21 thing what's happening here

00:19:24 >> a clear implant has been considered

00:19:26 as the gold standard for all forms of

00:19:29 congenital hearing loss

00:19:30 >> you're right

00:19:31 >> till date

00:19:32 >> of course for this auto related right

00:19:34 now gene therapy has come

00:19:36 >> what do you think is better the cocklear

00:19:38 implant or gene therapy or do you think

00:19:40 that gene therapy will replace the

00:19:43 cocklear implant

00:19:44 >> they're very tough questions So at least

00:19:46 for the uh uh let's talk about the auto

00:19:49 related deafness first. I think so far

00:19:52 the it it seems to be kind of routine or

00:19:55 it seems to be uh appropriate to um do a

00:19:59 gene therapy in in one side and then to

00:20:02 to do an the implant on the contrlateral

00:20:05 side and to see if how how it goes

00:20:07 because uh to do a genetic uh gene

00:20:10 therapy in the bilateral side is kind of

00:20:12 could impose some risk because not all

00:20:14 the patient benefited from the gene

00:20:17 therapy. Some of them about 10 to 15%

00:20:20 did not respond to the gene therapy. We

00:20:22 don't know exactly why. There could be

00:20:24 some kind of the um some neutralizing

00:20:26 antibbody is kind of uh result of the

00:20:29 immune reactions because the AAV virus

00:20:32 can elicit the immune reactions. But if

00:20:35 some of the uh the patient that already

00:20:37 had some kind of antibodies against that

00:20:40 AAV virus

00:20:41 >> uh in that cases the autogene therapy

00:20:44 even otogene therapy uh could could

00:20:47 fails. So uh you know thinking about the

00:20:52 importance of the only intervention

00:20:54 along the uh side of the um the the

00:20:57 speech development. So considering that

00:21:00 risk so just one side gen therapy and

00:21:03 one side coal implantation is a safer

00:21:05 options at least for the autopheness

00:21:08 and then uh for the other part of the

00:21:10 deafness I think the scientists are

00:21:12 working on now turn their focus on the

00:21:16 GJB2 and other rapidly progressive

00:21:19 sensory neuro hearing loss. For example,

00:21:21 tempest gene TMP RSS gene is a very

00:21:25 rapidly progressive hearing loss in

00:21:27 pediatric patients and it initially it

00:21:30 manifest as a normal low frequency

00:21:33 hearing loss and a mild uh decrease in

00:21:35 the mid to high frequencies but over

00:21:38 time it rapidly the high frequency

00:21:40 hearing progressive declines and then

00:21:42 followed by the the decline in the

00:21:44 mid-frequency and the low frequencies.

00:21:46 So in that type of the hearing loss can

00:21:48 benefit from the uh the gene therapy uh

00:21:51 because actually the many scientists are

00:21:52 working on that TMPR SF3. So eventually

00:21:56 that type of the the the hearing loss

00:22:00 can benefit from the gene therapy

00:22:01 because uh we can have kind of w time

00:22:04 window

00:22:06 before the the the outer hair cells or

00:22:09 in hair cell dies. So probably uh the

00:22:13 the the focus of the gene therapy can

00:22:15 move toward kind of rapidly progressive

00:22:18 hearing loss. uh but before that I can

00:22:21 we just wish it uh the the followup on

00:22:24 the how the gene therapy for the GJB2 uh

00:22:28 by the sensorian company uh goes

00:22:31 >> very very well put uh professor and

00:22:33 you're being very clean and crisp here

00:22:36 stating that auto related gene therapy

00:22:39 the success what we expect almost 10%

00:22:43 that is what you were mentioning 10% of

00:22:45 the kids they didn't benefit from this

00:22:47 yes auto and also So you were mentioning

00:22:50 about the AAV associated immune reaction

00:22:53 >> right

00:22:53 >> which [snorts] was happening.

00:22:54 >> So uh if I could just elongate this

00:22:57 question

00:22:58 >> uh see professor if we look at the

00:23:01 safety profile of the cocklear implant

00:23:04 it has decades of safety data behind it

00:23:06 and uh we know what are the risks what

00:23:09 are the benefits of it what are the pros

00:23:11 versus cons to do when not to do

00:23:14 >> but this gene therapy is just on the

00:23:16 bleeding edge right now right

00:23:18 >> right now. So if you could just

00:23:20 enlighten us what are the risks that

00:23:22 every patient parent should know when

00:23:25 they are proceeding for this gene

00:23:26 therapy to expect is there any child who

00:23:29 didn't benefit completely from this as

00:23:31 you said earlier

00:23:32 >> if you could just let us know about that

00:23:35 professor

00:23:35 >> okay judge um to be honest we don't have

00:23:39 a long-term availability of long-term

00:23:42 effect and long-term safety profile

00:23:44 either we don't have that data either

00:23:46 because the FDA approval of the out of

00:23:48 or that the name of the drug is or many

00:23:51 so many utili

00:23:55 is actually um doesn't cover the long

00:23:58 term because it just approved just four

00:24:02 months ago and then the uh the the four

00:24:05 papers which addressed the effect of the

00:24:07 gene therapy was published only uh at

00:24:09 2024 so we don't have any we don't know

00:24:14 what would happen so the injected adeno

00:24:17 associate virus, the vehicle could

00:24:19 elicit in the future unknown immune

00:24:21 reaction. We don't know that. And then

00:24:24 we don't know either about the long-term

00:24:27 durability of that the gene therapy

00:24:29 material. So if let's say if the AAV

00:24:32 virus the the lifespan is only 10 years

00:24:35 and we have to inject

00:24:37 >> the second round of injection. But the

00:24:39 you know what once the AV virus is

00:24:41 introduced in the our the health system

00:24:44 actually the antibbody the immune system

00:24:46 can generate the antibbody. So we don't

00:24:48 know what would happen if the uh if the

00:24:51 second injection happens. Many people

00:24:54 worry that the second injection would

00:24:57 fail due to the the antibbody which was

00:24:59 generated from the first injection. So

00:25:02 in that case we have to modify the virus

00:25:05 vehicles to avoid the the immune

00:25:07 reaction. So, so that type of things

00:25:09 actually has not been addressed well.

00:25:11 Honestly, we have to that type of risk

00:25:13 against the the potential benefits of

00:25:16 the hearing uh of the gene therapy

00:25:17 because you know you know gene therapy

00:25:19 restores the normal hearing ecosystem.

00:25:22 So they don't need the hearing aid, they

00:25:24 don't need the coke implantation and

00:25:26 they can um they hear the music and they

00:25:28 can enjoy the music just in the same way

00:25:31 as just the normal people do. So there's

00:25:33 a uh clear and huge advantage but also

00:25:37 there are some unknown

00:25:39 >> there could be unknown the um the side

00:25:42 effects or there could be unknown

00:25:44 limitations such as the uh only the

00:25:47 durability the short durability. So at

00:25:49 this point we should very carefully the

00:25:51 risk this potential risk against the the

00:25:53 benefits.

00:25:54 >> Very well said professor. If I could

00:25:56 just for my understanding as well, I

00:25:59 could take two crucial points from this.

00:26:02 One is the durability, the timeline. How

00:26:05 long is that going to be there? We never

00:26:08 know. As I can just compare it to with a

00:26:11 battery that we buy, we buy a new cell

00:26:14 phone, the battery will be there. It'll

00:26:16 be full.

00:26:17 >> But as time goes on, right,

00:26:20 >> it fades off.

00:26:21 >> Exactly. So once again we'll have to buy

00:26:23 a new one or probably we have to change

00:26:25 the battery.

00:26:26 >> Similarly the for the auto we have

00:26:29 injected once a genetically modified AV

00:26:31 wirus vector

00:26:33 >> but we cannot comment on the durability

00:26:34 and you were mentioning around 10 years

00:26:36 is the span.

00:26:37 >> I don't know actually some people say

00:26:39 would say just 5 years or some people

00:26:41 say 10 years we don't who knows we don't

00:26:43 know.

00:26:43 >> Yeah yeah so we don't know about the

00:26:45 durability. So if it fades off there is

00:26:48 no option of giving once again one more.

00:26:50 It becomes an anaphylactic reaction kind

00:26:52 of stuff because it's after all a virus.

00:26:56 It it does its job. It penetrates it

00:26:59 penetrates into the cells and sometimes

00:27:02 it of course it it definitely causes

00:27:04 this immune reaction antibbody

00:27:06 production and the second time if we

00:27:08 inject that's something which is very

00:27:10 bad. So durability and once again immune

00:27:14 reactions are something which are the

00:27:16 crucial risks that a parent should

00:27:18 understand when they pose their kids for

00:27:20 uh gene therapy.

00:27:22 >> That's that's what I understood

00:27:24 professor. Is that correct?

00:27:25 >> Yeah. Yeah. But um uh I have to mention

00:27:28 that the most devastating part of the of

00:27:30 the virus has actually was removed. the

00:27:33 the only the um the the vehicle role the

00:27:36 vector role vehicle role is retained

00:27:39 while the removing the most uh dangerous

00:27:42 part of the uh the virus has has been

00:27:44 removed. So uh we don't have to worry

00:27:47 about that point but still it could

00:27:50 elicit the immune response. That's the

00:27:52 most

00:27:53 >> just critical part.

00:27:54 >> This is one more important what you

00:27:55 mentioned doctor people may think that

00:27:57 we are injecting some virus into the

00:27:59 ear. Um

00:28:01 >> that's not correct. Vehicle it is just

00:28:03 being used as a vehicle itself. The

00:28:06 dangerous part the DNA or RNA within the

00:28:10 virus is being removed and the shell

00:28:12 itself is used and then you are placing

00:28:16 that material and then you are injecting

00:28:18 >> into the ear. Am I correct professor?

00:28:20 You're right. Exactly.

00:28:21 >> That's why we call it as a genetically

00:28:23 modified virus viral vector.

00:28:26 >> Right. Right. Right. Exactly. modified

00:28:28 vectors to to remove the uh critical

00:28:31 dangerous part

00:28:33 >> and that is called adino associated

00:28:35 >> adeno associated virus it doesn't it

00:28:38 doesn't integrate into genome it just

00:28:40 delivers

00:28:41 >> kind of kind of kind of delivers it it's

00:28:43 just deliver the normal uh the DNA into

00:28:46 the nucleus that's all

00:28:47 >> no penetration

00:28:48 >> no pen into the genomes

00:28:50 >> okay

00:28:50 >> at least

00:28:51 >> as a as at least the current type of the

00:28:53 gene therapy is like that

00:28:56 [clears throat]

00:28:56 >> perfect Nowadays actually genome editing

00:28:59 technology has been developed. It's

00:29:01 genome editing technology technology is

00:29:04 actually correct is correct the the

00:29:06 nucleotide. So it's a it's a little bit

00:29:08 different story but the autofilling gene

00:29:11 therapy is actually um uh is developed

00:29:13 in a way that it just delivers the

00:29:15 normal auto gene into the nucleus of the

00:29:18 uh the hair cells of the

00:29:20 >> uh the coia that's all

00:29:23 >> perfect

00:29:24 >> professor. So if I may ask one more

00:29:27 important question that many people are

00:29:30 asking. Can any person in case if a

00:29:33 child is born completely deaf as of

00:29:36 right now

00:29:37 >> u they are born with this hearing loss

00:29:39 GJP2 [clears throat] or any kind of

00:29:41 congenital hearing loss

00:29:42 >> can they wait for this gene therapy

00:29:45 >> or should they have to proceed with

00:29:48 colear implant

00:29:49 >> that's very tough questions to answer

00:29:51 but um if so that for for the patients I

00:29:56 just um proposed the strategies of one

00:29:58 side gen therapy on one side coke

00:30:00 implantation because you know the the

00:30:02 speech development requires the timely

00:30:05 intervention so I don't want to just

00:30:08 wait until the the gen therapies

00:30:10 available. So that's it and another

00:30:12 interesting study from our laboratory is

00:30:15 tells that even after co implantation

00:30:19 >> the hair cells in hair cells and out

00:30:21 hair cells looks intact especially in

00:30:23 the auto patients.

00:30:25 >> So the criteria I didn't talk about the

00:30:28 criteria

00:30:29 >> after colear implantation.

00:30:30 >> Yeah. Yeah. So, so people think that oh

00:30:32 once we implant then probably hair cells

00:30:36 probably would die and the the chance of

00:30:39 gene therapy just completely diminished

00:30:41 and that doesn't seem to be the case

00:30:44 because I think at least about 30 to 40%

00:30:47 of the DFN9 because related patients who

00:30:51 were implanted

00:30:52 >> shows the presence of the auto otocostic

00:30:56 emissions OE auto emission at least

00:31:00 until um after six six years after the

00:31:03 implantations. Yeah.

00:31:05 >> So in that case uh I don't know probably

00:31:09 the gene therapy in the implanted ear is

00:31:11 very difficult because you know but I

00:31:13 have to tell that I want to mention that

00:31:16 klay implantation itself abol doesn't

00:31:20 abolish

00:31:21 >> the future potential the possibility of

00:31:24 the gene therapy that's what I want to

00:31:26 mention

00:31:27 >> but anyway so at this point the one side

00:31:30 gene therapy and one side implantation

00:31:32 is seems to be uh appropriate in at

00:31:34 least is in the autoph related patients

00:31:36 and for other uh the patients I think I

00:31:40 don't want them to just wait for the

00:31:42 other gen therapy becomes available

00:31:44 because you know timely intervention is

00:31:46 very important so I think just people

00:31:49 should get the implantation yeah

00:31:51 >> and then see how it goes or sometimes

00:31:54 people can um be implanted only one side

00:31:57 but I don't think it is reasonable just

00:32:00 uh so at at point so uh let's say So

00:32:04 other than the OT patients,

00:32:06 >> the other deafness patients I think

00:32:08 should get implanted in a timely

00:32:10 fashion. That's what I'm

00:32:12 >> Thank you professor. Thank you for this

00:32:13 clarity.

00:32:16 >> If there are auto related genetic

00:32:18 deafness then they have to go ahead with

00:32:20 implant on one side

00:32:22 >> and the other side they can wait for

00:32:23 gene therapy.

00:32:24 >> That could be a ideal options. any

00:32:26 genetic mutations apart from they should

00:32:30 not wait for gene therapy because the

00:32:32 amount of time we never know and it is

00:32:36 humanly impossible for the brain to just

00:32:39 stay static. So that brain development

00:32:42 has to happen and hence they have to go

00:32:44 ahead with the colear implantation.

00:32:46 >> Exactly.

00:32:47 >> Perfect.

00:32:47 >> You put it beautifully.

00:32:48 >> Thank you. Thank you professor.

00:32:51 >> Now these questions are for from my side

00:32:53 also not just for the parents. Mhm.

00:32:56 >> I know how a cocklear implant sounds

00:32:58 like because this is a neuroprothetic

00:33:00 device.

00:33:01 >> Um it's it it just collects the sound

00:33:04 from through the microphones and then

00:33:06 >> finally electrically it stimulates the

00:33:09 cockia nerve.

00:33:10 >> Right. Right.

00:33:11 >> So it's a kind of electrical stimulus.

00:33:14 >> What about this gene therapy? How does a

00:33:16 child who underwent gene therapy, how

00:33:18 does this sound sound like?

00:33:21 >> Yeah.

00:33:21 >> Is it normal? perfectly normal just like

00:33:24 us or

00:33:24 >> den therapy is to restore the normal

00:33:28 hearing ecosystem. So if it works

00:33:31 >> it makes people just um uh hear just

00:33:34 like a normal people hear. But one main

00:33:37 difference lies in the fact that

00:33:39 actually so let's say that oh I got the

00:33:42 gene therapy yesterday so and then don't

00:33:44 and and the next day it it just doesn't

00:33:48 um come out just immediately after gene

00:33:50 therapy. it just because we have to wait

00:33:52 for the new genes new corrected normal

00:33:56 gene to produce the protein and then the

00:33:59 reproduce the protein should work and

00:34:02 you should restore the functions. So it

00:34:04 takes time. So usually according to the

00:34:05 the four papers published in 2024

00:34:08 regarding the autogen therapy um

00:34:10 according to their papers people would

00:34:13 restore their normal not normal hearing

00:34:15 restore their substantial um portion of

00:34:18 the normal hearing uh over times. So

00:34:22 probably three months or six months. So

00:34:24 there the hearing level just goes higher

00:34:27 until about the three to six month and

00:34:30 then at that point the hearing normal

00:34:32 hearing the um final hearing threshold

00:34:34 just um ranges probably 35 to 50 dB.

00:34:39 >> So it's not perfectly normal but but but

00:34:42 significantly good and then their speech

00:34:44 the recognition

00:34:46 uh reaches about range of the 75%.

00:34:49 >> Then the music perception is almost

00:34:52 normal.

00:34:53 >> Wow. That's usual. That's the average

00:34:56 the the level of the the B gene therapy

00:34:59 the uh the imp gene therapy recipients

00:35:02 uh the fields.

00:35:04 >> Oh wow. That's

00:35:05 >> so if it works it is fantastic actually.

00:35:08 >> Yeah. So PTA the pureon aometry levels

00:35:12 they range between 35 which is quite

00:35:14 good

00:35:15 >> which is quite good right

00:35:16 >> and speech discrimination score or SRT

00:35:18 levels around 70%. 75% exactly

00:35:21 >> excellent

00:35:22 >> and music which cannot be appreciated

00:35:25 >> right that's strongest point of gene

00:35:26 therapy but 10% of patient didn't

00:35:28 respond to gene therapy at all I have to

00:35:30 mention that

00:35:31 >> yes that's a thing 10 person they didn't

00:35:34 respond at all so professor you were

00:35:36 mentioning that the PTI ranges between

00:35:38 35 to 50

00:35:39 >> so does these patient do they require

00:35:42 any hearing aid after undergoing this

00:35:44 gene therapy or any external devices

00:35:47 because 50 dibbels they cannot

00:35:49 understand the clarity of speech, the

00:35:50 volume. You're right. Do they require

00:35:52 any hearing aid later rather than the

00:35:54 cockar implant?

00:35:55 >> Here's an interesting point. Usually the

00:35:56 um it's actually the the phenotype of

00:35:59 autoph related deafness is audiary

00:36:01 neuropathy spectrum disorder. They

00:36:03 actually uh their um response to hearing

00:36:06 aid doesn't seem to be great compared

00:36:08 with the other people. But

00:36:09 interestingly,

00:36:11 >> gene therapy recipients, let's say their

00:36:13 hearing threshold is um is restored to a

00:36:16 level of the 50 dB.

00:36:18 Usually the uh the neuropathy auditor

00:36:20 neuropathy patient doesn't respond well

00:36:22 to the hearing aid but recipients does

00:36:25 respond well

00:36:27 >> to the to the hearing aid. So right the

00:36:30 if the hearing restoration is just is 50

00:36:32 dB then right it requires hearing aids

00:36:35 but there the responsiveness to the

00:36:37 hearing aid is way better than

00:36:39 non-recipients to gener therapy. So

00:36:41 you're right hearing aids is actually um

00:36:44 is mandatory for them but 35 decibel

00:36:46 then they can do without the hearing

00:36:48 aids. Okay.

00:36:49 >> Oh wow. [laughter]

00:36:51 >> Yes.

00:36:52 >> Until 40 decibels they don't require any

00:36:54 hearing aid. They're completely normal.

00:36:57 >> So just advancing so good.

00:36:59 >> I mean they are born with some hearing

00:37:01 loss and

00:37:03 >> boom with gene therapy they are able to

00:37:04 hear. That's why the United States FDA

00:37:07 approved the or many and three months

00:37:10 ago.

00:37:10 >> That's fantastic.

00:37:12 >> Professor, I would also like to know

00:37:14 about the permanency of the results.

00:37:16 >> Mhm.

00:37:17 >> Are the results going to be permanent?

00:37:20 >> Or do they require first or second dose

00:37:23 or third dose of injection? Because this

00:37:26 is something what every person they ask.

00:37:29 >> You're born with this hearing and this

00:37:31 will be permanent until unless we age.

00:37:35 Is that the same thing with this auto

00:37:37 related gene therapy also once we inject

00:37:39 are the results going to be permanent?

00:37:41 >> See very important questions. So far the

00:37:43 the strategy of auto related definition

00:37:46 is a gene transfer type of gene therapy.

00:37:50 There is a several type of gene therapy.

00:37:53 Eventually

00:37:54 gene therapy moves toward the genome

00:37:57 editing type of gene therapy. Genome

00:38:00 editing is just to correct the

00:38:02 mutations. So it could be permanent

00:38:04 right?

00:38:04 >> Mhm.

00:38:05 >> But the current type of gene therapy is

00:38:06 a gene transfer driven by the um a aav

00:38:10 virus. So inevitably current type of the

00:38:12 gene therapy depends on the lifespan of

00:38:16 the AAV virus which about which we we

00:38:20 don't know exactly. So if the lifespan

00:38:22 of AAV in human bodies if let's say it's

00:38:24 10 years then in 10 years later and

00:38:27 their autofillion protein expression is

00:38:30 significantly diminished and then

00:38:31 neurotransmitter release is stopped and

00:38:34 then we have to inject again.

00:38:35 >> So that's what we think. So that's the

00:38:38 reason why many scientists actually um

00:38:40 turn their focus onto the developing of

00:38:43 the genome editing technology in a type

00:38:45 of therapy which require only one type

00:38:48 of just a injection. Mhm.

00:38:51 >> Okay. Okay. Now it makes sense.

00:38:54 >> Yeah. Yeah. Yeah.

00:38:55 >> Okay.

00:38:55 >> So now our company is also working on

00:38:58 the developing the general editing drug

00:39:01 >> to um correct the rapidly progressive

00:39:04 type of the hearing loss. So that's the

00:39:05 reason because you know the um regenery

00:39:09 the big pharmaceutical company already

00:39:11 approved the gain the approval from the

00:39:13 FDA. So uh our small company doesn't

00:39:16 have any room for uh competing with them

00:39:18 in the congenital auto for example auto.

00:39:21 So uh our company actually has turned

00:39:23 our focus on the different genes which

00:39:27 um shows the rapidly progressive hearing

00:39:30 loss. Yeah. Okay. You should succeed

00:39:31 super fast uh professor because there

00:39:33 are millions of people with this rapidly

00:39:36 progressive hearing loss and the amount

00:39:40 of uh problems that they face because

00:39:42 this is something which is hidden

00:39:43 deformity everything looks good they say

00:39:46 this you look perfectly fine are you

00:39:49 dumb but they should understand that

00:39:52 >> he's deaf that's why he's not responding

00:39:56 it's not just because of his IQ or

00:39:58 something

00:39:58 >> exactly

00:39:59 >> so please I wish you all the best

00:40:02 regarding that uh development of uh

00:40:04 progressive hearing loss therapy gene

00:40:07 therapy for that.

00:40:08 >> Oh, thank you for your kind words.

00:40:11 >> Professor uh this is for the clinicians

00:40:14 who are watching this gene therapy

00:40:15 thing. M

00:40:16 >> I read a couple of your articles and one

00:40:18 of the [clears throat] article it just

00:40:19 mentioned that

00:40:21 >> the treatment for this auto related

00:40:23 hearing loss.

00:40:24 >> It's an unusually fortunate case

00:40:27 >> right

00:40:28 >> because we didn't get the we were

00:40:31 completely blindfolded by the uh

00:40:34 response that they got in the mouse

00:40:36 models but it's not happening in the

00:40:38 human models.

00:40:39 >> Exactly. Why did you mention so why is

00:40:42 this auto related gene therapy an

00:40:44 unusually fortunate case?

00:40:46 >> Because fortunately it meets the

00:40:49 criteria which um criteria which the

00:40:53 gene therapy should meet. So but it's

00:40:56 very difficult for many other genes to

00:40:59 meet that criteria. So it should be the

00:41:02 the the hair cells should be intact uh

00:41:05 before the interventions. the the degree

00:41:07 of the hearing loss should be eventually

00:41:09 profound. Let's say that for example uh

00:41:13 the hearing loss caused by the mutations

00:41:15 in STRC which is the most decommon cause

00:41:19 of the moderate degree of hearing loss

00:41:21 STRC

00:41:23 >> it the hearing level is 40 decibel and

00:41:26 then it doesn't progress at all until

00:41:28 the prespicus is imposed if and the gene

00:41:32 therapy the cost is for example let's

00:41:33 say the million dollars

00:41:36 >> are you gonna are you going to have that

00:41:37 therapy

00:41:39 Let's say the the hearing threshold is

00:41:42 only 40 decel and even hearing aid it

00:41:44 would suffice and then it doesn't

00:41:46 progress and what do what do you what do

00:41:49 you think are you going to are you

00:41:51 willing to get the gen therapy in that

00:41:53 cases um paying the billions of dollars?

00:41:57 >> No.

00:41:58 >> Yeah. So in that point actually there

00:42:02 are not many genes that cause the

00:42:03 profound duffness. So and then the while

00:42:06 the the preserving the hair cells think

00:42:09 about that not many genes actually meet

00:42:11 that criteria.

00:42:12 >> So and then the auto uh the prevalence

00:42:15 autotogene is is relatively uh as

00:42:18 prevalent in the kind of Spanish

00:42:20 populations and in United States there

00:42:22 are many the Spanish the people there.

00:42:25 So there are many situations which

00:42:28 renders the auto to be a candidate of

00:42:30 the genes but I I I don't think many

00:42:33 genes can be can meet that criteria. So

00:42:36 that that's the reason why I just

00:42:38 mentioned that uh gene therapy utov is a

00:42:40 very very unusually fortunate case.

00:42:46 Well said professor. It's very lucky.

00:42:49 >> Very lucky.

00:42:49 >> Very lucky.

00:42:51 >> Very lucky.

00:42:53 >> You were mentioning about the criteria

00:42:55 professor. That's something which is

00:42:56 very very uh important.

00:43:00 >> Imagine there is a 25 year old person

00:43:03 who has been going through this profound

00:43:05 hearing loss.

00:43:07 >> This person he never used a hearing aid.

00:43:10 He does not have any speech. Suddenly he

00:43:13 understood that autoph related gene

00:43:15 therapy is there. He gets his he gets

00:43:17 his genetic evaluation done and it turns

00:43:20 out to be autof

00:43:22 >> and now can this person undergo gene

00:43:24 therapy and if he under goes where how

00:43:27 will the results be?

00:43:28 >> Okay. So we have to take the OA test

00:43:30 first

00:43:32 >> because if even if he uh his hearing

00:43:35 loss is caused by the auto mutations if

00:43:37 the auto oto acoustic emission is gone

00:43:40 >> then he's just he's not he's not

00:43:42 eligible for the gene therapy. If he

00:43:45 luckily has the intact OA then he could

00:43:49 be a candidate of gene therapy but you

00:43:52 know gene therapy doesn't rescue the

00:43:54 brain you know you know what you know

00:43:56 the term of the auditory brain so it

00:43:58 does gene therapy doesn't doesn't rescue

00:44:01 the um the neurotransmitter release into

00:44:04 an audiary nerve not affecting the brain

00:44:07 plasticity so let's say if um he has the

00:44:11 normal OA until the age of the 25 the if

00:44:14 he gets the gene therapy then he can

00:44:17 detect the sound normally

00:44:19 >> and okay he can uh enjoy the music but

00:44:22 he cannot recognize the word and he

00:44:24 cannot have the speech um the

00:44:26 perceptions that's what I expect

00:44:29 >> very well said if I could just extend

00:44:32 this beyond you mean to say that he will

00:44:37 be there for the eligibility criteria

00:44:38 because he has OA pass the autoacostic

00:44:41 emission which tells that the hair cells

00:44:44 I'm good. I'm intact. So that's why once

00:44:46 you inject he'll be able to produce

00:44:48 autofallene protein and he'll be able to

00:44:50 hear.

00:44:51 >> Exactly.

00:44:52 >> But

00:44:52 >> the brain

00:44:54 >> it cannot understand what it is.

00:44:57 >> No.

00:44:57 >> Because of neuroplasticity.

00:44:59 >> Exactly.

00:45:00 >> That window period is already gone.

00:45:02 >> Mhm. So

00:45:03 >> this 25 year old person maybe if he

00:45:06 would have had speech and he suddenly

00:45:09 lost his hearing and it turned out to be

00:45:11 auto then he'll be getting any benefit

00:45:14 with the auto of related gene therapy

00:45:18 but not immediately after gene therapy

00:45:20 when he was not using anything is that

00:45:22 makes sense from

00:45:23 >> right exactly

00:45:24 >> that's that's perfect

00:45:26 >> now

00:45:27 >> another let me another so there here's

00:45:30 an interesting story that um you know

00:45:34 what is most important for eligibility

00:45:36 of gene therapy especially in terms of

00:45:38 the um uh in auto fields hair cells

00:45:42 integrity is very important

00:45:44 >> but hearing aid

00:45:47 turn out to be kind of kind of um bad

00:45:50 prognostic factors for survival so let's

00:45:53 say there is a patient if he wears the

00:45:55 hearing aid so much then it is more

00:45:58 likely that hair cells could have

00:46:01 >> damage Ed

00:46:01 >> due to the kind of noise induced.

00:46:05 >> So uh if in there is a kids and then for

00:46:09 some reason he cannot have the coke

00:46:12 implant and he could not have the gene

00:46:13 therapy at this point. But using too

00:46:16 much of time of the hearing aid actually

00:46:19 would potentially negatively affect the

00:46:22 eligibility of gene therapy.

00:46:23 >> Oh my god.

00:46:24 >> That is specifically that is um only for

00:46:27 the ot.

00:46:29 So that's the what um that's published

00:46:31 probably a couple of years ago by the

00:46:34 Christian PT lab or yeah this

00:46:37 >> so this hearing aid it causes noise

00:46:39 induced hearing loss and it causes death

00:46:41 of hair cells

00:46:42 >> yeah especially out of patient

00:46:43 >> out of patients

00:46:45 >> okay and that's why

00:46:48 could you just brush up the knowledge of

00:46:50 all the surgeons the clinicians and also

00:46:52 the parents who are watching

00:46:54 >> what is the eligibility criteria for the

00:46:58 patients who can undergo auto related

00:47:00 gene therapy. officer. Yes. Can you just

00:47:02 >> Okay. So, um currently so bilateral co

00:47:07 implantes are excluded.

00:47:10 >> Bilateral unilateral co implantes can be

00:47:13 included because the contrlateral site

00:47:15 is preserved reserved for the gen

00:47:17 therapy. So number one bilateral co

00:47:19 implantes are excluded. Number two dpoa

00:47:23 oae should be intact. Mhm.

00:47:26 >> U it doesn't have to be 100 perfect but

00:47:29 just I think at least uh at least from

00:47:33 the three frequencies there should be

00:47:35 significant OE responses. It doesn't

00:47:38 have to be five or six frequencies three

00:47:40 frequencies. So if you can observe the

00:47:44 uh meaningful OA responses uh at least

00:47:47 from the three frequencies and then

00:47:49 there should be genetic documentations

00:47:52 two mutant alals two mutations of auto

00:47:54 should be documented.

00:47:58 >> So currently the three are the main uh

00:48:01 the eligibility criteria for autogen

00:48:03 therapy

00:48:04 >> and severe to profound hearing. Yeah, of

00:48:06 course. Of course. The ABR should be at

00:48:08 least I think over 80 dB 70 or 80

00:48:12 decibel. Right. Right. Sometimes uh for

00:48:15 example the temperature sensitive auto

00:48:18 variants there are

00:48:20 >> it's a unique type of the auto variance

00:48:22 and not all auto patients

00:48:24 >> show the severe to profound duffness.

00:48:27 >> Some of the p some of the variants of

00:48:29 auto can cause only the temperature

00:48:32 sensitive audiary neuropathy.

00:48:34 >> What does it mean? So uh usual

00:48:37 conditions the he can speak and he can

00:48:40 uh understand perfectly but with uh high

00:48:42 fevers temperature high fever he doesn't

00:48:45 she doesn't he or she doesn't recognize

00:48:47 anything at all. So ABR responses just

00:48:50 go down to the 100 dB threshold only for

00:48:53 the time of the high fevers. So but

00:48:57 there is a mutations there is a certain

00:48:58 of mutations are documented to uh uh the

00:49:02 result in that kind of temperature

00:49:04 sensitive al so the fourth algebraic

00:49:06 criteria is that

00:49:08 >> even though the patient have the auto

00:49:10 variance it should not be related to the

00:49:12 temperature sensitive al that's the

00:49:14 fourth conditions

00:49:18 >> perfect I mean it's sounding really like

00:49:22 a science fiction movie even for me

00:49:25 professor Yeah. Right. Right. But

00:49:26 interesting. Yeah. So yeah, so for for

00:49:30 we should remember the four conditions.

00:49:32 So exclude bilateral implantes are not

00:49:36 the candidates and then OA should be um

00:49:39 meaningfully present at least from the

00:49:41 three frequencies and then it the auto

00:49:44 varants are documented but uh the uh

00:49:47 temperature sensitive uh the alil auto

00:49:50 variant should be excluded. That's what

00:49:53 the current elig eligibility criteria

00:49:55 mentioned.

00:49:56 >> Professor, just now you mentioned about

00:49:59 temperature sensitive cottoalin

00:50:01 mutations.

00:50:02 >> Mhm.

00:50:03 >> U there are couple of patients who have

00:50:05 been asking me doctor if you just look

00:50:08 at me from front

00:50:10 >> and talk I'll be able to hear.

00:50:12 >> Mhm. But if you just go behind

00:50:15 >> or if someone two or three members call

00:50:18 me or some conversation is happening I'm

00:50:21 not able to understand anything.

00:50:24 >> It's a classic case of auditory

00:50:25 neuropathy A and SD. So for them are

00:50:29 there any specific things that they need

00:50:31 to get testing done any specific testing

00:50:34 apart from whole exam sequencing so that

00:50:37 we can rule out certain things? Uh very

00:50:39 good question. Um actually um um you

00:50:43 know so the there are kids ov kids that

00:50:47 means that their parents carried at

00:50:49 least one

00:50:51 >> mutations of auto right even though they

00:50:53 are perfectly normal.

00:50:55 >> The their parents tends to show the

00:50:59 hidden type of hearing loss. Hidden

00:51:01 hearing loss means that uh they are

00:51:03 somewhat affected uh their spiranga

00:51:06 cells or their inner hair synapses are

00:51:08 certain amount affected but not leading

00:51:10 to the u significant hearing loss. So

00:51:13 actually their parents shows some u

00:51:16 problems in the uh the discrimination in

00:51:18 especially in the low frequencies and

00:51:20 then they can not hear in in noisy

00:51:22 conditions. So we call that type of

00:51:24 situations as a hidden hidden hearing

00:51:27 loss because their purton threshold is

00:51:30 normal

00:51:31 >> but they actually doesn't produce uh in

00:51:33 noisy conditions either in the noise

00:51:35 conditions or either in the um uh uh in

00:51:39 in in certain distance u the locations.

00:51:43 So uh in that case actually what I

00:51:46 usually do is actually to see if there

00:51:48 is any uh uh uh kids the pat the kids

00:51:52 and then the other possibility is that

00:51:56 um uh so in that case the parent might

00:51:59 have only one mutations of

00:52:01 >> then the p the that that

00:52:04 >> not patient that carriers

00:52:06 >> parents

00:52:06 >> may yeah may tend that kind of

00:52:09 situations. So difficulty in uh having a

00:52:12 conversation in noisy conditions that's

00:52:14 the first conditions and there are in

00:52:16 that case actually uh I do the auto

00:52:19 sequencing and uh uh and the other

00:52:22 possibility is I just take the ABR

00:52:25 responses

00:52:27 >> and then in that case the wave one the

00:52:30 amplitude is diminished compared with

00:52:32 the normal hearing people. So I usually

00:52:36 do the abr responses ABR test. So that

00:52:41 the uh the uh uh so hidden hearing loss

00:52:43 patients show the decrease in the

00:52:45 amplitude in the ABR especially in the

00:52:48 first wave.

00:52:49 >> So in that case the patients tend to

00:52:52 show that kind of phenotypes

00:52:54 difficulty although their hearing

00:52:56 threshold is perfectly normal.

00:52:58 >> They complain of the difficulty in

00:53:00 conversation in

00:53:02 >> in in certain situations.

00:53:03 >> We call that as hidden hearing loss.

00:53:05 >> Hidden hearing loss. Exactly. Right.

00:53:06 >> How do we treat such situations?

00:53:08 Unfortunately, no treatment at so far.

00:53:10 Just just counsel them. You may have the

00:53:13 hidden hearing loss. And unfortunately,

00:53:16 at this point, there's no cure or no

00:53:18 treatment.

00:53:19 >> But it it's good to know.

00:53:22 >> Will their kids go through the same

00:53:24 situation or will their kids go through

00:53:27 profound hearing loss?

00:53:28 >> No. No. They won't develop the just full

00:53:31 minute on the the auditory neuropathy.

00:53:33 just complain of some difficulty in

00:53:37 certain situations. Yeah.

00:53:38 >> Okay. Professor, there are many many

00:53:41 parents who are asking once again the

00:53:43 same question. [laughter] This gene

00:53:45 therapy is not available in our India.

00:53:48 >> In almost all the developing countries,

00:53:50 it's not available in India. But we have

00:53:53 huge population and we have many kids

00:53:56 who are going through auto related

00:53:57 hearing loss.

00:53:59 >> What can all these kids do? what any

00:54:02 guidance for our Indian parents. Is

00:54:04 there any way that u they can approach

00:54:07 our drd hospital and we can guide them

00:54:10 to you?

00:54:12 >> Okay, tough questions but very important

00:54:14 questions for Indian um DFM denine

00:54:17 patients. I think uh first of all at

00:54:22 this point there are two ways actually

00:54:23 the first official way through the

00:54:26 official

00:54:28 establishment of the gene therapy

00:54:31 >> through the FDA approval in in Indian uh

00:54:33 FDA approval that's the official way of

00:54:36 course it would take time I think that's

00:54:38 what you I think you uh you should do

00:54:41 first so given that the the United

00:54:45 States FDA has already approved the uh

00:54:48 utani. So I think it's not it would not

00:54:51 that difficult for Indian the FDA to

00:54:54 approve the gene therapy. So I think the

00:54:56 first thing you have to do is just

00:54:58 contact the uh Indian FDA and or Indian

00:55:02 uh the ministry of welfare to see if

00:55:06 there is availability of [clears throat]

00:55:08 um the approval of the um the many or

00:55:11 other type of the auto gene therapy

00:55:13 materials. That's the first thing. The

00:55:16 second thing is that although the

00:55:18 regenerance uh there was actually three

00:55:21 companies which was involved with the um

00:55:24 developing the oaf related deafness gen

00:55:27 therapy the first one is regeneran which

00:55:30 turned out to be a winner and the lilies

00:55:33 uh liies is is another country another

00:55:36 company I'm sorry and the third one was

00:55:38 sensorian so given that the uh the

00:55:41 regenerant has already approved the um

00:55:44 has already obtained the approval from

00:55:46 the FDA but still the lily and censorian

00:55:50 still running the clinical trials. So

00:55:54 the another way of Indian DFNB9 patients

00:55:57 to have the uh the autogen therapy is to

00:56:02 contact Lily could be a contact point

00:56:05 >> or so or I can help the the Indian DF

00:56:09 main patients to contact Lily because I

00:56:11 was working with the regenerant and I

00:56:13 actually our I was trying to uh perform

00:56:17 the clinical trial in our university

00:56:19 hospital but uh unfortunately there the

00:56:22 clinical trial has finished because they

00:56:24 already have obtained the FDA approval.

00:56:26 So they don't need to run the clinical

00:56:27 trial. So so the contact the regenerate

00:56:30 actually has has actually meaningless

00:56:33 actually. So contact contacting Lily

00:56:36 which actually is still running the

00:56:38 clinical trial is uh I think gives could

00:56:42 potentially give us a proposed give us

00:56:44 an opportunity to for Indian the FM9

00:56:47 patients to have the gene therapy is as

00:56:49 a clinical trial the form. So I think

00:56:52 that there are two two u forms of the

00:56:55 possibility.

00:56:57 So we should open open up the the

00:56:59 opportunity for Indian DFM9 patients in

00:57:02 some ways.

00:57:03 >> We'll do professor and we we'll be

00:57:05 requiring your help for that.

00:57:07 >> I I would I would

00:57:08 >> thank you so much professor for that.

00:57:11 >> Prophecy you are forget that you are a

00:57:14 doctor now you forget that you are a

00:57:16 surgeon. Mhm.

00:57:17 >> Just imagine

00:57:18 >> you have operated on kids. You have seen

00:57:22 them hearing getting back their hearing.

00:57:24 >> Right. Right.

00:57:25 >> And you have performed gene therapy

00:57:27 without performing any surgery and you

00:57:29 have seen kids recover their hearing.

00:57:32 >> How do you feel inside as a human being?

00:57:35 >> Yeah. Yeah. Yeah.

00:57:37 But well, I just um it's I think it's a

00:57:40 privilege of of our ENT surgeons to be

00:57:44 able to witness the kids with the

00:57:47 hearing impairment to recover their

00:57:49 hearing and to uh can to be able to

00:57:52 listen to able to enjoy the music. So

00:57:55 yeah, I think uh it is our privilege and

00:57:59 I'm very happy to be able to be in that

00:58:01 position just like you. So I think yeah

00:58:05 just I think it's our privilege and I

00:58:06 really appreciate that as a human

00:58:08 beings.

00:58:09 >> Yes professor after all we do all this

00:58:12 at the end of the day for to satisfy our

00:58:15 little heart and

00:58:16 >> Right. Right.

00:58:16 >> You are truly following your passion and

00:58:19 you're doing the best and helping

00:58:21 millions and millions of people who are

00:58:23 going through this hearing loss. Sincere

00:58:25 thanks to you regarding that.

00:58:27 >> That's my pleasure. So, professor, this

00:58:30 is almost the final question that I'm

00:58:33 asking you.

00:58:34 >> What is the future of this gene therapy?

00:58:37 What are you really excited about now at

00:58:40 the moment?

00:58:41 >> Okay. Um, which is are very your your

00:58:44 actually comments are very important

00:58:46 actually. the um uh the future the

00:58:48 trends or future direction of the gene

00:58:51 therapy should move I think um just

00:58:55 beyond the congenital deafness

00:58:58 >> probably it would expand or it would

00:59:00 evolve to involve the rapidly

00:59:03 progressive hearing loss

00:59:05 >> uh that would be like the next target

00:59:08 which actually has a higher the

00:59:09 prevalence actually

00:59:11 >> so and then uh as you mentioned as we

00:59:14 already discussed

00:59:16 uh single injection should be mandatory

00:59:19 to avoid the multiple injection. So

00:59:21 rather than just this gene transfer

00:59:25 um just performing the genome editing

00:59:28 which requires only one injection one

00:59:31 fix. So probably uh our gene therapies

00:59:35 uh would evolve into that direction. So

00:59:38 to involve the rapidly progressive

00:59:40 hearing loss and to involve the genome

00:59:43 editing rather than the simple gene

00:59:46 transfer that I think that that's the

00:59:48 way I think

00:59:49 >> perfect professor

00:59:51 >> thank you so much for this for your

00:59:53 science for your dedication

00:59:56 >> uh for the entire patients well-being um

01:00:01 >> that's all professor

01:00:02 >> thank you thank you so

01:00:04 >> heartful heartful

01:00:07 >> thank you so for your invitation and

01:00:09 it's it's my privilege to um to

01:00:12 participate in this the hearing circle.

01:00:15 It's my great honor.

01:00:17 [laughter]

01:00:18 >> Thank you so much professor. Thank you

01:00:19 for flying all the way from Seol, South

01:00:22 Korea to India and answering all the

01:00:25 questions that our Indian parents have.

01:00:28 Thank you.

01:00:28 >> Thank you.

01:00:29 >> Thank you. Namaste.

01:00:30 >> Namaste. Namaste. No.