Frequency Therapeutics — Hearing Loss Regeneration

[HootOwl]

Taking a shower or having an ambulance drive by while staying inside and hearing the sound through walls isn't going to damage your hearing. That's just scientifically impossible.

You would be surprised what can damage an already inflamed cochlea. 3 years ago when I had my first worsening I was in the hospital and someone shouted down the hall to a nurse while I was a good 100 feet away. Couldn't have been more than a split second of 60 decibels or so. It should be impossible for something like that to cause additional damage. But my ear popped and boom, new tinnitus tone.

Another time I had a worsening from calling out to my mom from the kitchen - it wasn't loud at all. Nothing that should ever theoretically be possible, and yet, it happened.

But it's true that yours could be an entirely separate issue. Have you done any work ups regarding TMJ or gotten any blood panels for autoimmune diseases? It could potentially be viral as well. Viruses love the inner ear and even without any exposure to sound, they can devastate the structures, resulting in worse tinnitus or hyperacusis. It's why people can wake up deaf in one ear out of the blue.

 

[Flyingsheep]

You would be surprised what can damage an already inflamed cochlea. 3 years ago when I had my first worsening I was in the hospital and someone shouted down the hall to a nurse while I was a good 100 feet away. Couldn't have been more than a split second of 60 decibels or so. It should be impossible for something like that to cause additional damage. But my ear popped and boom, new tinnitus tone.

Another time I had a worsening from calling out to my mom from the kitchen - it wasn't loud at all. Nothing that should ever theoretically be possible, and yet, it happened.

But it's true that yours could be an entirely separate issue. Have you done any work ups regarding TMJ or gotten any blood panels for autoimmune diseases? It could potentially be viral as well.

I have never had any "pop" or weird ear sensation, or any sudden onset of increased tinnitus from hearing any sudden noise. So for me if I start thinking that certain noises caused me to permanently get worse, I'm just making random unscientific guesses which is a product of my own anxiety. Not that I'm discounting that others do actually get worse by one loud sound, I'm just saying in my case there seems to be no evidence of that. It just does what it wants.

I do have TMJ and I am seeing an ENT who is looking into that as a possible reason. They said worst case scenario they will do an MRI and send me to a neurologist. So I'm going down a rabbit hole that may either provide insight or leave me with nothing answered.

 

[serendipity1996]

You would be surprised what can damage an already inflamed cochlea. 3 years ago when I had my first worsening I was in the hospital and someone shouted down the hall to a nurse while I was a good 100 feet away. Couldn't have been more than a split second of 60 decibels or so. It should be impossible for something like that to cause additional damage. But my ear popped and boom, new tinnitus tone.

Another time I had a worsening from calling out to my mom from the kitchen - it wasn't loud at all. Nothing that should ever theoretically be possible, and yet, it happened.

But it's true that yours could be an entirely separate issue. Have you done any work ups regarding TMJ or gotten any blood panels for autoimmune diseases? It could potentially be viral as well. Viruses love the inner ear and even without any exposure to sound, they can devastate the structures, resulting in worse tinnitus or hyperacusis. It's why people can wake up deaf in one ear out of the blue.

Agreed - I have experienced significant hyperacusis setbacks from sound that *shouldn't* have been anywhere near damaging. For healthy ears, sure it would be pretty improbable to experience damage when exposed to, say, ambulance sirens when inside but the consensus on already damaged ears isn't so clear-cut.

 

[dan]

Progenitor cells are divided and then turned into a new haircell. So you don't end up with less progenitor cells than you had before recieving FX-322.

There's no evidence at all to suggest we would have "glass ears". I'm going to take care of mine regardless, though.

Thats good news... so when we talk about progenitor and support cells, they are the same thing right?

 

[xyz]

You would be surprised what can damage an already inflamed cochlea. 3 years ago when I had my first worsening I was in the hospital and someone shouted down the hall to a nurse while I was a good 100 feet away. Couldn't have been more than a split second of 60 decibels or so. It should be impossible for something like that to cause additional damage. But my ear popped and boom, new tinnitus tone.

This is also my experience. When you already have tinnitus it is much easier to damage your ear. So sounds below 85 dB are not safe for everyone. Do you know any studies which support this?

 

[AtlasFainted]

Thats good news... so when we talk about progenitor and support cells, they are the same thing right?

I think progenitor cells are a specific kind of support cell. They're basically stem cells that could have turned into hair cells while in the womb but didn't.

 

[HootOwl]

I have never had any "pop" or weird ear sensation,

Sorry, I really should stop saying "pop"... What I meant was the tinnitus "popped" into my ear suddenly. The ear didn't actually make a sound and I didn't feel any sensation along with it.

So for me if I start thinking that certain noises caused me to permanently get worse, I'm just making random unscientific guesses which is a product of my own anxiety. Not that I'm discounting that others do actually get worse by one loud sound, I'm just saying in my case there seems to be no evidence of that. It just does what it wants.

Ah, understandable. I get what you mean.

 

[HootOwl]

This is also my experience. When you already have tinnitus it is much easier to damage your ear. So sounds below 85 dB are not safe for everyone. Do you know any studies which support this?

I do not unfortunately. If you find some let me though, I would be very interested. The only study I'm vaguely aware of is for "uncompromised" ears and was trying to raise awareness that prolonged exposure to 70 dB level sounds can be harmful, but it was a long time ago when I read that. I don't remember much about it tbh.

 

[Nobody19]

It's important to remember though that the severity of tinnitus isn't necessarily related to the degree of hearing damage/loss you have, but instead to the degree of hyperactivity and central gain you have. Inflammation can also play a serious role. As a result, you can have very, very minor damage and yet still get very strong central gain.

The question as to why some people have such severe hyperactivity as a response to decreased cochlear input is still hotly debated, but one of the current theories being investigated is the ability of the Kv7 ion channels to self regulate. Those who don't develop hyperactivity even after significant hearing loss seem to have ion channels that re-equalize their voltage much easier or faster than those that do.

Edit: I should clarify that this relates to tinnitus of cochlear origin. Tinnitus stemming from TMJ, TMI, autoimmune, etc. could be different. The studies regarding central gain/hyperactivity all involve hearing loss, via noise or ototoxicty.

Dang I have had tinnitus since 2012 and this is the first I hear about this!

 

[dan]

And why would we still have glass ears?

Well technically we have defective Kv7 channels. I just used a layman phrase for our problem... A deaf person can have zero tinnitus and a person with tiny hearing loss can have severe tinnitus
(Like @acute does).
So the underlying cause of tinnitus is not damaged cochlea, but out of whack gating channels. Granted hearing loss triggers a gating response, and which way that goes determines tinnitus or not, as I understood from @HootOwl.
If regeneration calms the hyperactivity, that doesn't mean you have a superman auditory system... You will still be able to get worse tinnitus at any inkling of further hearing loss, or destabilization of your Kv7 system, due to life stress, noise insults, ototoxic meds, etc.

What we need to cure us is a highly effective Kv drug.

Sure curing hearing loss is great, but FX-322 intended treatment is not tinnitus.
They hope it brings some relief as a secondary outcome...
@FGG would you agree?

 

[Croaker]

Well technically we have defective Kv7 channels. I just used a layman phrase for our problem... A deaf person can have zero tinnitus and a person with tiny hearing loss can have severe tinnitus
(Like @acute does).
So the underlying cause of tinnitus is not damaged cochlea, but out of whack gating channels. Granted hearing loss triggers a gating response, and which way that goes determines tinnitus or not, as I understood from @HootOwl.
If regeneration calms the hyperactivity, that doesn't mean you have a superman auditory system... You will still be able to get worse tinnitus at any inkling of further hearing loss, or destabilization of your Kv7 system, due to life stress, noise insults, ototoxic meds, etc.

What we need to cure us is a highly effective Kv drug.

Sure curing hearing loss is great, but FX-322 intended treatment is not tinnitus.
They hope it brings some relief as a secondary outcome...
@FGG would you agree?

I am way out of my depth with explaining how these various ion channels work. That being said, I'm not sure we were all born with defective Kv7 channels. Wouldn't we all have gotten childhood epilepsy or something if that were true? IDK, I agree that the potassium drugs are the most promising for tinnitus/hyperacusis right now. We'll just have to wait for some trial data.

 

[HootOwl]

Well technically we have defective Kv7 channels. I just used a layman phrase for our problem... A deaf person can have zero tinnitus and a person with tiny hearing loss can have severe tinnitus
(Like @acute does).
So the underlying cause of tinnitus is not damaged cochlea, but out of whack gating channels. Granted hearing loss triggers a gating response, and which way that goes determines tinnitus or not, as I understood from @HootOwl.
If regeneration calms the hyperactivity, that doesn't mean you have a superman auditory system... You will still be able to get worse tinnitus at any inkling of further hearing loss, or destabilization of your Kv7 system, due to life stress, noise insults, ototoxic meds, etc.

What we need to cure us is a highly effective Kv drug.

Sure curing hearing loss is great, but FX-322 intended treatment is not tinnitus.
They hope it brings some relief as a secondary outcome...
@FGG would you agree?

Defective Kv7 channels (specifically 2 and 3) is one theory amongst several. A very plausible one to be sure though, and one that I understand better scientifically after reading through the transcript of the most recent Tinnitus Talk Podcast with Thanos Tzounopoulos.

Potassium channels seem to be responsible for stopping hyperactivity in the fusiform cells/neurons within the DCN. They are, as Thanos described, the "brakes" for any hyperactivity that occurs following cochlear damage. When these channels open - via voltage gating - the "brakes" are applied, and the hyperactivity quelled.

However, for some reason, sometimes these channels do not open properly. This feeds into the theory that some people naturally have potassium ion channels that can open more readily than others; i.e. self regulate. It could also explain why some people see their tinnitus improve after a period of time. The ion channels might have finally been able to open by themselves, resulting in the neurons finally hitting the breaks.

I'm also just spitballing here, but it might also be the reasoning behind fluctuating tinnitus. If your ion channels are constantly opening and closing for some reason (and never quite stabilize in either direction) then you would get periods with tinnitus, and periods without. This is all of course assuming you don't have Meniere's (or ETD), both of which which have entirely separate reasons for fluctuating tinnitus.

I imagine we will probably see more research on this in the upcoming years.

But I do agree that I think people seem to be confusing the "cause" of cochlear tinnitus with the "generation" of cochlear tinnitus. Hearing loss causes cochlear tinnitus, but the tinnitus signal is generated in the DCN, as a result of reduced input.

So if you are genetically pre-dispositioned to have Kv7.2/7.3 channels that like to stay closed, you will still most likely be susceptible to future tinnitus, even after fixing your cochlear damage with regenerative medicine.

However, imo, you don't need to "cure" this predisposition. As long as you can repair the cochlear structure and/or open the channels (should the tinnitus worsen again) you should be okay.

 

[FGG]

Well technically we have defective Kv7 channels. I just used a layman phrase for our problem... A deaf person can have zero tinnitus and a person with tiny hearing loss can have severe tinnitus
(Like @acute does).
So the underlying cause of tinnitus is not damaged cochlea, but out of whack gating channels. Granted hearing loss triggers a gating response, and which way that goes determines tinnitus or not, as I understood from @HootOwl.
If regeneration calms the hyperactivity, that doesn't mean you have a superman auditory system... You will still be able to get worse tinnitus at any inkling of further hearing loss, or destabilization of your Kv7 system, due to life stress, noise insults, ototoxic meds, etc.

What we need to cure us is a highly effective Kv drug.

Sure curing hearing loss is great, but FX-322 intended treatment is not tinnitus.
They hope it brings some relief as a secondary outcome...
@FGG would you agree?

I think it's reasonable to assume anyone could always get hearing damage again. But hopefully that is where things like the Hough Pill and Strekin AG would come in as post exposure protection.

 

[DoNotGoGentle]

Looks like once FX-322 is approved it will have to go through another trial to get approved by FDA to be used with (check 14:14) Otomagnetics Looks like Carl LeBel was on this team before Frequency. Check video at 5:21.

 

[all to gain]

The more and more I read this thread the more I realise that FX-322 probably isn't going to be a cure for tinnitus and may only help a little bit, but boy I hope I am proved wrong. Luckily, I suppose, I also have hearing loss, which I am hopeful this drug will help me and others with.

 

[UKBloke]

Well technically we have defective Kv7 channels. I just used a layman phrase for our problem... A deaf person can have zero tinnitus and a person with tiny hearing loss can have severe tinnitus
(Like @acute does).
So the underlying cause of tinnitus is not damaged cochlea, but out of whack gating channels. Granted hearing loss triggers a gating response, and which way that goes determines tinnitus or not, as I understood from @HootOwl.
If regeneration calms the hyperactivity, that doesn't mean you have a superman auditory system... You will still be able to get worse tinnitus at any inkling of further hearing loss, or destabilization of your Kv7 system, due to life stress, noise insults, ototoxic meds, etc.

What we need to cure us is a highly effective Kv drug.

Sure curing hearing loss is great, but FX-322 intended treatment is not tinnitus.
They hope it brings some relief as a secondary outcome...
@FGG would you agree?

This explanation makes sense and articulates the problem well.

I think the issue we're facing rectifying hearing damage is whether or not this will be the nudge the hearing system needs to reset the tinnitus creating channels back to zero. It kind of reminds me of tuning a car engine, which is possible if nothing is damaged, practically impossible at times, if there is an underlying part that has failed and needs replacing.

If the tendency of the human body is to try and run in tune then as long as these various channels aren't damaged, I suppose there may be quite a bit of hope. If FX-322 doesn't resolve tinnitus that well, however, at least it may shed some further light on where the fault may lie.

 

[mrbrightside614]

Well technically we have defective Kv7 channels. I just used a layman phrase for our problem... A deaf person can have zero tinnitus and a person with tiny hearing loss can have severe tinnitus
(Like @acute does).
So the underlying cause of tinnitus is not damaged cochlea, but out of whack gating channels. Granted hearing loss triggers a gating response, and which way that goes determines tinnitus or not, as I understood from @HootOwl.
If regeneration calms the hyperactivity, that doesn't mean you have a superman auditory system... You will still be able to get worse tinnitus at any inkling of further hearing loss, or destabilization of your Kv7 system, due to life stress, noise insults, ototoxic meds, etc.

What we need to cure us is a highly effective Kv drug.

Sure curing hearing loss is great, but FX-322 intended treatment is not tinnitus.
They hope it brings some relief as a secondary outcome...
@FGG would you agree?

I'm pretty sure you'll be only as likely, or slightly less likely to acquire tinnitus after FX-322 after regeneration. Reversing the hearing loss should absolutely reverse the hyperactivity. Brand new functional hair cells attached at new synapses may prove more resilient to future damage than our compromised ones.

 

[sssing]

Defective Kv7 channels (specifically 2 and 3) is one theory amongst several. A very plausible one to be sure though, and one that I understand better scientifically after reading through the transcript of the most recent Tinnitus Talk Podcast with Thanos Tzounopoulos.

Potassium channels seem to be responsible for stopping hyperactivity in the fusiform cells/neurons within the DCN. They are, as Thanos described, the "brakes" for any hyperactivity that occurs following cochlear damage. When these channels open - via voltage gating - the "brakes" are applied, and the hyperactivity quelled.

However, for some reason, sometimes these channels do not open properly. This feeds into the theory that some people naturally have potassium ion channels that can open more readily than others; i.e. self regulate. It could also explain why some people see their tinnitus improve after a period of time. The ion channels might have finally been able to open by themselves, resulting in the neurons finally hitting the breaks.

I'm also just spitballing here, but it might also be the reasoning behind fluctuating tinnitus. If your ion channels are constantly opening and closing for some reason (and never quite stabilize in either direction) then you would get periods with tinnitus, and periods without. This is all of course assuming you don't have Meniere's (or ETD), both of which which have entirely separate reasons for fluctuating tinnitus.

I imagine we will probably see more research on this in the upcoming years.

But I do agree that I think people seem to be confusing the "cause" of cochlear tinnitus with the "generation" of cochlear tinnitus. Hearing loss causes cochlear tinnitus, but the tinnitus signal is generated in the DCN, as a result of reduced input.

So if you are genetically pre-dispositioned to have Kv7.2/7.3 channels that like to stay closed, you will still most likely be susceptible to future tinnitus, even after fixing your cochlear damage with regenerative medicine.

However, imo, you don't need to "cure" this predisposition. As long as you can repair the cochlear structure and/or open the channels (should the tinnitus worsen again) you should be okay.

Where do these channels reside? In the brain or the cochlea synapses? I agree reluctantly with @all to gain that the problem of tinnitus may not be as 'easy' as regrowing the hair cells, though even doing that is already a feat. Just like many diseases, we can treat the symptoms and not the root cause, thereby getting rid of the problem altogether. I am super worried that for something as complicated as the inner ear that might happen, but treating the symptoms is still better than no treatment at all.

 

[serendipity1996]

I'm pretty sure you'll be only as likely, or slightly less likely to acquire tinnitus after FX-322 after regeneration. Reversing the hearing loss should absolutely reverse the hyperactivity. Brand new functional hair cells attached at new synapses may prove more resilient to future damage than our compromised ones.

Yeah I agree and even if we are perhaps more susceptible to hearing damage I don't think that, following regeneration, we will necessarily be one cinema-trip/gig/loud bar away from disaster.

 

[HootOwl]

The more and more I read this thread the more I realise that FX-322 probably isn't going to be a cure for tinnitus and may only help a little bit, but boy I hope I am proved wrong. Luckily, I suppose, I also have hearing loss, which I am hopeful this drug will help me and others with.

Don't be discouraged. I think people get a bit too hung up on a single, grand unifying tinnitus cure. All elements of cochlear tinnitus are being addressed by one company or another.

And after speaking to another forum member about this topic, I'm also of the mind that almost all forms of non-cochlear tinnitus can addressed as well (such as TMJ), as long as you can get a proper work-up.

 

[HootOwl]

If the tendency of the human body is to try and run in tune then as long as these various channels aren't damaged

The good news is that the channels themselves don't seem to be damaged, they simply won't open properly. A truly damaged channel won't open at all, but the research Thanos has done implies that the channel needs help opening after noise trauma, not that it is non-operational entirely.

 

[dan]

I'm pretty sure you'll be only as likely, or slightly less likely to acquire tinnitus after FX-322 after regeneration. Reversing the hearing loss should absolutely reverse the hyperactivity. Brand new functional hair cells attached at new synapses may prove more resilient to future damage than our compromised ones.

That's a really good point there Mister...

 

[HootOwl]

Where do these channels reside? In the brain or the cochlea synapses?

If I'm understanding correctly, the channels reside in the fusiform neurons themselves. The fusiform neurons are located in the CN - specifically the DCN.

So in that little fusiform cell there, you have ion channels that can open or close depending on the associated voltage.

If I'm getting this wrong, please feel free to correct me. I have a pretty good handle on the cochlea, but once we move past the auditory nerve I'm a bit more lost at sea.

 

[HootOwl]

Brand new functional hair cells attached at new synapses may prove more resilient to future damage than our compromised ones.

This is what I'm hoping as well.

 

[Christiaan]

The good news is that the channels themselves don't seem to be damaged, they simply won't open properly. A truly damaged channel won't open at all, but the research Thanos has done implies that the channel needs help opening after noise trauma, not that it is non-operational entirely.

I hope you're right. @HootOwl. However, I've just read the transcript of the podcast with Tzounopoulos, and he mentioned that there are two possibilities that ion potassium channels may not work:

1) the ion channels are permanently damaged after acoustic trauma (RL-81 might not help)
2) the ion channels are present, but are not functioning properly (RL-81 might help)

So, considering the 1st possibility, it seems that there is a chance some of us have permanent damage to the ion channel?

Here's the quote about the 1st possibility:
''What is the problem, why do they not work? Again, there are two major ways that a channel can stop working. One is that these channels they have to synthesise inside the cell, and they have to go to the membrane of the neuron to allow for this in and out of the ions that I told you. It could be that the channels never make it to the membrane, they are not formed somehow after noise trauma and tinnitus. They are ruined for whatever reason.'' (p.8)

 

[dan]

I'm not sure we were all born with defective Kv7 channels. Wouldn't we all have gotten childhood epilepsy or something if that were true?

We all had great working channels but life stress ran down the battery voltage and we can no longer use the push to start button... we need to use the kickstarter to fire it back to life.
Notice how so many people here say that tinnitus began after a period of stress/anxiety/depression/loss of loved one, etc. Seems these channels are very sensitive to our mental state.

Regeneration should help a lot because there will be less need for the "brakes"...
The brain will regain some input from the cochlea and that would reduce hyperactivity directly. The amount of regained input will be directly proportional with tinnitus reduction.
Ideally zero hearing loss=zero tinnitus.
That's why nature created gating mechanism to compensate for lack of input. Kind of inefficient system, would be much simpler to evolve an auditory cortex that only has input and no "output".

Those with severe tinnitus may end up with mild/moderate tinnitus, which would be a cake walk after this daily torture...

 

[Emgee]

I wonder about the potential impact of FX-322 on those afflicted with forms of reactive or sound-sensitive tinnitus. In theory, should regenerative medicine work the same way in treating reactive cases versus those with consistent tinnitus baselines?

If restoration of hearing leads to reduced tinnitus, the form of tinnitus should not matter, right?

 

[Frédéric]

If I'm getting this wrong, please feel free to correct me. I have a pretty good handle on the cochlea, but once we move past the auditory nerve I'm a bit more lost at sea.

It is really the case for all of us. Since the time I read medical publications on hearing, I have not seen an objective and certain demonstration on the process of hearing beyond the auditory nerve. I have the impression that the most far where research has gone in the understanding and control of auditory signals is the auditory brainstem implant (the limit between auditory nerve and DCN if I understood correct):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361749/

 

[WickedCarnival]

Looks like once FX-322 is approved it will have to go through another trial to get approved by FDA to be used with (check 14:14) Otomagnetics Looks like Carl LeBel was on this team before Frequency. Check video at 5:21.

That's still progress though! I'm glad they are aware of FX-322 and hope there is some degree of good communication between Otomagnetics and Frequency Therapeutics!

 

[HootOwl]

I hope you're right. @HootOwl. However, I've just read the transcript of the podcast with Tzounopoulos, and he mentioned that there are two possibilities that ion potassium channels may not work:

1) the ion channels are permanently damaged after acoustic trauma (RL-81 might not help)
2) the ion channels are present, but are not functioning properly (RL-81 might help)

So, considering the 1st possibility, it seems that there is a chance some of us have permanent damage to the ion channel?

Here's the quote about the 1st possibility:
''What is the problem, why do they not work? Again, there are two major ways that a channel can stop working. One is that these channels they have to synthesise inside the cell, and they have to go to the membrane of the neuron to allow for this in and out of the ions that I told you. It could be that the channels never make it to the membrane, they are not formed somehow after noise trauma and tinnitus. They are ruined for whatever reason.'' (p.8)

Ah, I see what you mean about the first possibility. But aren't the ion channels present at birth? I have to admit I'm a bit confused by his explanation in them not forming after acoustic trauma. Perhaps I'll email him asking for clarification.