Frequency Therapeutics — Hearing Loss Regeneration

[Zugzug]

Of course there's a place for symptom management if curing the underlying disease is too complicated.

I must say, for the life of me, I do not understand the hardcore pessimistic attitude (that's beyond being analytically critical). Should no one invest because it's never been done before?

There's this weird projection of like the people feeding life into this movement are the weak ones, too emotionally weak to accept reality. What about the weakness of being unwilling to emotionally (which leads to financially) invest? What if every single investor just said "I'm too scared of it failing"? How exactly does hearing research progress?

None of the blind pessimists ever care to answer this question. They want Will McLean to just sit in his basement and cure them or something.

 

[FGG]

This is not true. If there are any examples out there they will be anecdotal.

I'm not sure what you mean by 2012 ideas? This is still ongoing. It works on the same principles as phantom limb syndrome and chronic pain. How do you explain why some get tinnitus with hearing loss and some don't? I think you are looking at this far too simplistically. The complexity of this condition goes far beyond hearing loss.

Almost everyone will get tinnitus with severe enough (especially sudden) hearing loss. As to why people with more mild hearing loss get tinnitus, there are a few theories.

Both Dr. Thanos Tzounopoulos and Dr. Will Sedley have talked about some brains having a more "predictive" nature and appear to respond with hyperexcitabilty when the "expected signal" doesn't match the actual signal. What this difference in brains could be possibly something like ion channel polymorphism or a tendency to less favorable GABA/glutamate ratios (in fact severe stress at time of hearing loss is associated with increased tinnitus generation but that might also be due to things like axonal dynorphin release in the cochlea).

Anyway, if we look at treatable causes, we can see that tinnitus isn't "stuck in the brain". People with long standing TMJ have successfully treated tinnitus.

Cochlear implants are somewhat crude and electrode based (hitting some frequencies and not others) but people with very long term hearing loss have seen relief. Tinnitus from hydrops can be very episodic. None of these things would be true if neuroplasticity was stuck in one maladaptive direction.

And I'm not saying we shouldn't look at gating but that's clearly not the whole picture. People who got relief from Trobalt usually reverted back after cessation precisely because they didn't treat the underlying cause.

I'm glad they are researching symptomatic treatment as well as the underlying causes but personally I find treating underlying causes a better direction to go (and people will disagree on this).

I do agree with your statement that it's more complicated than "hearing loss causes tinnitus" and I have argued that it's much more correct to say "hearing interference" does. After all, even ear wax can cause tinnitus.

 

[Ed209]

If I have a faulty gating mechanism, why is my tinnitus extremely loud one day, then hardly noticeable the very next? It's intermittently faulty? Also, people with Meniere's disease who get random attacks of tinnitus. That's due to faulty gating mechanism as well?

Who knows? I ask that question all the time. The gating mechanism is just a hypothesis, and I only used it as an example.

 

[Ed209]

Both Dr. Thanos Tzounopoulos and Dr. Will Sedley have talked about some brains having a more "predictive" nature and appear to respond with hyperexcitabilty when the "expected signal" doesn't match the actual signal. What this difference in brains could be possibly something like ion channel polymorphism or a tendency to less favorable GABA/glutamate ratios (in fact severe stress at time of hearing loss is associated with increased tinnitus generation but that might also be due to things like axonal dynorphin release in the cochlea).

Anyway, if we look at treatable causes, we can see that tinnitus isn't "stuck in the brain". People with long standing TMJ have successfully treated tinnitus.

Cochlear implants are somewhat crude and electrode based (hitting some frequencies and not others) but people with very long term hearing loss have seen relief. Tinnitus from hydrops can be very episodic. None of these things would be true if neuroplasticity was stuck in one maladaptive direction.

And I'm not saying we shouldn't look at gating but that's clearly not the whole picture. People who got relief from Trobalt usually reverted back after cessation precisely because they didn't treat the underlying cause.

I'm glad they are researching symptomatic treatment as well as the underlying cause but personally I find treating the underlying cause a better direction to go (and people will disagree on this).

I do agree with your statement that it's more complicated than "hearing loss causes tinnitus" and I have argued that it's much more correct to say "hearing interference" does. After all, even ear wax can cause tinnitus.

I've followed their research for years and understand the various ideas that are out there. Nobody knows for sure what is really going on; there's a lot more to learn.

Almost everyone will get tinnitus with severe enough (especially sudden) hearing loss. As to why people with more mild hearing loss get

This is true, but in a lot of people, it fades in a matter of hours. It doesn't become chronic universally. We have pieces of the jigsaw, but nobody has put it all together yet.

I question those like Tezcatlipoca who believe it's entirely related to hearing loss. This cannot be true otherwise tinnitus would be present in everyone.

 

[FGG]

I've followed their research for years and understand the various ideas that are out there. Nobody knows for sure what is really going on; there's a lot more to learn.

This is true, but in a lot of people, it fades in a matter of hours. It doesn't become chronic universally. We have pieces of the jigsaw, but nobody has put it all together yet.

I question those like Tezcatlipoca who believe it's entirely related to hearing loss. This cannot be true otherwise tinnitus would be present in everyone.

I see it more like this. Not everyone who loses a leg gets "phantom limb" pain, but you aren't going to get phantom limb pain if you don't. It doesn't mean amputation isn't the cause of phantom limb.

 

[Tezcatlipoca]

I question those like Tezcatlipoca who believe it's entirely related to hearing loss. This cannot be true otherwise tinnitus would be present in everyone.

I'll give you that one, it's not entirely hearing related, but in most cases it is hearing related, we are on a hearing related tinnitus thread after all.

"The U.S. Centers for Disease Control estimates that nearly 15% of the general public — over 50 million Americans — experience some form of tinnitus. Roughly 20 million people struggle with burdensome chronic tinnitus, while 2 million have extreme and debilitating cases."

 

[Ed209]

I see it more like this. Not everyone who loses a leg gets "phantom limb" pain, but you aren't going to get phantom limb pain if you don't. It doesn't mean amputation isn't the cause of phantom limb.

That's how I see it too. Question is, why do some develop phantom limb syndrome whilst others don't? Same applies to tinnitus. What is the underlying mechanism that drives it into the higher functioning parts of the brain in some but not others?

Hearing loss has always been at the heart of tinnitus, but it's very heterogeneous. There are other ways in which people notice the onset of their tinnitus that has nothing to do with hearing loss, such as neck and vascular problems (non-objective), nerve issues, stress and burnout, pregnancy, etc, etc. I agree that hearing loss underpins the vast majority of cases, but it cannot explain all of them.

Although there's a good chance that regenerating one's hearing will help with tinnitus, it's not a full gone conclusion, and there are no studies to confirm what effect it will have. More research is needed.

 

[Toby1972]

I sent an eMail to Frequency Therapeutics about how they can avoid cheating at the entrance tests (with WR etc.). I'll tell you more soon. I'm trying to be more of a go-getter than a babbler.

 

[FGG]

That's how I see it too. Question is, why do some develop phantom limb syndrome whilst others don't? Same applies to tinnitus. What is the underlying mechanism that drives it into the higher functioning parts of the brain in some but not others?

Hearing loss has always been at the heart of tinnitus, but it's very heterogeneous. There are other ways in which people notice the onset of their tinnitus that has nothing to do with hearing loss, such as neck and vascular problems (non-objective), nerve issues, stress and burnout, pregnancy, etc, etc. I agree that hearing loss underpins the vast majority of cases, but it cannot explain all of them.

Although there's a good chance that regenerating one's hearing will help with tinnitus, it's not a full gone conclusion, and there are no studies to confirm what effect it will have. More research is needed.

This is a tangent, but neck and jaw problems interfere with nerve function in the middle ear. TMJ can even raise intracochlear pressure and prevent normal hair cell function as well as contribute to inflammation the same way other "pressure" injuries can. It's further complicated by the fact that the Trigeminal nucleus is in the cervical spine and the Trigeminal and Facial nerves control middle ear muscle function. The Trigeminal Nerve even controls cochlear blood flow:

Direct evidence of trigeminal innervation of the cochlear blood vessels

Anyway, there is a reason the lumbar spine doesn't affect tinnitus the way the cervical spine does.

But that is why I prefer referring to "hearing interference" as causative and not "hearing loss".

But just because not everyone with hearing interference gets tinnitus, it doesn't mean it's not the cause.

Not everyone with HIV gets AIDS, not everyone with obesity gets type 2 diabetes etc etc.

 

[FGG]

I sent an eMail to Frequency Therapeutics about how they can avoid cheating at the entrance tests (with WR etc.). I'll tell you more soon. I'm trying to be more of a go-getter than a babbler.

I'm dying to know how you worded this...

 

[Paul Walter]

They should research how to eliminate tinnitus with a process that renders one deaf permanently.

It would provide results far sooner than all this study into regeneration of hearing, plasticity, gate channeling, vagus nerve stimulation with tones etc.

All these approaches that have now been going on for years have gained and provided nothing.

We want a solution in our lifetime. 200 years into the future is of no use to anyone on this forum.

 

[Ed209]

This is a tangent, but neck and jaw problems interfere with nerve function in the middle ear. TMJ can even raise intracochlear pressure and prevent normal hair cell function as well as contribute to inflammation the same way other "pressure" injuries can. It's further complicated by the fact that the Trigeminal nucleus is in the cervical spine and the Trigeminal and Facial nerves control middle ear muscle function. The Trigeminal Nerve even controls cochlear blood flow:

Direct evidence of trigeminal innervation of the cochlear blood vessels

Anyway, there is a reason the lumbar spine doesn't affect tinnitus the way the cervical spine does.

But that is why I prefer referring to "hearing interference" as causative and not "hearing loss".

But just because not everyone with hearing interference gets tinnitus, it doesn't mean it's not the cause.

Not everyone with HIV gets AIDS, not everyone with obesity gets type 2 diabetes etc etc.

I like this answer but I feel there's more going on. Sleep affects how loud or intrusive it can be in many individuals, and for some it can come and go (and change) as freely as the wind. I believe that something is happening within the auditory pathway that is unique to certain individuals. The brain is infinitely complex, though.

Everyone with hearing loss likely has some form of tinnitus signal being generated within their brain, but only a certain percentage pick up that signal and tune into it. It seems that once it is detected it's extremely difficult to "un-hear" it and fMRI studies (Fatima Hussain, for example) have shown that people with tinnitus tend to light up other areas of their brain (compared to non-tinnitus sufferers) under certain conditions. There also seems to be involvement from other areas of the brain relating to memory, behaviour, and emotion, like the caudate and putamen (dorsal striatum), nucleus accumbens, ventromedial caudate, and ventral putamen (ventral striatum) and the amygdala, hippocampus, thalamus, hypothalamus, etc, etc.

I think it's a complex puzzle to solve, but each piece of novel research brings us closer to the truth.

 

[FGG]

I like this answer but I feel there's more going on. Sleep affects how loud or intrusive it can be in many individuals, and for some it can come and go (and change) as freely as the wind. I believe that something is happening within the auditory pathway that is unique to certain individuals. The brain is infinitely complex, though.

Everyone with hearing loss likely has some form of tinnitus signal being generated within their brain, but only a certain percentage pick up that signal and tune into it. It seems that once it is detected it's extremely difficult to "un-hear" it and fMRI studies (Fatima Hussain, for example) have shown that people with tinnitus tend to light up other areas of their brain (compared to non-tinnitus sufferers) under certain conditions. There also seems to be involvement from other areas of the brain relating to memory, behaviour, and emotion, like the caudate and putamen (dorsal striatum), nucleus accumbens, ventromedial caudate, and ventral putamen (ventral striatum) and the amygdala, hippocampus, thalamus, hypothalamus, etc, etc.

I think it's a complex puzzle to solve, but each piece of novel research brings us closer to the truth.

I definitely don't want to sound like I am trying to oversimplify it. There is, without a doubt, heterogeneous higher central involvement, but I would still argue that the involvement is a *response* to the problem and not the underlying problem itself.

How do I know that? If you treat the treatable causes, the tinnitus goes away. Not to say there can't be good symptomatic treatments that could come from that kind of research until the underlying causes are addressed. A pill a day that reduces tinnitus but has to be taken daily would still be a very attractive option. But I don't think that research (again, my personal opinion) is necessarily more useful.

For example, let's say you had chronic pancreatitis but could improve the pain and nausea with meds. That's an important step in feeling better but you could get much better symptom resolution but addressing the underlying cause.

Both types of research are important. My greater point is still, though, that hearing research is absolutely tinnitus research.

 

[Ed209]

My greater point is still, though, that hearing research is absolutely tinnitus research.

I'm not sure why this breakaway point even started. Surely that goes without saying? I see no differentiation between the two as they fall under the same umbrella.

 

[FGG]

I'm not sure why this breakaway point even started. Surely that goes without saying? I see no differentiation between the two as they fall under the same umbrella.

It wasn't you but it has been suggested here many times that money should go to "tinnitus research" rather than "hearing research."

It sounds like we are on the same page though.

 

[Ed209]

Many treatments are discovered by accident whilst researching other conditions, as you are no doubt aware, as you're a very smart person. One famous example is how Viagra was found to help with erectile dysfunction whilst they were looking for ways to treat heart-related chest pain.

Hopefully tinnitus will fall upon a similar happy accident.

 

[Zugzug]

It wasn't you but it has been suggested here many times that money should go to "tinnitus research" rather than "hearing research."

It sounds like we are on the same page though.

I haven't seen what others have said, but I will offer an argument.

I completely agree that tinnitus, of almost any cause, even TMJ, somehow relates back to hearing. Hence, hearing research makes the most sense.

However, as you well know, there is such a thing as tinnitus research that has nothing to do with hearing. For example, Professor Tzounopoulos and the Pitt Hearing Research Center are focusing on potassium channels. Obviously, there's the XENON drugs as well. I don't understand the mechanisms of OTO-313 too well, but it sounds to me like a hearing/tinnitus hybrid.

The issue though, and this is where I would agree with you, is that the brain isn't necessarily easier to treat than the ears, particularly when side effects are taken into account. I'm not surprised at all that a drug like Trobalt had severe adverse effects.

But theoretically speaking, if the tinnitus symptoms were easier to treat than healing the ear, I do think there would be a ton of value in throwing research funding at this. At this point, hearing regeneration is picking up steam so the choice of treatment/cure over limited to treatment only sort of makes sense.

Treatments are important though. I promise that I won't be cured of anything anytime soon, probably not in my lifetime. I'm sure you are in the same boat with your health problems (others as well). I'm starting to accept the value of treatments or any other way to climb 10-20% up from hell.

 

[GBB]

My point was that there is much more funding than it appears because people dismiss the funding that goes towards the individual causes. Take Meniere's for instance. Meniere's causes tinnitus in some people and research is increasingly funded.

And to @Diesel's point, hearing loss research is tinnitus research.

I had a sad observation earlier today which was probably obvious to everyone else, but we often say something to the effect of, if Jeff Bezos got tinnitus, it would be cured in a year!

Well the Texas Roadhouse guy was worth $600m, and he simply killed himself, and left a pittance to research. Like I said, self evident, but sad

 

[ploughna]

Does anyone have any thoughts as to why none of the major pharmaceuticals are working in this field (or if they are, I'm not aware)?

Instead we have well intentioned startups with a small fraction the resources of any of the big pharmas that would probably have a much better shot at solving in a fraction the time if they made it a priority. Unless of course they've simply decided it's too difficult/risky and the ROI isn't there. As it stands, we have maybe half a dozen potential products in the pipeline with a questionable chance of success in the next decade or so.

I mean if the Tzounopoulos research were truly promising, why wouldn't big pharma throw some proper money behind it and see where it goes? As it stands it'll be donkeys years before we see anything, if it doesn't just die in the meantime. Is it that much a long-shot that it's not worth their time?

At least (and back on topic), FREQ are committed to FX-322. My hope is that the single shot will at least make it through in a reasonable timeframe and offer at least partial relief.

 

[FGG]

I haven't seen what others have said, but I will offer an argument.

I completely agree that tinnitus, of almost any cause, even TMJ, somehow relates back to hearing. Hence, hearing research makes the most sense.

However, as you well know, there is such a thing as tinnitus research that has nothing to do with hearing. For example, Professor Tzounopoulos and the Pitt Hearing Research Center are focusing on potassium channels. Obviously, there's the XENON drugs as well. I don't understand the mechanisms of OTO-313 too well, but it sounds to me like a hearing/tinnitus hybrid.

The issue though, and this is where I would agree with you, is that the brain isn't necessarily easier to treat than the ears, particularly when side effects are taken into account. I'm not surprised at all that a drug like Trobalt had severe adverse effects.

But theoretically speaking, if the tinnitus symptoms were easier to treat than healing the ear, I do think there would be a ton of value in throwing research funding at this. At this point, hearing regeneration is picking up steam so the choice of treatment/cure over limited to treatment only sort of makes sense.

Treatments are important though. I promise that I won't be cured of anything anytime soon, probably not in my lifetime. I'm sure you are in the same boat with your health problems (others as well). I'm starting to accept the value of treatments or any other way to climb 10-20% up from hell.

This isn't important for this thread but for your own info:

OTO-313 is for tinnitus (gacyclidine, NMDA receptor antagonist)
OTO-413 is cochlear synaptopathy (BDNF to promote synaptogenesis)

Two different drugs.

Yes, there is value is symptomatic treatment but it's not as universally effective of an approach as it would appear.

Take OTO-313 for instance. It is a drug being tested solely for tinnitus and less than half of the participants (43%) got a response to the drug:

And that's including responses of 13-15 TFI.

Is that still worth trying? Absolutely. An improvement is an improvement and some improved quite a bit ("super responders" if you will).

Trobalt wasn't universally effective, either.

Right or wrong, I approach all of this the way I would think about treating all of my own patients when I could, which is to try to tackle the underlying cause if possible and if not, treat symptoms.

And btw, I am way more optimistic about treatments to bring me to at least a liveable level in my lifetime (even as you pointed out with all the hearing damage I have). I'm only in my early 40s. But I will have given up a lot along the way (career, the possibility of a family, etc).

 

[Diesel]

Does anyone have any thoughts as to why none of the major pharmaceuticals are working in this field (or if they are, I'm not aware)?

Instead we have well intentioned startups with a small fraction the resources of any of the big pharmas that would probably have a much better shot at solving in a fraction the time if they made it a priority. Unless of course they've simply decided it's too difficult/risky and the ROI isn't there. As it stands, we have maybe half a dozen potential products in the pipeline with a questionable chance of success in the next decade or so.

I mean if the Tzounopoulos research were truly promising, why wouldn't big pharma throw some proper money behind it and see where it goes? As it stands it'll be donkeys years before we see anything, if it doesn't just die in the meantime. Is it that much a long-shot that it's not worth their time?

At least (and back on topic), FREQ are committed to FX-322. My hope is that the single shot will at least make it through in a reasonable timeframe and offer at least partial relief.

It really depends on how you define "Big Pharma." The more I read that term here, the more it sounds like a conspiracy or a boogie man, like the "Deep State."

In reality, it depends on where the innovation starts. Many of the Langer projects started in a lab and spun off into small pharma operations until their IP/entity was acquired by a larger firm/drug manufacturer.

Often times, innovation in these spaces aren't worth the investment/sunk costs to move the needle for larger biotech firms. They also may have a very long-term strategy where a lot of investment is already locked up. Consider the millions that have already been sunk into hearing regeneration by a few of the notable players in the last 5 years. What firm would want to single-handedly pull that weight when other divisions look more promising in the short term? It's usually easier to sit back and wait until one gets de-risked enough to buy out.

For example, I could see a firm like Astellas taking a major stake in Frequency Therapeutics if things continue to improve for FX-322.

 

[Zugzug]

This isn't important for this thread but for your own info:

OTO-313 is for tinnitus (gacyclidine, NMDA receptor antagonist)
OTO-413 is cochlear synaptopathy (BDNF to promote synaptogenesis)

Two different drugs.

Yes, there is value is symptomatic treatment but it's not as universally effective of an approach as it would appear.

Take OTO-313 for instance. It is a drug being tested solely for tinnitus and less than half of the participants (43%) got a response to the drug:

View attachment 44513

And that's including responses of 13-15 TFI.

Is that still worth trying? Absolutely. An improvement is an improvement and some improved quite a bit ("super responders" if you will).

Trobalt wasn't universally effective, either.

Right or wrong, I approach all of this the way I would think about treating all of my own patients when I could, which is to try to tackle the underlying cause if possible and if not, treat symptoms.

And btw, I am way more optimistic about treatments to bring me to at least a liveable level in my lifetime (even as you pointed out with all the hearing damage I have). I'm only in my early 40s. But I will have given up a lot along the way (career, the possibility of a family, etc).

Yeah, I realize OTO-313 and OTO-413 are totally different. When I said OTO-313 was a hearing/tinnitus hybrid, I meant that the mechanism of NMDA receptor antagonist could have minor otoprotective capacity, no? Definitely not a form of regenerative medicine.

I see your point about the results being underwhelming, but they don't seem that much worse than FX-322 Phase 1/2.

I'm totally with you on career and family. Both appear to be a pipedream. Fucking sucks.

 

[FGG]

I see your point about the results being underwhelming, but they don't seem that much worse than FX-322 Phase 1/2.

Just like FX-322, patient selection with OTO-313 is key. This is why I emphasize the need to treat the underlying causes for each person.

As far as OTO-313, i suspect that a certain kind of patient has more glutamate related local inflammation acting on cochlear NMDA receptors chronically. Everyone with SNHL, for instance, seems to get this to at least some degree very acutely but chronically, there seems to be a divergence (and, at that point, you are maybe dealing with mostly central receptors and ion channels in the "maladaptive neuroplasticity" state predominately and have less additive contribution of the local cochlear excitability being propagated up the authority system).

This is my own speculation, but I think the studies showing dynorpin cochlear release from chronic severe psychological stress sensitizing the NMDA receptors may point to the drug working better for people who are very stressed by their tinnitus and/or have more severe tinnitus may have the best results.

And so far the data seems to show that (but not the mechanism):

So, like with FX-322, there seems to be a certain kind of ideal patient for this.

 

[GlennS]

I'd love to learn of a genuine success story where the decibel level of tinnitus has actually reduced.

If you're talking about treatments in general, sure, there are isolated anecdotes. Remember @Clare B? But there hasn't been a reliable and reproducible treatment.

if Jeff Bezos got tinnitus, it would be cured in a year!

This makes me roll my eyes.

Ever heard of Blue Origin? If money was the only impediment to accomplishing anything then why hasn't Bezos landed on the moon? Heck, why hasn't he invented warp drive already? Why is he bald and why does he still have one eye that is stuck open more than the other?

Point is that while R&D takes money, it is not a magic wand. You can not conjure anything into existence just because you have money. Some things will reveal themselves to be effectively impossible, money or no money.

 

[Jazzer]

Some things will reveal themselves to be effectively impossible, money or no money.

"Exactly my point Glen."

Well said buddy.

Eye rolling is the accurate response.

 

[Matchbox]

Blue Origin I thought was Branson's baby?

 

[Ed209]

They should research how to eliminate tinnitus with a process that renders one deaf permanently.

This has already been done. There was a case where somebody had tinnitus and their auditory nerve was cut. Unfortunately, this made everything worse, as the person still had tinnitus but no longer had any hearing to help mask it.

Making people deaf is a very silly idea that can make the situation a whole lot worse.

 

[Ed209]

I get the impression that I'm seen as a pessimist for some reason, but nothing could be further from the truth. I think it's important that we remain objective, and I see nothing wrong with people speaking their minds or giving honest opinions. This is probably why I'm perceived as being negative, which is not true BTW.

I've put a lot of time and money into this cause to help with research and awareness, so nobody would be happier to see a treatment that works than me.

 

[Ed209]

"Exactly my point Glen."

Well said buddy.

Eye rolling is the accurate response.

I agree with what Glenn said, that money can't always buy what you want. It doesn't buy people happiness, for example. However, if you don't try, you'll never find out what is and isn't possible, and that's where I stand. I would rather explore and fail than not explore at all.

I can appreciate that we all come at this from different angles with varying views of what's important in the world.

Hope you're keeping well, Dave.

 

[Diesel]

I get the impression that I'm seen as a pessimist for some reason, but nothing could be further from the truth. I think it's important that we remain objective, and I see nothing wrong with people speaking their minds or giving honest opinions. This is probably why I'm perceived as being negative, which is not true BTW.

I've put a lot of time and money into this cause to help with research and awareness, so nobody would be happier to see a treatment that works than me.

Your arguments/positions are just all over the place. Respectfully.