Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

Do you mean to dig it in the PubMed journal?
I can try to do that but it will take time.

That or I posted it on this thread somewhere (or a related thread).

This might help. It's not the study I referenced above but it concerns the "why" humans are different:

Human auditory nerve afferents consist of two separate systems; one is represented by the large type I cells innervating the inner hair cells and the other one by the small type II cells innervating the outer hair cells. Type I spiral ganglion neurons (SGNs) constitute 96% of the afferent nerve population and, in contrast to other mammals, their soma and pre- and post-somatic segments are unmyelinated. Type II nerve soma and fibers are unmyelinated.

From:
The pre- and post-somatic segments of the human type I spiral ganglion neurons – Structural and functional considerations related to cochlear implantation

 

[Drachen]

Secondly, the age-related hearing loss Phase 1b trial is set to end in Q2. This should reaffirm that patients who have likely had hearing loss for DECADES were still responders to the treatment.

This is an extremely good point to mention. If there is remarkable progress in this study, then that should speak to the robustness both of the human support cells and FX-322 itself.

@FGG had also mentioned previously how the instance in which the drug may not be effective due to support cell loss when epithelial scarring is present, which should only occur after profound hearing loss with severe trauma. I'm not positive, but I don't think this would be the case if you just have accumulated hearing loss over the years, whether it be noise-induced or presbycusis.

 

[vermillion]

So far no mention of a therapeutic window has been established for either drug. In fact, Chris Loose at Frequency Therapeutics mentioned in a past interview that the Phase 1/2 specifically targeted patients with a history of hearing loss and established relationship with their ENT. So, that tells me these patients that saw improvement had been living with hearing loss for years.

Secondly, the age-related hearing loss Phase 1b trial is set to end in Q2. This should reaffirm that patients who have likely had hearing loss for DECADES were still responders to the treatment.

That is absolutely encouraging, as it pertains to FX-322. I was mostly referring to OTO-413. I am kinda interested in the latter, as I believe that my case falls in that category. Unless FX-322 does evoke synaptic regeneration as well.

That or I posted it on this thread somewhere (or a related thread).

This might help. It's not the study I referenced above but it concerns the "why" humans are different:

Human auditory nerve afferents consist of two separate systems; one is represented by the large type I cells innervating the inner hair cells and the other one by the small type II cells innervating the outer hair cells. Type I spiral ganglion neurons (SGNs) constitute 96% of the afferent nerve population and, in contrast to other mammals, their soma and pre- and post-somatic segments are unmyelinated. Type II nerve soma and fibers are unmyelinated.

From:
The pre- and post-somatic segments of the human type I spiral ganglion neurons – Structural and functional considerations related to cochlear implantation

Thank you very much @FGG.

I will need to look a little bit more thoroughly on the scientific terminology as well.
This is great insight from you as always.

I do sometimes wonder whether this gradual worsening of mine each year, especially regarding my dysacusis symptoms (if that is a valid term), might be a manifestation of this gradual cellular apoptosis process.

 

[FGG]

This is an extremely good point to mention. If there is remarkable progress in this study, then that should speak to the robustness both of the human support cells and FX-322 itself.

@FGG had also mentioned previously how the instance in which the drug may not be effective due to support cell loss when epithelial scarring is present, which should only occur after profound hearing loss with severe trauma. I'm not positive, but I don't think this would be the case if you just have accumulated hearing loss over the years, whether it be noise-induced or presbycusis.

I was told (by one researcher) that you don't start to lose support cells until after you lose both OHC and IHC and this is reflected in being in the profound range (> 90 dB). I don't think it matters how you get there (i.e. acute or chronic). There was a study on cats that showed this too.

Obviously, if you are in the profound range due to some conductive/mixed hearing loss, that probably wouldn't apply.

 

[Diesel]

This is an extremely good point to mention. If there is remarkable progress in this study, then that should speak to the robustness both of the human support cells and FX-322 itself.

@FGG had also mentioned previously how the instance in which the drug may not be effective due to support cell loss when epithelial scarring is present, which should only occur after profound hearing loss with severe trauma. I'm not positive, but I don't think this would be the case if you just have accumulated hearing loss over the years, whether it be noise-induced or presbycusis.

Yes, it is believed that areas of the cochlea with severe-profound losses may be missing the LGR5+ Support Cells, and therefore unable to regenerate fully from FX-322 activation. Fortunately, we'll also learn whether FX-322 can treat at least those with severe hearing loss in Q3.

Carl LeBel did mention, I believe on the Tinnitus Talk Podcast, that adults with severe-profound age-related hearing loss (we're talking probably people in their 90s) may also have flat epithelials in some areas of their cochlea. Which tells me that natural aging over time has the same effect as an acoustic shock.

As it relates to severe acoustic traumas, it seems as though even that is increasingly rare. In the googling I've done to fine just how much of a blast we're talking about to physically cause that type of damage, it seems to be in cases where there is direct sound pressure applied to the ear. Like a blast/explosion loud enough to rupture the eardrum and cause shockwaves into the cochlea.

I definitely think that anyone with tinnitus that is a result of acquired SNHL probably has some significant deficits somewhere in their cochlea. However, it must not be so extreme, or not require maximum regeneration, as those patients in the Phase 1/2 did see relief from one dose of FX-322. So, maybe it only takes getting back a handful of decibels, or restoring that inner hair cell to start seeing relief.

 

[Drachen]

I was told (by one researcher) that you don't start to lose support cells until after you lose both OHC and IHC and this is reflected in being in the profound range (> 90 dB). I don't think it matters how you get there (i.e. acute or chronic). There was a study on cats that showed this too.

Can you clarify what you mean by if you "lose both OHC and IHC"? Are there sets of OHC and IHC that are linked together, such as per a specific frequency? Does this mean you could have mild to moderate hearing loss but have gotten unlucky where a linked OHC and IHC were damaged or destroyed? Otherwise, if they are independent, I would assume everyone has some mixture of loss of both OHC or IHC, but when does it lead into support cells being threatened?

Sorry if this is a dumb question. I don't know much about the anatomy of the ear beyond some biology and this site.

 

[FGG]

I do sometimes wonder whether this gradual worsening of mine each year, especially regarding my dysacusis symptoms (if that is a valid term), might be a manifestation of this gradual cellular apoptosis process.

This is unrelated to this thread, but I think there is a huge inflammatory component to a lot of people's dysacusis (vs. tinnitus which is often just structural damage) of a certain type.

Also, emotional stress itself not only increases IL-1 (and therefore is directly pro-inflammatory) but it puts your neuro-transmitters in a more neuro-excitatory state (i.e. extremely anxious people might not only not improve but continue to worsen). Just in case that applies to you.

 

[FGG]

Can you clarify what you mean by if you "lose both OHC and IHC"? Are there sets of OHC and IHC that are linked together, such as per a specific frequency? Does this mean you could have mild to moderate hearing loss but have gotten unlucky where a linked OHC and IHC were damaged or destroyed? Otherwise, if they are independent, I would assume everyone has some mixture of loss of both OHC or IHC, but when does it lead into support cells being threatened?

Sorry if this is a dumb question. I don't know much about the anatomy of the ear beyond some biology and this site.

If you were "unlucky enough to lose both", it means you are in the profound range and you would definitely already know.

 

[Drachen]

In the googling I've done to fine just how much of a blast we're talking about to physically cause that type of damage, it seems to be in cases where there is direct sound pressure applied to the ear. Like a blast/explosion loud enough to rupture the eardrum and cause shockwaves into the cochlea.

I wonder if the mice subjected to the "pretty severe trauma" Carl LeBel mentioned during the Tinnitus Talk Podcast would have fit this category. If that's the case, then I imagine there must have been scarring present, unless the scarring takes time to develop. Either way, this could be a very positive sign for the ability of the drug to undo significant damage, even in humans.

I definitely think that anyone with tinnitus that is a result of acquired SNHL probably has some significant deficits somewhere in their cochlea. However, it must not be so extreme, or not require maximum regeneration, as those patients in the Phase 1/2 did see relief from one dose of FX-322. So, maybe it only takes getting back a handful of decibels, or restoring that inner hair cell to start seeing relief.

This last paragraph truly highlights a lot of the legitimate optimism for the upcoming results. So much to be learned from the results of this study, and I only hope they are positive. Beyond positive, even.

 

[vermillion]

Also, emotional stress itself not only increases IL-1 (and therefore is directly pro-inflammatory) but it puts your neuro-transmitters in a more neuro-excitatory state (i.e. extremely anxious people might not only not improve but continue to worsen). Just in case that applies to you.

I am extremely anxious. Yes. Due to worsening after worsening. Like I'm stuck in a vicious cycle. The question is how do I break that and whether this damage of psychological reasons is reversible. I really want to get better or at least not get worse anymore.

 

[FGG]

I am extremely anxious. Yes. Due to worsening after worsening. Like I'm stuck in a vicious cycle. The question is how do I break that and whether this damage of psychological reasons is reversible. I really want to get better or at least not get worse anymore.

I should add that it's possible to mitigate some of the neuroexcitability with drugs such as Ebselen (in clinical trials currently).

 

[Diesel]

That is absolutely encouraging, as it pertains to FX-322. I was mostly referring to OTO-413. I am kinda interested in the latter, as I believe that my case falls in that category. Unless FX-322 does evoke synaptic regeneration as well.

You might be in luck:

 

[Gb3]

Also, emotional stress itself not only increases IL-1 (and therefore is directly pro-inflammatory) but it puts your neuro-transmitters in a more neuro-excitatory state (i.e. extremely anxious people might not only not improve but continue to worsen). Just in case that applies to you.

What are you referring to when you say continue to worsen? Hearing loss or tinnitus?

 

[FGG]

What are you referring to when you say continue to worsen? Hearing loss or tinnitus?

Neither.

In my opinion, "Reactivity" or dysacusis, which mostly improves/resolves for people over time so it can't be structural (the way chronic tinnitus is).

Inflammation is designed to be self limiting except where there is a continued inciting cause or as a Nobel Prize for Medicine nominated doctor (Fuad Lechin--I met him many years ago and discussed his work at length with him) discovered when you have an abnormal TH-1/TH-2 balance which can come about with certain conditions. In particular, "uncoping stress" which is changes over time due to stress mixed with severe anxiety.

Also, independent of Lechin's findings, stress increases IL-1 which is an important pro inflammatory cytokine:

Interleukin-1 (IL-1): A central regulator of stress responses

 

[vermillion]

You might be in luck:

View attachment 42952

Did you make this table?

Nailed it!

 

[Jrblovsky]

Yes, it is believed that areas of the cochlea with severe-profound losses may be missing the LGR5+ Support Cells, and therefore unable to regenerate fully from FX-322 activation. Fortunately, we'll also learn whether FX-322 can treat at least those with severe hearing loss in Q3.

Carl LeBel did mention, I believe on the Tinnitus Talk Podcast, that adults with severe-profound age-related hearing loss (we're talking probably people in their 90s) may also have flat epithelials in some areas of their cochlea. Which tells me that natural aging over time has the same effect as an acoustic shock.

As it relates to severe acoustic traumas, it seems as though even that is increasingly rare. In the googling I've done to fine just how much of a blast we're talking about to physically cause that type of damage, it seems to be in cases where there is direct sound pressure applied to the ear. Like a blast/explosion loud enough to rupture the eardrum and cause shockwaves into the cochlea.

I definitely think that anyone with tinnitus that is a result of acquired SNHL probably has some significant deficits somewhere in their cochlea. However, it must not be so extreme, or not require maximum regeneration, as those patients in the Phase 1/2 did see relief from one dose of FX-322. So, maybe it only takes getting back a handful of decibels, or restoring that inner hair cell to start seeing relief.

Do they talk about cochlear dead regions? For example I cannot hear anything at any volume over 8 kHz. When this started I could hear 12 kHz and before the trauma 16 kHz. It seems that possibly the Meniere's disease is destroying my inner ear due to pressure. Not sure.

 

[Diesel]

Did you make this table?

Nailed it!

I did because the question comes up almost daily now.

 

[ThomasC]

Do they talk about cochlear dead regions? For example I cannot hear anything at any volume over 8 kHz. When this started I could hear 12 kHz and before the trauma 16 kHz. It seems that possibly the Meniere's disease is destroying my inner ear due to pressure. Not sure.

It doesn't mean you have profound hearing loss. For instance, I have moderately severe hearing loss above 8 kHz (tested multiple times) but I can't hear anything through headphones.

 

[Gb3]

Do they talk about cochlear dead regions? For example I cannot hear anything at any volume over 8 kHz. When this started I could hear 12 kHz and before the trauma 16 kHz. It seems that possibly the Meniere's disease is destroying my inner ear due to pressure. Not sure.

Usually Meniere's affect the low frequencies, I believe.

 

[FGG]

Do they talk about cochlear dead regions? For example I cannot hear anything at any volume over 8 kHz. When this started I could hear 12 kHz and before the trauma 16 kHz. It seems that possibly the Meniere's disease is destroying my inner ear due to pressure. Not sure.

Meniere's tends to affect low frequency hearing more until end stage. Since yours came after severe acoustic trauma in your case, I would still get 3rd window syndromes like perilymph fistula fully ruled out (at least get another opinion). They, like Meniere's, can also cause the dizziness you experience.

Even if it ends up being Meniere's (which is odd without discrete attacks), that could probably manage it way better than they are if you are rapidly declining.

 

[Bill Arsenault]

There isn't a fixed number of frequencies like that, though, and our perception of pitch is not linear, it's logarithmic. So the pitch difference between 1,000 Hz and 2,000 Hz is the same as the pitch difference between 4,000 Hz and 8,000 Hz. Nonetheless, a doubling of pitch is still kind of a large jump; when you play a note on a piano and then play the next higher note (including all keys, black and white), the increase in pitch is about 6%.

That's so awesome - I have always had a fascination with basic music theory.
Even though I know what your talking about - it never clicked for me until you pointed that out.
I have been a self-taught guitarist since 1981 and enjoy studying college music theory text books.

For those who do not yet have a basic understanding of Sound Frequency.
What follows is a basic example of the use of the Helmholtz frequency system -
And I guess how humans perceive pitch - but I don't want to get too crazy here.

The easiest way that I know is to use the Chromatic Musical Scale and the Grand Piano keyboard as references.
I'm going to play teacher's pet now and hopefully get a gold star.

The keyboard of the Grand Piano has 88 keys.
The notes of the keys repeat themselves every 12 keys:

A1, A#, B, C, C#, D, D#, E, F, F#, G, G#, / A2, A#, B, C, C#, etc...

Each time the set of notes (or Octave) repeat the musical tones get higher in pitch as the frequencies increase.
The first key on a Grand Piano (furthest left) produces the note "A2" (55 Hz).

1st Key / "A2" (55 Hz).
13th Key / "A3" (110 Hz).
25th Key / "A4" (220 Hz).
37th Key / "A5" (440 Hz).
49th Key / "A6" (880 Hz).
61st Key / "A7" (1600 Hz).
73rd Key / "A8" (3200 Hz).
85th Key / "A9" (6400 Hz).
88th Key / "C9" (8372 Hz).

(Beyond the Grand Piano):

"A10" (12,800 Hz).
"C10" (16,700 Hz).

So to test the human ear using every "musical note" between 55 Hz and 16,700 Hz - We would only have to suffer through 120 test tones and NOT the 16,000 I first proposed - due to logarithmic nature of the Helmholtz frequency system and the non-linear way humans perceive pitch.

To just test from 12,800 Hz to 16,700 Hz would only take the span of 4 adjacent musical notes - A10, A#10, B10, C10.

To turn a standard test into an extended test (6,400 Hz to 16,700 Hz) would only take an extra 16 test tones using this example.

 

[Jrblovsky]

Usually Meniere's affect the low frequencies, I believe.

It does. I have moderately severe hearing loss there too. The only frequency I have that is normal is 1000 Hz. It's a 20 dB loss. Every other frequency is at least a 50 dB loss now.

 

[Keith Handy]

What follows is a basic example of the use of the Helmholtz frequency system

Yep, you've got it! The only difference between music and sound-in-general being that we (at least in Western culture) divide the musical octave* up into 12 distinct subdivisions. Now, from a non-musical, sound-only perspective, 12 is a completely arbitrary number... but it at least gives us a frame of reference. 12 isn't necessarily the exact number of pitches per octave we should check, but it gives us an idea of how absurdly far apart those standard test tones are.

*Note: "octave" derives from the root word for "eight," but ignore that, because that's only relevant to non-chromatic scales that skip some of the notes... and it's wrong, even for that, because we're calling the bottom note of a scale "1" and the top note "8", which would be a difference of 7, not 8. And that's a mix of whole steps and half steps, not equal divisions, so it's all the more meaningless.

 

[Jrblovsky]

Meniere's tends to affect low frequency hearing more until end stage. Since yours came after severe acoustic trauma in your case, I would still get 3rd window syndromes like perilymph fistula fully ruled out (at least get another opinion). They, like Meniere's, can also cause the dizziness you experience.

Even if it ends up being Meniere's (which is odd without discrete attacks), that could probably manage it way better than they are if you are rapidly declining.

I've asked about this before. I've been to 5 different neurotologists who have told me that cannot be it. It doesn't make sense being not even a year ago I had extremely mild hearing loss.

 

[Danad]

More evidence linking hearing loss, brain plasticity and tinnitus:

Tinnitus-like "hallucinations" elicited by sensory deprivation in an entropy maximization recurrent neural network

 

[twa]

Really, unless the price is significantly more than a new car, I would happily take out a loan if that is what it took to really decrease my tinnitus. If it was a $200,000 drug treatment I don't know what I'd do.

It may be comparable to patient financing plastic surgeons and dentists have for elective and semi-elective procedures. Personally, I would be willing to pay out of pocket if it was an effective, safe treatment.

 

[vermillion]

More evidence linking hearing loss, brain plasticity and tinnitus:

Tinnitus-like "hallucinations" elicited by sensory deprivation in an entropy maximization recurrent neural network

View attachment 42971

Shall we guess irreversible plasticity?

Or shall we guess that this suggests, once you find the way to undo this sensory deprivation, plasticity kicks in again... The other way around. Therefore no tinnitus.

 

[serendipity1996]

Shall we guess irreversible plasticity?

Or shall we guess that this suggests, once you find the way to undo this sensory deprivation, plasticity kicks in again... The other way around. Therefore no tinnitus.

Surely even the term 'plasticity' implies that it is not an irreversible process, though?

 

[serendipity1996]

Does Will McLean no longer work at Frequency Therapeutics? He's not listed under the leadership team any longer - I thought he was one of the co-founders?

https://www.frequencytx.com/role/leadership/

 

[Diesel]

Does Will McLean no longer work at Frequency Therapeutics? He's not listed under the leadership team any longer - I thought he was one of the co-founders?

https://www.frequencytx.com/role/leadership/

He does still work there. Vice President, Biology & Regenerative Medicine, Co-Founder on the Investor Presentation. Langer also referenced some of the work he's doing there on the recent webinar. Could be that they want the leadership page to be specific executives, or he doesn't want to be in such a highly visible role.