Frequency Therapeutics — Hearing Loss Regeneration

Blown away that you just take contact with these people. So incredibly awesome.
Haha thanks, it's really not hard. Anyone on here could do the same I'm sure. The only silver lining to all of my terrible hearing problems is that it made me ngaf about contacting researchers. Before I would be petrified and now I'm just like "hey so I have this question."
 
A couple questions: are these results discussed in the link new information? Is it from the current phase 2 clinical trial or from the previously completed phase 1?
 
A couple questions: are these results discussed in the link new information? Is it from the current phase 2 clinical trial or from the previously completed phase 1?
Everything discussed was from phase 1 but a few more details emerged, especially in the Q and A.
 
Hi and welcome!

Hearing damage scenarios:

Hearing loss can happen at different points in the auditory system. It is likely that damage happens on several layers. It is however known that synapses are more fragile than hair cells.

You can have damaged stereocilia on the hair cells and perhaps you can also have dysfunctional hair cells that are still present. Lastly, you can simply have dead hair cells that are entirely removed from the epithelium after some time.

You have multiple synapse ribbons per hair cell. It is possible to have a functional hair cell with only one synapse ribbon instead of three for example (not sure about the maximum per hair cell).

It's also possible that the nerve endings to the hair cells are retracted, but I'm not sure if the hair cells remain alive when that happens.

It is obviously also possible that something is wrong upstream in the brainstem or beyond that, but my knowledge is limited in that regard.

Maybe someone can complement on all the possible scenarios.

How to test your hearing to have an idea what is damaged:

Hair cell functionality is tested with a pure tone audiometry, and it's obviously best to have an extended audiogram. It's a very basic test and my main problem with it is that they only test intervals instead of all frequencies. You could have gaps between the intervals and the test would not reveal that at all (even if they say it's not necessary I'm still in doubt).

To my knowledge, and this is common in my country, you can test hair cells also by doing a DPOAE test, which is objective and not subjective as is the case with an audiogram. Both tests should give you a rough idea to what extent you have hair cell damage. I believe the DPOAE test is more solid than an audiogram, but my research shows it is perhaps only for outer hair cells. This point is not entirely clear to me. My audiologist did not mention anything about that, but Wikipedia refers to OHCs and not IHCs as well.

To test if you may have cochlear synaptopathy, you should do a word recognition test, as well as a word in noise test. This is also a subjective test, but it gives you a rough idea if you have synapse degradation. The reasoning behind it, is that you need to have multiple synapses working per hair cell (at a certain frequency) to have a higher (better or more clear) understanding of what is being said. This is something that an audiogram will never be able to tell.

I do not know to what extent you can detect nerve damage or partial neuropathy. Perhaps you can test this to a certain degree with a FMRI done by a neurotologist. I have not done so.

I believe there is something called an Auditory Brain Response (ABR) test which could tell you if you have an issue in your brainstem. I did not take this test as I believe they briefly blast your ears with high volume sound. No thanks.

The more tests you do, the better you will know what type of damage you may have and what solution may work the best in the future to restore your hearing.

Again, it's logical to assume you have various levels of damage.

Lastly, these are all hearing regeneration solutions we are talking about and it remains a hypothesis if this will actually alleviate the tinnitus or not. We hope so, but until we get there, we don't really know for sure. At least that's my opinion. Most people seem to think it will help to reduce tinnitus.

If anyone wants to elaborate on that, please do.
Many thanks for your reply. Did you get this out of some book or what? I'm amazed at how research has come forward and how I have been left behind. I knew about the inner and outer hair cells since the 1990's. But synaptopathy? Above my head. I ain't no rocket surgeon.

But to my point. In appreciation of your kind information let me tell you how I handle "the night".

The coping mechanism that I kind of developed or stumbled onto is a follows: From way back in my teens I learned the yoga techniques of concentrating on your breath. Also concentrating on your heart beat and finally your pulse.

Years later when I got my tinnitus I had a try at Autogenic training -- it's a kind of "fast yoga" if I could borrow a term from the fast-food industry. This takes daily practice for about a two or three months until you get it to be part of your nature.

Now here is the thing: I found that in the early morning, when I would awake and my tinnitus would be most intrusive I somehow was subconsciously using the pulse on the left side of my face... i.e. my left cheek to drown out the sound of my tinnitus and could get back to my forty-winks. I think the success of this might have had something to do with the pillow I had then.

And here the story gets semi tragic. The pillow I was using -- I believe it had your regular polyester filling-- but somehow much harder than the regular polyester. I think it had a cotton cover to it, but that might have been polyester too. Well long story short, it served the purpose very well in somehow amplifying or echoing the sound of my pulse. And then someone nicked it. :( You don't know what you've got till it's gone.

I have another pillow now after trying many of them. It's OK but not as good as the original -- or maybe it's that my tinnitus has got much louder and more intrusive with the passing years.
These days I get about four hours sleep and then, waking in the early morning I try to use mindfulness/autogenic training to home in on my pulse just like I explained. It's hard work -- but often it works and I manage to get for more sleep. I also use a sound machine. and finally if I don't get back to sleep the radio with a timer helps too.

Maybe I have got this entry in the wrong section, it's more about coping than research, but if you can regain the night and get a good sleep, it helps divert from your tinnitus during the day.
Easier said than done I know.
 
Flopped over permanently means they can't vibrate anymore and hence no longer transduce a signal? I'm not sure. I think they still vibrate and transduce, but not a signal as expected. I Suspect there are some variations here and I'm wondering if flopped over or entangled stereocilia do actually still emit a faulty signal and are therefore technically not considered eligible for replacement. So they would remain in place and transduce a non perfect signal.
It is a weird gray area. The only reason I don't think this is the case is that the sterocilia need to be up right to sway left and right. It's the swaying motion that generates the signal, so I can't imagine when they are flopped or deformed that they are able to sway at all.

And at the end of the day any damage to the stereocilia will send out chemical signals showing that they are in no longer functioning properly - which is I think the key here. Remember that they are flopped because the cell body is damaged enough to not keep them upright, and that damaged cell body will eventually undergo apoptosis and take the sterocilia along with it.
 
I remember @FGG saying that it might not even need to be testing as a medical device because polymers are already an approved method. Hey FGG, did I misinterpret this? I hope not :(
It shouldn't need a full trial, no. I suspect it will go through a 505 (b) (2) NDA instead which is much shorter. It seems like they are hiring for the pre-clinical work on that now. I read the median time for those is 13 months.
 
Slide 31 is basically saying only 10 dB improvement at 8000 Hz on 27% of patients?

Isn't it very bad news?

If I read the slide correctly then our last hope is that a higher dose has a better effect...
Please watch their JP Morgan presentation. Doubling word scores does not ever happen with placebo. They discuss the ultra high frequencies in that presentation too and suggest they are seeing evidence great improvements there from their small safety dose. The issue is not that it doesn't work. The issue they used a tiny dose and it didn't "reach" far enough.
 
So at this point we still don't know if the cure we're looking for is the one healing the inner ear, the nerve or the brain.

The bet in this thread is that healing the inner ear with FX-322 will imply a healing of all the rest while reactivating the nerve and brain controls.

It is still a bet, isn't it?
 
Please watch their JP Morgan presentation. Doubling word scores does not ever happen with placebo. They discuss the ultra high frequencies in that presentation too and suggest they are seeing evidence great improvements there from their small safety dose. The issue is not that it doesn't work. The issue they used a tiny dose and it didn't "reach" far enough.
Alright, I'm keeping hope then :)
 
Wow. Such a positive, constructive vibe around here at the moment. Thanks guys.
Agree. Speaking for myself, I feel this is largely due to the recent absence of one key source of negative vibes and, at times, personal insults towards forum members speaking up against the opinion of that source of negative vibes. My $0.02.
By the way, I'm still not sure what they mean when they say that 4 out of 6 had 'statistically significant' improvements and 2 didn't. Statistical significance is applied to a group, not individuals in that group. That's the way I always understood it.
I had the same concern, too, initially. I interpret that statement like that those 6 individuals were measured, say, 10 times each (or any other sufficiently large number of times), like once per week over 10 weeks, yielding 60 measurements / samples which you can then subject to dependable significance analysis. Six measurement points alone would not suffice for any kind of significance statement, I am sure.

If those four out of six only claimed / pretended improvements to speech understanding, any such illusion would be hard to maintain upon repeated tests of the same individuals.
 
Please watch their JP Morgan presentation. Doubling word scores does not ever happen with placebo. They discuss the ultra high frequencies in that presentation too and suggest they are seeing evidence great improvements there from their small safety dose. The issue is not that it doesn't work. The issue they used a tiny dose and it didn't "reach" far enough.
Would the improved word scores be because of repair of synaptopathy or hearing gains above 8 kHz? The latter doesn't seem very plausible I guess?
 
Would the improved word scores be because of repair of synaptopathy or hearing gains above 8 kHz? The latter doesn't seem very plausible I guess?
I think it's the latter. Look at slide 18 of their JP Morgan Presentation. AND one other possibility with it and that is that it may be regenerating inner hair cells at lower frequencies than outer hair cells because it may need less drug to do so.

They have said that they are not a synaptopathy drug independent from the new synapse that forms with the new hair cell.
 
Many thanks for your reply. Did you get this out of some book or what? I'm amazed at how research has come forward and how I have been left behind. I knew about the inner and outer hair cells since the 1990's. But synaptopathy? Above my head. I ain't no rocket surgeon.

But to my point. In appreciation of your kind information let me tell you how I handle "the night".

The coping mechanism that I kind of developed or stumbled onto is a follows: From way back in my teens I learned the yoga techniques of concentrating on your breath. Also concentrating on your heart beat and finally your pulse.

Years later when I got my tinnitus I had a try at Autogenic training -- it's a kind of "fast yoga" if I could borrow a term from the fast-food industry. This takes daily practice for about a two or three months until you get it to be part of your nature.
No, just a quick top of mind summary, which is obviously not complete. There is a lot more to it. My condition is life-changing and I'm simply very interested in understanding what is happening in my ears and brain to cause this condition which honestly broke my soul.

I'm digging deep to understand to the best of my abilities what is potentially wrong and correlate that knowledge with our current research and actual development in terms of hearing regeneration and neurology. I'm trying to see to what extent I have a shot at getting better.

We all try to cope differently, but my coping mechanism almost instantly turned into learning about tinnitus and seeing actual progress towards a real treatment. There's a lot happening at the moment to keep me engaged into the subject.

Wish you all the best.
 
It is a weird gray area. The only reason I don't think this is the case is that the sterocilia need to be up right to sway left and right. It's the swaying motion that generates the signal, so I can't imagine when they are flopped or deformed that they are able to sway at all.

And at the end of the day any damage to the stereocilia will send out chemical signals showing that they are in no longer functioning properly - which is I think the key here. Remember that they are flopped because the cell body is damaged enough to not keep them upright, and that damaged cell body will eventually undergo apoptosis and take the sterocilia along with it.
I suspect they will still move. Physics. They won't sway perfectly anymore, but sound waves will still affect them. When I look at electron microscopy images I cannot imagine that these messed up stereocilia are no longer susceptible to sound waves.

So you suspect that the hair cell must be damaged if the stereocilia are messed up (no longer standing upright, nicely aligned) and that apoptosis should happen. Don't know if that's the case. Wouldn't dissected cochleas show that the stereocilia of the remaining hair cells look fine for the most part? I'm under the impression this is not the case, but I could be wrong.

Will be interesting to see what the experts you contacted will say on the subject.
 
It shouldn't need a full trial, no. I suspect it will go through a 505 (b) (2) NDA instead which is much shorter. It seems like they are hiring for the pre-clinical work on that now. I read the median time for those is 13 months.
It would still have to
a) undergo some safety testing
b) be evaluated clinically how well it works

Right?

I can imagine though that it would undergo much shorter trials.
 
I suspect they will still move. Physics. They won't sway perfectly anymore, but sound waves will still affect them. When I look at electron microscopy images I cannot imagine that these messed up stereocilia are no longer susceptible to sound waves.

So you suspect that the hair cell must be damaged if the stereocilia are messed up (no longer standing upright, nicely aligned) and that apoptosis should happen. Don't know if that's the case. Wouldn't dissected cochleas show that the stereocilia of the remaining hair cells look fine for the most part? I'm under the impression this is not the case, but I could be wrong.

Will be interesting to see what the experts you contacted will say on the subject.
I know this wasn't directed at me but how would you have this kind of damage with zero damage to the attachment of the stereocilia to the cell body?

Also, if it's flopped over but still "functional" then a loud enough sound should restore the input and reduce the tinnitus and that doesn't seem to happen. I think this kind of damage results in a non functional hair cell where damage has also occurred at the attachment site.
 
Please watch their JP Morgan presentation. Doubling word scores does not ever happen with placebo. They discuss the ultra high frequencies in that presentation too and suggest they are seeing evidence great improvements there from their small safety dose. The issue is not that it doesn't work. The issue they used a tiny dose and it didn't "reach" far enough.
Doubling their word scores would have to mean there is improvement in the ultra high frequencies, right? UHF provides clarity of understanding, as they explain in the presentation.

The problem is just that they didn't do extended audiograms and therefore they can't objectify improvements on the standard audiogram other than at 8kHz, which is most likely caused due to the delivery challenge as they explained.

The second trial will hopefully confirm threshold shifts in the extended audiogram from 3.5kHz all the way up to 16kHz. Then we will know if they're sitting on gold.
 
So you suspect that the hair cell must be damaged if the stereocilia are messed up (no longer standing upright, nicely aligned) and that apoptosis should happen. Don't know if that's the case. Wouldn't dissected cochleas show that the stereocilia of the remaining hair cells look fine for the most part? I'm under the impression this is not the case, but I could be wrong.
So I'm looking into the morphology of sterocilia and what is integral to the transmit process are the tip links that touch each other when they bend. A flopped over stereocilia would not be able to touch these top links to each other, so I don't think a signal is being generated either way. Some papers even refer to the tip link as the "gating spring" for vibration.

Edit: I think this paper (https://new.hindawi.com/journals/np/2018/3170801/) explains it really well. Basically any sort of noise exposure will damage stereocilia structure which will in turn cause a cascade of chemical reactions from within the cell body leading eventually to apoptosis. Feel free to tell me if you're reading it a different way.
 
I know this wasn't directed at me but how would you have this kind of damage with zero damage to the attachment of the stereocilia to the cell body?

Also, if it's flopped over but still "functional" then a loud enough sound should restore the input and reduce the tinnitus and that doesn't seem to happen. I think this kind of damage results in a non functional hair cell where damage has also occurred at the attachment site.
If there is a general scientific consensus that messy stereocilia mean that the hair cell is damaged and that apoptosis will follow, then we're good I guess, but at the moment I certainly lack the knowledge.
 
If there is a general scientific consensus that messy stereocilia mean that the hair cell is damaged and that apoptosis will follow, then we're good I guess, but at the moment I certainly lack the knowledge.
I just personally can't understand how it would be possible for a hair to be flopped over without damage to its site of attachment at the cell body.
 
So I'm looking into the morphology of sterocilia and what is integral to the transmit process are the tip links that touch each other when they bend. A flopped over stereocilia would not be able to touch these top links to each other, so I don't think a signal is being generated either way. Some papers even refer to the tip link as the "gating spring" for vibration.

Edit: I think this paper (https://new.hindawi.com/journals/np/2018/3170801/) explains it really well. Basically any sort of noise exposure will damage stereocilia structure which will in turn cause a cascade of chemical reactions from within the cell body leading eventually to apoptosis. Feel free to tell me if you're reading it a different way.
Need some time to study it and understand it better.

Thanks a lot for your input.
 
Doubling their word scores would have to mean there is improvement in the ultra high frequencies, right? UHF provides clarity of understanding, as they explain in the presentation.
I find this strange. There have been enough scientific studies that researched the frequency distribution of speech and there's very little information over 8kHz. Even over 4kHz. What does clarity mean exactly? In this context it's a vague term... Of course, the word scores don't lie. But what's causing it? It'll be really interesting once they know for sure...
 

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