Frequency Therapeutics — Hearing Loss Regeneration

[dan]

I used to think this as well but my view now is that these particular symptoms are down to inflammation. There's a lot of text of trigeminal nerve sensitization causing modulated tinnitus in the link below. I am a sufferer of modulated tinnitus and it always follows setbacks and is a symptom that improves again over time. For this reason I put it down to the temporary flare up of inflammation that follows a setback. Although not mentioned specifically in the paper, I also get morse code tinnitus (in my good ear) that behaves in the same way (I personally see this as just a different form of modulated tinnitus). Also hearing distortions, blown speaker effects, again for me follows the same pattern.

My baseline tinnitus is permanent but fairly manageable to be honest. After a noxacusis setback blast though it all goes to hell until it settles down again. Again, it's temporary, and I see a certain logic / pattern to it that inflammation is also temporary. It also rides the same wave as the facial pain I get and it's the trigeminal nerve that appears to be the link in all of it.

I'm becoming less and less convinced that there are 'damaged hair cells', I do think they either function or are dead.

Here's the paper regarding modulated tinnitus:

An Integrative Model Accounting for the Symptom Cluster Triggered After an Acoustic Shock

OHC damage causes bad stuff. FX-322 to fix.

 

[100Hz]

OHC damage causes bad stuff. FX-322 to fix.

Yep. If a trigeminal nerve now sensitized by an acoustic shock, plus Type II afferents now sensitized by OHC death, plus the dead OHCs themselves are presumed to be the fundamental permanent damage, primed for relapse, and if a setback is caused as a result of noise stimulating dead OHC support cells in the cochlea resulting in ATP release (resulting in the inflammation that causes all these symptoms by stimulating the sensitized trigeminal nerve), then I feel very confident about FX-322. It will in theory break the setback cycle.

Again though my only reservation is if the Type II afferents remain sensitized after FX-322 (which I presume they do), and the ATP release resulting from noise exposure is still coming from somewhere else despite the fact that the now fixed OHCs are presumably not leaking it anymore via their support cells. (In other words something that FX-322 did not / was never designed to fix). I feel that this is a less likely scenario though, based on a couple of factors.

 

[weab00]

Yep. If a trigeminal nerve now sensitized by an acoustic shock, plus Type II afferents now sensitized by OHC death, plus the dead OHCs themselves are presumed to be the fundamental permanent damage, primed for relapse, and if a setback is caused as a result of noise stimulating dead OHC support cells in the cochlea resulting in ATP release (resulting in the inflammation that causes all these symptoms by stimulating the sensitized trigeminal nerve), then I feel very confident about FX-322. It will in theory break the setback cycle.

Again though my only reservation is if the Type II afferents remain sensitized after FX-322 (which I presume they do), and the ATP release resulting from noise exposure is still coming from somewhere else despite the fact that the now fixed OHCs are presumably not leaking it anymore via their support cells. (In other words something that FX-322 did not / was never designed to fix). I feel that this is a less likely scenario though, based on a couple of factors.

So would a treatment like SPI-1005 only be superficially treating the symptom of inflammation but still leaving you prone to a setback/relapse since the underlying OHC damage remains? And what role do synapses play?

 

[100Hz]

So would a treatment like SPI-1005 only be superficially treating the symptom of inflammation but still leaving you prone to a setback/relapse since the underlying OHC damage remains? And what role do synapses play?

Yes that's what I'd like to believe could happen. SPI-1005 would be like a band-aid for emergencies when you'd been over exposed to noise, whereas FX-322 would be the actual fix.

Synapses, I'm not sure at all. It didn't jump out at me how they might fit into those models in any particular way. Personally I'm sold on the OHC death / Type II afferent sensitization research now when it comes to the cochlea part of noxacusis. I've just not seen anything, that I can remember at least, to suggest synapses have anything to do with noxacusis, (admittedly though I haven't really searched for it. It was pure speculation when I started that other thread based on the fact that I believed if OHC damage was behind noxacusis why don't so many more people get it? Therefore I believed it had to be something else. Synapses?). I'd be interested to see how noxacusis sufferers extended audiograms compare in the ultra high frequencies.

Just a pure wild guess but could synapses maybe have more to do with tinnitus? (The permanent, stable, fixed type of tinnitus assuming no inflammation, which then gets modulated by noxacusis / any other type of inflammation?) Pure speculation though.

EDIT - I don't know the answer to this, might even be a stupid question, but would disconnected synapses show up as hearing loss on a audiogram the same way that hair cell damage does? If so, you wouldn't be able to differentiate between the 2 pathology would you?

 

[Lucifer]

Me personally I think if we fix the issues in the ear such as OHCs, IHCs and synapses then this should get rid of both hyperacusis and tinnitus. I don't think these issues are due to inflammation.

 

[100Hz]

Me personally I think if we fix the issues in the ear such as OHCs, IHCs and synapses then this should get rid of both hyperacusis and tinnitus. I don't think these issues are due to inflammation.

I agree with you that actual hair cell death and synaptopthy are not due to inflammation but blunt force noise trauma, but I do think that the further stimulation by noise to the resulting damaged areas (OHC support cells in particular, not sure about synapses), causes the ATP release that lead to setbacks and inflammation, that in turn causes the symptoms of noxacusis and certain tinnitus symptoms.

I agree with you though that if that underlying damage gets fixed it stands a good chance of fixing noxacusis and tinnitus.

 

[tommyd87]

I used to think this as well but my view now is that these particular symptoms are down to inflammation. There's a lot of text of trigeminal nerve sensitization causing modulated tinnitus in the link below. I am a sufferer of modulated tinnitus and it always follows setbacks and is a symptom that improves again over time. For this reason I put it down to the temporary flare up of inflammation that follows a setback. Although not mentioned specifically in the paper, I also get morse code tinnitus (in my good ear) that behaves in the same way (I personally see this as just a different form of modulated tinnitus). Also hearing distortions, blown speaker effects, again for me follows the same pattern.

My baseline tinnitus is permanent but fairly manageable to be honest. After a noxacusis setback blast though it all goes to hell until it settles down again. Again, it's temporary, and I see a certain logic / pattern to it that inflammation is also temporary. It also rides the same wave as the facial pain I get and it's the trigeminal nerve that appears to be the link in all of it.

I'm becoming less and less convinced that there are 'damaged hair cells', I do think they either function or are dead.

Here's the paper regarding modulated tinnitus:

An Integrative Model Accounting for the Symptom Cluster Triggered After an Acoustic Shock

I think that there is definitely a role played by inflammation in all this rubbish. I think you are right with your theory that the symptoms vary depending on when you get increased inflammation.

Me personally I think if we fix the issues in the ear such as OHCs, IHCs and synapses then this should get rid of both hyperacusis and tinnitus. I don't think these issues are due to inflammation.

My ears might be inflamed. While I think that you are accurate for the most part, I still think that there is some negative issues caused by inflammation. I personally would be treating inflammation in order to stabilise stuff prior to having hearing regeneration treatments. It's precautionary and a good thing to do, just like you do when you injure and inflame any other body part. I think that the inflammation medicine is fairly low risk also and as a result it will be a case of no harm done if taken.

So would a treatment like SPI-1005 only be superficially treating the symptom of inflammation but still leaving you prone to a setback/relapse since the underlying OHC damage remains? And what role do synapses play?

I think that the treatment of inflammation is inevitably going to mitigate and also reduce tinnitus, though I think that the theory you put forward about it only being a temporary measure is correct. Clearly if the ears act like any other area of the body when they are inflamed such as the calf then we know that if you only treat the inflammation, it will only provide temporary relief and some benefit in dealing with the situation. It won't simply deal with the actual issue with the calf which might be a strained muscle or whatever which will continue to be strained until it is treated.

Same goes for the ears where treating their inflamed nature will stabilise them and also again likely reduce things like hyperacusis, however there is the likelihood that the symptoms will persist until the underlying cause(s) like busted synapses are treated.

 

[sssing]

So would a treatment like SPI-1005 only be superficially treating the symptom of inflammation but still leaving you prone to a setback/relapse since the underlying OHC damage remains? And what role do synapses play?

Yes that's what I'd like to believe could happen. SPI-1005 would be like a band-aid for emergencies when you'd been over exposed to noise, whereas FX-322 would be the actual fix.

Synapses, I'm not sure at all. It didn't jump out at me how they might fit into those models in any particular way. Personally I'm sold on the OHC death / Type II afferent sensitization research now when it comes to the cochlea part of noxacusis. I've just not seen anything, that I can remember at least, to suggest synapses have anything to do with noxacusis, (admittedly though I haven't really searched for it. It was pure speculation when I started that other thread based on the fact that I believed if OHC damage was behind noxacusis why don't so many more people get it? Therefore I believed it had to be something else. Synapses?). I'd be interested to see how noxacusis sufferers extended audiograms compare in the ultra high frequencies.

Just a pure wild guess but could synapses maybe have more to do with tinnitus? (The permanent, stable, fixed type of tinnitus assuming no inflammation, which then gets modulated by noxacusis / any other type of inflammation?) Pure speculation though.

EDIT - I don't know the answer to this, might even be a stupid question, but would disconnected synapses show up as hearing loss on a audiogram the same way that hair cell damage does? If so, you wouldn't be able to differentiate between the 2 pathology would you?

There's a recent trial done by Fan Gang Zeng. Upon sending electrical stimulation to the cochlea in order to excite or activate those broken synapses, it stopped or reduced the tinnitus for half of the patients, though the tinnitus came back again. Disconnected synapses may not show up on audiograms so that's why the term 'hidden hearing loss'. Hearing is imperfect but the audiograms are normal.

 

[weab00]

I personally would be treating inflammation in order to stabilise stuff prior to having hearing regeneration treatments. It's precautionary and a good thing to do, just like you do when you injure and inflame any other body part. I think that the inflammation medicine is fairly low risk also and as a result it will be a case of no harm done if taken.

Why would taking an anti-inflammatory drug before getting regenerative treatments be helpful? And wouldn't your cochlea be reinflamed by the time FX-322 came out?

While I agree it probably wouldn't do any physical harm, it might hurt my bank account if it isn't absolutely necessary.

 

[FGG]

There's a recent trial done by Fan Gang Zeng. Upon sending electrical stimulation to the cochlea in order to excite or activate those broken synapses, it stopped or reduced the tinnitus for half of the patients, though the tinnitus came back again. Disconnected synapses may not show up on audiograms so that's why the term 'hidden hearing loss'. Hearing is imperfect but the audiograms are normal.

This may just be a phrasing thing but wouldn't he be just stimulating the SGN directly with this, similar to how a cochlear implant works not "exciting the broken synapses" (how do you excite something that isn't there?).

 

[100Hz]

There's a recent trial done by Fan Gang Zeng. Upon sending electrical stimulation to the cochlea in order to excite or activate those broken synapses, it stopped or reduced the tinnitus for half of the patients, though the tinnitus came back again. Disconnected synapses may not show up on audiograms so that's why the term 'hidden hearing loss'. Hearing is imperfect but the audiograms are normal.

@sssing Thanks you jogged my memory with hidden hearing loss, I knew there was something about synapses.

I can't help thinking about this now but I've got to ask, if say you had dead hair cells with no synapse damage at 4 kHz, and then you also had total synapse disconnection with no hair cell damage at 8 kHz, how might this look on an audiogram? Because I'm imagining a dip at 4 kHz and 8 kHz. I'm only guessing here but if you had only a percentage of synapse disconnection I can see how that might not show up on an audiogram and also might explain hidden hearing loss because you would still be getting something through the remaining synapses? In the case of total synapse disconnection I'm finding it hard to see how you could hear at that frequency even though the hair cell is still OK? Sorry for going off topic, just interesting, I haven't thought or read much about synapses to date.

 

[FGG]

@sssing Thanks you jogged my memory with hidden hearing loss, I knew there was something about synapses.

I can't help thinking about this now but I've got to ask, if say you had dead hair cells with no synapse damage at 4 kHz, and then you also had total synapse disconnection with no hair cell damage at 8 kHz, how might this look on an audiogram? Because I'm imagining a dip at 4 kHz and 8 kHz. I'm only guessing here but if you had only a percentage of synapse disconnection I can see how that might not show up on an audiogram and also might explain hidden hearing loss because you would still be getting something through the remaining synapses? In the case of total synapse disconnection I'm finding it hard to see how you could hear at that frequency even though the hair cell is still OK? Sorry for going off topic, just interesting, I haven't thought or read much about synapses to date.

The synapses in "synaptopathy" are between IHCs and the SGNs. Audiograms mostly measure OHC loss.

 

[Diesel]

The synapses in "synaptopathy" are between IHCs and the SGNs. Audiograms mostly measure OHC loss.

So, if we've come to understand that FX-322 may help with tinnitus due to regrowing IHC and OHC; if we see that tinnitus improves with a synaptopathy drug like OTO-413/PIPE-505, would that imply that IHC damage may be a more likely cause for tinnitus?

 

[Bartoli]

I personally would be treating inflammation in order to stabilise stuff prior to having hearing regeneration treatments. It's precautionary and a good thing to do, just like you do when you injure and inflame any other body part. I think that the inflammation medicine is fairly low risk also and as a result it will be a case of no harm done if taken.

I think you would know if there's inflammation happening when Prednisone would affect your current tinnitus. I agree it would be just a temporary fix for the reasons you mentioned.

 

[Paulmanlike]

There's a recent trial done by Fan Gang Zeng. Upon sending electrical stimulation to the cochlea in order to excite or activate those broken synapses, it stopped or reduced the tinnitus for half of the patients, though the tinnitus came back again. Disconnected synapses may not show up on audiograms so that's why the term 'hidden hearing loss'. Hearing is imperfect but the audiograms are normal.

I thought Fan Gang Zeng was the genius behind CRISPR - Broad Institute?

 

[tommyd87]

This may just be a phrasing thing but wouldn't he be just stimulating the SGN directly with this, similar to how a cochlear implant works not "exciting the broken synapses" (how do you excite something that isn't there?).

This sounds like when an electrician uses their tool to stimulate an electrical connection to check whether it is working or not. It makes the thing work effectively while it gets the stimulation but it doesn't fix the underlying problem that tends to be the reason why the thing isn't working correctly to begin with. Thus while the researcher might show that this is a cause of tinnitus and that fixing this then eliminates tinnitus, it doesn't fix the underlying issue. It is therefore not going to be effective in the long term then either.

I also think that the probable reason that this only worked for a portion of those involved was for the exact same reason you mentioned above, not being able to excite synapses if they are not there. Therefore I would not actually see this as being a plausible treatment option but rather it does give insight into what needs to get done to deal with the underlying issues appropriately.

 

[FGG]

So, if we've come to understand that FX-322 may help with tinnitus due to regrowing IHC and OHC; if we see that tinnitus improves with a synaptopathy drug like OTO-413/PIPE-505, would that imply that IHC damage may be a more likely cause for tinnitus?

There isn't a single cause of tinnitus. Anything that interferes with sound transmission can cause it. That's why hydrops can do it without any IHC, OHC or synapse damage.

So in some people, it might be synapse, in others hair cell etc.

In others, it's outside the cochlea (e.g., middle ear disease), TM rupture etc.

 

[FGG]

I think you would know if there's inflammation happening when Prednisone would affect your current tinnitus. I agree it would be just a temporary fix for the reasons you mentioned.

Prednisone and all steroids have a *highly* variable intracochlear penetrance. So much so that Otonomy has a phase 3 drug that is just Dexamethasone in a penetrative gel which would be completely unnecessarily if steroids were easy to get in the cochlea.

 

[tommyd87]

I think you would know if there's inflammation happening when Prednisone would affect your current tinnitus. I agree it would be just a temporary fix for the reasons you mentioned.

Isn't there information now suggesting that Prednisone is not appropriate for inflammation in all areas of the body though? This is why I thought that there is now a shift to looking at other stuff to deal with inflammation.

 

[100Hz]

The synapses in "synaptopathy" are between IHCs and the SGNs. Audiograms mostly measure OHC loss.

Thanks, knowing that I would now be really interested in seeing firstly how noxacusis sufferer ultra high frequency audiograms compare among themselves, and then how those results compare against the ultra high frequency audiograms of tinnitus (without noxacusis) sufferers.

If ultra high frequency OHC death is a prime factor in noxacusis you could imagine the results showing a substantial ultra high frequency hearing loss for noxacusis sufferers, but if IHC synaptopathy could possibly be a prime factor in tinnitus then the results for purely tinnitus sufferers may indicate little or no ultra high frequency hearing loss.

 

[Diesel]

There isn't a single cause of tinnitus. Anything that interferes with sound transmission can cause it. That's why hydrops can do it without any IHC, OHC or synapse damage.

So in some people, it might be synapse, in others hair cell etc.

In others, it's outside the cochlea (e.g., middle ear disease), TM rupture etc.

I should have clarified; tinnitus as a symptom of NIHL/SNHL.

 

[FGG]

I should have clarified; tinnitus as a symptom of NIHL/SNHL.

What I mean is, I don't believe it's synapse or hair cell as the universal cause of SNHL. It depends on what is damaged in the individual.

I think in some people it's hair cell and in others it's synapse. I don't think that loss needs to be universally in one structure.

In my mind it's sort of like ocular Horner's syndrome where a lesion any where on this pathway to interrupt the nerve fibers can give you the symptoms:

The analogy isn't perfect because the eye is receiving the input in this case (where the brain is in the case of tinnitus so it's almost the reverse, but hopefully the analogy makes sense).

It seems if it didn't work this way, it wouldn't make sense for there to be so many extra cochlear causes as well as the SNHL intra cochlear causes.

 

[tommyd87]

What I mean is, I don't believe it's synapse or hair cell as the universal cause of SNHL. It depends on what is damaged in the individual.

I think in some people it's hair cell and in others it's synapse. I don't think that loss needs to be universally in one structure.

In my mind it's sort of like ocular Horner's syndrome where a lesion any where on this pathway to interrupt the nerve fibers can give you the symptoms:

View attachment 41148

The analogy isn't perfect because the eye is receiving the input in this case (where the brain is in the case of tinnitus so it's almost the reverse, but hopefully the analogy makes sense).

It seems if it didn't work this way, it wouldn't make sense for there to be so many extra cochlear causes as well as the SNHL intra cochlear causes.

Would this theory be why you think that some people will potentially need to trial treat and/or use treatments for both hair cells and for synapses because there is no guarantee that one will work over another?

 

[FGG]

Would this theory be why you think that some people will potentially need to trial treat and/or use treatments for both hair cells and for synapses because there is no guarantee that one will work over another?

That's what I believe and also why both Hough Ear Institute and Frequency Therapeutics have noticed anecdotal improvements in some patients' tinnitus despite addressing different structures.

I also think this is why it's better that Frequency Therapeutics is using tinnitus as an experimental outcome and not a primarily outcome because I personally worry that if you have someone with more bothersome synaptopathy relayed tinnitus in part of their cochlea, for instance, then their TFI might not change much with hair cell regrowth even if their hearing does while others might get a more life changing result.

It bothers me that none of these studies tone match tinnitus frequencies to better assess this but I guess if it were a primary measure maybe they might.

 

[tommyd87]

Speculation is fine when its grounded in evidence and educated guesses. The pessimistic speculation based on nothing is not good. Especially when there is a lot of solid reasons to be optimistic! There are numerous drugs that tackle hearing loss and/or tinnitus in trials now. Far enough in trials that 2023 might see the first of these miracle drugs hit the market. Possibly even sooner if Sound Pharmaceuticals' drug is shown to help with coronavirus. This has never been the case, there is suddenly a tidal wave of medicine where up until recently there was not even a ripple.

In the end, the complicated neural network that makes up hearing is rooted in hair cells and synapses. 2 things which companies have shown they can repair with little to no side effects, using relatively simple, straightforward science.

Repairing synapses and hair cells should greatly improve a LOT of the issues people have. I understand it sucks to be caged in life because the issues are too debilitating but I think looking at all the legitimate science, backed by BIG money is plenty of reason to be optimistic. Optimism that will help everyone through the next few years.

Just think how we will feel when Frequency Therapeutics' phase 2 trial results are released and it shows that FX-322 fixed hearing and helped tinnitus? Even though it will still be over a year before the drug is available, that news would give people so much real, tangible hope. More than anything else has ever offered.

I truly believe that science has finally figured out how to fix something that has eluded medicine for all time. It's easy to be pessimistic when up until a couple years ago, the thought of recovering hearing was all theoretical.

I bet that if the internet was around prior to LASIK, people would have been saying "yeah right, they take a laser to you eye and suddenly you don't need glasses?! Not likely...".

There is no logical reason to be pessimistic in my opinion. It's fair to feel crappy right now, for those that have more than an irritating sizzle everyday can be another battle, it can be exhausting. But being pessimistic for the near future is both not good for your mental health, nor is it grounded in any evidence. The evidence is screaming that we should be getting our ducks in a row so that in a couple years so when the medicine comes out, everyone can get an injection or a pill.

I just wish we could have gotten the phase 2 results on time. We'd have the good news by now.

That's what I believe and also why both Hough Ear Institute and Frequency Therapeutics have noticed anecdotal improvements in some patients' tinnitus despite addressing different structures.

I also think this is why it's better that Frequency Therapeutics is using tinnitus as an experimental outcome and not a primarily outcome because I personally worry that if you have someone with more bothersome synaptopathy relayed tinnitus in part of their cochlea, for instance, then their TFI might not change much with hair cell regrowth even if their hearing does while others might get a more life changing result.

It bothers me that none of these studies tone match tinnitus frequencies to better assess this but I guess if it were a primary measure maybe they might.

Another relevant factor to consider why Frequency Therapeutics are not doing specific stuff relating to tinnitus is that they have seemed to be reasonably objective in all they have done and tinnitus tends to be a fairly subjective issue.

 

[serendipity1996]

Today my faith in humanity was restored by an NHS audiologist lol. I was very pleasantly surprised that he took my symptoms seriously and guess what? - he actually keeps up to date with the research. I went in with low expectations so when he started talking about cochlea nociceptors in pain hyperacusis I was bowled over - cochlear synaptopathy, acoustic shock and hidden hearing loss all got mentioned too - he told me has has 'a huge amount of respect' for Charles Liberman! I wasn't pressured into a hearing test or anything and we had a very civilised chat for a good half-hour.

He even asked me to send him details on Paul Fuchs' research.

It went so well this literally sounds like I'm trolling haha. Didn't get on to discussing FX-322 or anything but this somewhat restored my faith in ENTs/audiologists.

 

[sssing]

This may just be a phrasing thing but wouldn't he be just stimulating the SGN directly with this, similar to how a cochlear implant works not "exciting the broken synapses" (how do you excite something that isn't there?).

Maybe you're right, I could have misread the principle and it works like a cochlear implant. But it was promising because it preserved hearing and was minimally invasive.

 

[sssing]

I thought Fan Gang Zeng was the genius behind CRISPR - Broad Institute?

He's from UCI. Not the same person I think.

 

[weab00]

Today my faith in humanity was restored by an NHS audiologist lol. I was very pleasantly surprised that he took my symptoms seriously and guess what? - he actually keeps up to date with the research. I went in with low expectations so when he started talking about cochlea nociceptors in pain hyperacusis I was bowled over - cochlear synaptopathy, acoustic shock and hidden hearing loss all got mentioned too - he told me has has 'a huge amount of respect' for Charles Liberman! I wasn't pressured into a hearing test or anything and we had a very civilised chat for a good half-hour.

He even asked me to send him details on Paul Fuchs' research.

It went so well this literally sounds like I'm trolling haha. Didn't get on to discussing FX-322 or anything but this somewhat restored my faith in ENTs/audiologists.

Pretty much the opposite experience of mine.

 

[tommyd87]

Today my faith in humanity was restored by an NHS audiologist lol. I was very pleasantly surprised that he took my symptoms seriously and guess what? - he actually keeps up to date with the research. I went in with low expectations so when he started talking about cochlea nociceptors in pain hyperacusis I was bowled over - cochlear synaptopathy, acoustic shock and hidden hearing loss all got mentioned too - he told me has has 'a huge amount of respect' for Charles Liberman! I wasn't pressured into a hearing test or anything and we had a very civilised chat for a good half-hour.

He even asked me to send him details on Paul Fuchs' research.

It went so well this literally sounds like I'm trolling haha. Didn't get on to discussing FX-322 or anything but this somewhat restored my faith in ENTs/audiologists.

The good ones are absolutely focused on keeping up with the research and as a result will want the best outcomes for their patients. These are the ones I hope thrive.

Pretty much the opposite experience of mine.

I know that there were a few optometrists who were dismissive of LASIK in much the same way.