Frequency Therapeutics — Hearing Loss Regeneration

[Lucifer]

@mrbrightside614

Since Frequency Therapeutics has received fast track status from the FDA, if they finish Phase 2a and it is successful, can they request "Breakthrough Therapy" status?

What does "Breakthrough Therapy" status actually mean"? Is there a chance they could release FX-322 into the market after Phase 2a?

 

[Joly]

You are talking about support cells, the auditory nerve and other things that can be killed by ototoxic drugs.

Can damage to the auditory nerve and support cells cause tinnitus?

For the hair cells and the synapses, there will be treatments but what about for the others? At that time, if you are affected by the auditory nerve or the support cell, will we really see a decrease in tinnitus?

 

[brokensoul]

Do you have any sources on the stria and how it affects music? All I am finding so far is that, in addition to ototoxicity, stria damage and atrophy seems related to age-related hearing loss and the loss of endocochlear potential seems to not only cause hair cell damage over time, it apparently seems to produce audiogram changes as well.

No sources for the impact of stria vascularis damage on hearing, pure speculation on my part based on my current understanding of cochlear physiology.

I just want to point out that most people likely think that sound waves make the stereocilia vibrate and this produces a signal towards the auditory nerve. In reality though it's quite a complex process, which I'm still trying to understand even better.

I'm sure though that hair cells cannot work without a proper functioning stria vascularis. It provides the fuel (potassium) for the hair cells to depolarise when the basilar membrane vibrates. Without it they cannot generate an action potential and release glutamate to the ribbon synapses.

How much damage is required to affect hearing capacity is not clear to me.

 

[brokensoul]

Small adjustment:

Most common cochlear damage I suspect is:
1. OHC synapse reduction (synaptopathy)
2. IHC synapse reduction (synaptopathy)
3. OHC stereocilia damage
4. IHC stereocilia damage
5. OHC death (apoptosis)
6. IHC death (apoptosis)
7. Auditory nerve damage
8. Supporting cells
9. Stria Vascularis cells
10. Spiral ganglion cells
11. Other

Scenarios 1 to 7 are probably the source for tinnitus generation due to cochlear (and nerve) damage. The others will affect hearing capacity, but are probably not the source of tinnitus.

An IHC or OHC which lost all its ribbon synapses will probably undergo apoptosis (to be confirmed). Hair cells with reduced synapses still function and there will not be a threshold shift in your audiogram. However it affects the bandwidth towards and from the auditory nerve. It is speculated that this affects clarity of sound. It is also one of the hypotheses for the source of tinnitus, aside from IHC/OHC death.

I still cannot find a source that confirms that damaged stereocilia leads to hair cell apoptosis. Apoptosis is what we want, as we don't want hair cells with dysfunctional stereocilia to remain in place. I'm not sure how valid this scenario is, but for now I'm not excluding it as a potential scenario. FX-322 will not affect such hair cells. It can only move a new hair cell in place where apoptosis happened.

The tiplinks between the stereocilia can be damaged as well, but they restore after some time, so I'm leaving them out of the scenarios. It's the only thing that recovers! This can temporarily affect your hearing capacity, but this recovers over time. I suspect that people with noise induced damage experience this process where they don't hear well for some time, but suddenly recover.

Reduced spiral ganglion cells is also possible, but it seems it's not the primary concern.

Scenario 5. and 6. is what will be treated by FX-322 to some extent. Phase 2a should give better insight how well this scenario will be covered.

As far as I know we have some synaptopathy drugs in trial, but no efficacy results yet? That will cover scenario 1. and 2. We need some promising results in this regard to know that the two main forms of cochlear damage will be resolved this decade.

Please feel free to correct me or elaborate.

 

[ThomasC]

Small adjustment:

Most common cochlear damage I suspect is:
1. OHC synapse reduction (synaptopathy)
2. IHC synapse reduction (synaptopathy)
3. OHC stereocilia damage
4. IHC stereocilia damage
5. OHC death (apoptosis)
6. IHC death (apoptosis)
7. Auditory nerve damage
8. Supporting cells
9. Stria Vascularis cells
10. Spiral ganglion cells
11. Other

Scenarios 1 to 7 are probably the source for tinnitus generation due to cochlear (and nerve) damage. The others will affect hearing capacity, but are probably not the source of tinnitus.

An IHC or OHC which lost all its ribbon synapses will probably undergo apoptosis (to be confirmed). Hair cells with reduced synapses still function and there will not be a threshold shift in your audiogram. However it affects the bandwidth towards and from the auditory nerve. It is speculated that this affects clarity of sound. It is also one of the hypotheses for the source of tinnitus, aside from IHC/OHC death.

I still cannot find a source that confirms that damaged stereocilia leads to hair cell apoptosis. Apoptosis is what we want, as we don't want hair cells with dysfunctional stereocilia to remain in place. I'm not sure how valid this scenario is, but for now I'm not excluding it as a potential scenario. FX-322 will not affect such hair cells. It can only move a new hair cell in place where apoptosis happened.

The tiplinks between the stereocilia can be damaged as well, but they restore after some time, so I'm leaving them out of the scenarios. It's the only thing that recovers! This can temporarily affect your hearing capacity, but this recovers over time. I suspect that people with noise induced damage experience this process where they don't hear well for some time, but suddenly recover.

Reduced spiral ganglion cells is also possible, but it seems it's not the primary concern.

Scenario 5. and 6. is what will be treated by FX-322 to some extent. Phase 2a should give better insight how well this scenario will be covered.

As far as I know we have some synaptopathy drugs in trial, but no efficacy results yet? That will cover scenario 1. and 2. We need some promising results in this regard to know that the two main forms of cochlear damage will be resolved this decade.

Please feel free to correct me or elaborate.

Thank you for your explanations. Any idea what part of the cochlea can cause hyperacusis?

 

[brokensoul]

Thank you for your explanations. Any idea what part of the cochlea can cause hyperacusis?

I still need to have a deeper look at the current theories for tinnitus and hyperacusis and how exactly it relates to cochlear physiology and beyond. I have hyperacusis too, but it's not my primary concern.

I suspect it would still be scenario 1-7 that is primarily involved in the pathogenesis of hyperacusis, but I have to admit that currently it's not clear to me how or which cochlear damage exactly could lead to tinnitus and hyperacusis. Some say the cause is cochlear synaptopathy, other say it's the hair cells, others say it's a combination of cochlear damage and a thalamic (brain) malfunctioning that leads to tinnitus.

All we have is theories (brain filling in gaps, lack of filtering and increased central gain). If anyone wants to chime in with the main theories for tinnitus and hyperacusis, in correlation with physical damage, please do.

 

[FGG]

No sources for the impact of stria vascularis damage on hearing, pure speculation on my part based on my current understanding of cochlear physiology.

I just want to point out that most people likely think that sound waves make the stereocilia vibrate and this produces a signal towards the auditory nerve. In reality though it's quite a complex process, which I'm still trying to understand even better.

I'm sure though that hair cells cannot work without a proper functioning stria vascularis. It provides the fuel (potassium) for the hair cells to depolarise when the basilar membrane vibrates. Without it they cannot generate an action potential and release glutamate to the ribbon synapses.

How much damage is required to affect hearing capacity is not clear to me.

I spent a lot of last night reading about this so walk me through your theory. Why would this affect music different from other sounds? And if it has to do with potassium depletion as a function of time, would the first few notes of a song sound more normal? Why wouldn't speech (esp prolonged like in a movie) be affected?

Why would the endocochlear potential be normal but music affected (studies show that even in severely affected stria, the initial decline normalizes over time even if the stria doesn't heal)? Is this just a function of altered potassium levels in the fluid despite the EP staying the same?

Everything I read also says that stria damage leads to progressive OHC loss. I haven't had any audiogram changes in over a year and my hearing is otherwise the same. How does this relate to your theory about the stria and music?

 

[FGG]

Small adjustment:

Most common cochlear damage I suspect is:
1. OHC synapse reduction (synaptopathy)
2. IHC synapse reduction (synaptopathy)
3. OHC stereocilia damage
4. IHC stereocilia damage
5. OHC death (apoptosis)
6. IHC death (apoptosis)
7. Auditory nerve damage
8. Supporting cells
9. Stria Vascularis cells
10. Spiral ganglion cells
11. Other

Scenarios 1 to 7 are probably the source for tinnitus generation due to cochlear (and nerve) damage. The others will affect hearing capacity, but are probably not the source of tinnitus.

An IHC or OHC which lost all its ribbon synapses will probably undergo apoptosis (to be confirmed). Hair cells with reduced synapses still function and there will not be a threshold shift in your audiogram. However it affects the bandwidth towards and from the auditory nerve. It is speculated that this affects clarity of sound. It is also one of the hypotheses for the source of tinnitus, aside from IHC/OHC death.

I still cannot find a source that confirms that damaged stereocilia leads to hair cell apoptosis. Apoptosis is what we want, as we don't want hair cells with dysfunctional stereocilia to remain in place. I'm not sure how valid this scenario is, but for now I'm not excluding it as a potential scenario. FX-322 will not affect such hair cells. It can only move a new hair cell in place where apoptosis happened.

The tiplinks between the stereocilia can be damaged as well, but they restore after some time, so I'm leaving them out of the scenarios. It's the only thing that recovers! This can temporarily affect your hearing capacity, but this recovers over time. I suspect that people with noise induced damage experience this process where they don't hear well for some time, but suddenly recover.

Reduced spiral ganglion cells is also possible, but it seems it's not the primary concern.

Scenario 5. and 6. is what will be treated by FX-322 to some extent. Phase 2a should give better insight how well this scenario will be covered.

As far as I know we have some synaptopathy drugs in trial, but no efficacy results yet? That will cover scenario 1. and 2. We need some promising results in this regard to know that the two main forms of cochlear damage will be resolved this decade.

Please feel free to correct me or elaborate.

They have said FX-322 is for damaged or destroyed hair cells. "Damaged" implies you don't need apoptosis.

 

[FGG]

I've been looking into it and it actually looks like ototoxic damage could be somewhat mitigated by the BLB—a defense unavailable to acoustic-trauma induced tinnitus.

"Since hair cell loss occurs directly after noise exposure and SGN degeneration follows a much longer time course, this degeneration was believed to occur secondarily to hair cell loss (Stankovic et al., 2004; Kujawa and Liberman, 2009). However, evidence suggests that primary SGN loss can occur in the absence of hair cell loss over a period of several months to years after noise exposure (Kujawa and Liberman, 2006, 2009; Lin et al., 2011)."

Maybe OHC loss in the presence of intact corresponding SGN's leads to the presence of tinnitus, and the reason some experience complete remission is due to the eventual death of the SGN's? Just a theory. This stuff is super tough to digest and to be honest it makes me a little sick.

Source: https://www.frontiersin.org/articles/10.3389/fncel.2019.00285/full#B77

It has been since found that humans, with unmyelinated SGNs are not that susceptible to damage of SGNs no matter what the cause. Rodent studies on SGNs probably aren't very useful because theirs are myelinated.

 

[Frédéric]

Most common cochlear damage I suspect is:
1. OHC synapse reduction (synaptopathy)
2. IHC synapse reduction (synaptopathy)
3. OHC stereocilia damage
4. IHC stereocilia damage
5. OHC death (apoptosis)
6. IHC death (apoptosis)
7. Auditory nerve damage
8. Supporting cells
9. Stria Vascularis cells
10. Spiral ganglion cells
11. Other

I would say there are a lot more scenarios to study because you need to count the combinations of all or part of these local damages.

 

[FGG]

Thinking about this more, @brokensoul, I'm not sure stria vascularis damage is related to music in the way you have described. Age-related hearing loss is characterized by atrial atrophy and they do not have hearing distortion in music differently than speech and, in fact, seem to do well with hearing aids in terms of music. The strial loss does seem to result in their progressive loss of OHCs though.

 

[mrbrightside614]

I still cannot find a source that confirms that damaged stereocilia leads to hair cell apoptosis. Apoptosis is what we want, as we don't want hair cells with dysfunctional stereocilia to remain in place. I'm not sure how valid this scenario is, but for now I'm not excluding it as a potential scenario. FX-322 will not affect such hair cells. It can only move a new hair cell in place where apoptosis happened.

My theory is that temporary tinnitus and spikes are caused by damaged stereocilia resulting in temporary threshold shifts. I can't imagine a scenario where chronic tinnitus is not the product of actual death of hair cells and/or synapses, or more of us would be seeing marginal improvement over time. Perhaps this is just wishful thinking, though.

 

[Joeseph Stope]

If anyone wants to chime in with the main theories for tinnitus and hyperacusis, in correlation with physical damage, please do.

Red rag and bull. Now look at the avalanche you have set off.
I seem to recall reading some survey done in Germany of the most frequent components that led to the onset of tinnitus.

Foremost among them or most frequent was:
1]. Noise
2]. Negative stress
3]. Infection.

Noise? well that could be sudden and loud or it could be constant... depends on the frequencies too.

Negative stress. Well if your Boss or parents or spouse is constantly nagging at you and wearing you down, that causes stress. A day at the races or a night at the Folies Bergéres might have you in stress too, but that would be positive stress. quite different from the first type.
Infection... a cold or flu.
I suppose add in ototoxic medicines to treat an infection.

I recall reading of a theory that the noise of the tinnitus is some natural feedback from the brain. But people with normal hearing have the ability to filter it out. Tinnitus sufferers have lost or damaged this filtering mechanism. Some experiment was done in the 1950s where subjects (people) with normal hearing were put in a sound chamber for 20 minutes in absolute silence. All subjects afterwards related that they heard some noise in their head. The conclusion
was that tinnitus might be an inability to filter out this noise somehow.

It's easy to postulate this but how do you prove or disprove it?

I find your post very refreshing as it gets down to the nitty-gritty components of the inner ear. And (we hope and think) that that's where it's all at.
Just wait for the outcomes of the Frequency and Hough trials, I guess. We might be a little bit wiser.

 

[FGG]

My theory is that temporary tinnitus and spikes are caused by damaged stereocilia resulting in temporary threshold shifts. I can't imagine a scenario where chronic tinnitus is not the product of actual death of hair cells and/or synapses, or more of us would be seeing marginal improvement over time. Perhaps this is just wishful thinking, though.

It would seem pretty unusual imo to have damage that could decimate stereocilia without enough damage to the cell to signal an apoptosis pathway. It's not like the damage "stops" at the most superficial aspect of the attachment site.

The only studies that i can find that even show this happening (stereocilia gone in an otherwise intact cell) are in avian studies and birds have very different caspases and apoptosis pathways compared to mammals.

 

[brokensoul]

I spent a lot of last night reading about this so walk me through your theory. Why would this affect music different from other sounds? And if it has to do with potassium depletion as a function of time, would the first few notes of a song sound more normal? Why wouldn't speech (esp prolonged like in a movie) be affected?

Why would the endocochlear potential be normal but music affected (studies show that even in severely affected stria, the initial decline normalizes over time even if the stria doesn't heal)? Is this just a function of altered potassium levels in the fluid despite the EP staying the same?

Everything I read also says that stria damage leads to progressive OHC loss. I haven't had any audiogram changes in over a year and my hearing is otherwise the same. How does this relate to your theory about the stria and music?

It's just speculation on my part. I cannot imagine this having no effect. I suspect it would be most noticeable when your hearing is challenged and this will happen more likely with music as it's a complex mix of different frequencies and loudness and requires your hearing to work harder. So that would require a lot of potassium for a prolonged period of time. To be clear, I think it could affect anything though, including speech, but basic sounds might not create enough challenge for the hair cells. I suspected it may create a situation where you can hear something, but when potassium levels are becoming low it will start to create distortions as some sounds may no longer be processed or not well enough. I could obviously be wrong, it's just my laymen opinion, based on my current understanding.

Maybe it's a bad analogy, but perhaps it is somewhat comparable to a racing car that requires high potency fuel for top performances. If the potency of the fuel is reduced it would no longer allow for top performances.

Again, I don't know for sure and I don't know to what extent the stria vascularis cells are redundant. Some damage may have zero effect, but if the stria vascularis doesn't work at all, there is no hearing. Of course that situation is probably highly exceptional or non-existent.

I have not read anything specific on it in terms of actual impact on hearing. It is purely based on my understanding of cochlear physiology. So feel free to disregard what I said in regards of impact on hearing.

I didn't know it actually leads to OHC loss. That is very interesting and worrying at the same time. Did you read any specific theory on why this is the case?

 

[brokensoul]

I would say there are a lot more scenarios to study because you need to count the combinations of all or part of these local damages.

Absolutely, but these would be the main individual components. Anyone surely has a combination of different scenarios. It is even possible that it is due to the mix of different issues that the brain reacts erroneously.

 

[brokensoul]

They have said FX-322 is for damaged or destroyed hair cells. "Damaged" implies you don't need apoptosis.

That would actually be great news. Do you remember where they stated this?

 

[Christopher805]

@Joeseph Stope
I heard about that experiment. Given the archaic nature of audiograms of today one could only image how accurate they were in the 1950s in determining what constitutes normal hearing. Unfortunately, there are so many moving parts in the human ear that even today it's hard to prove or disapprove the cause(s) of most conditions.

 

[brokensoul]

Red rag and bull. Now look at the avalanche you have set off.
I seem to recall reading some survey done in Germany of the most frequent components that led to the onset of tinnitus.

Foremost among them or most frequent was:
1]. Noise
2]. Negative stress
3]. Infection.

Noise? well that could be sudden and loud or it could be constant... depends on the frequencies too.

Negative stress. Well if your Boss or parents or spouse is constantly nagging at you and wearing you down, that causes stress. A day at the races or a night at the Folies Bergéres might have you in stress too, but that would be positive stress. quite different from the first type.
Infection... a cold or flu.
I suppose add in ototoxic medicines to treat an infection.

I recall reading of a theory that the noise of the tinnitus is some natural feedback from the brain. But people with normal hearing have the ability to filter it out. Tinnitus sufferers have lost or damaged this filtering mechanism. Some experiment was done in the 1950s where subjects (people) with normal hearing were put in a sound chamber for 20 minutes in absolute silence. All subjects afterwards related that they heard some noise in their head. The conclusion
was that tinnitus might be an inability to filter out this noise somehow.

It's easy to postulate this but how do you prove or disprove it?

I find your post very refreshing as it gets down to the nitty-gritty components of the inner ear. And (we hope and think) that that's where it's all at.
Just wait for the outcomes of the Frequency and Hough trials, I guess. We might be a little bit wiser.

I think the triggers are reasonably well known. Question is what the exact physical damage is (in the ear or even the brain) that creates tinnitus. That is still not clear today as far as I know.

I have read that some people speculate that some people with tinnitus are picking up somatic brain sounds due to a broken filter mechanism. So this is a completely different theory than the brain filling in the missing gaps in the ear (maladaptive neuroplasticity). It's a valuable theory. This broken filter theory is fully aligned with why people have visual snow. Visual snow is not created by an issue in the visual periphery. It is purely caused by a brain anomaly. Some scientists who research visual snow syndrome say that all the symptoms (including tinnitus) are caused by this brain dysfunction, so it could be the case for some people with tinnitus as well.

 

[ThomasC]

I think the triggers are reasonably well known. Question is what the exact physical damage is (in the ear or even the brain) that creates tinnitus. That is still not clear today as far as I know.

I have read that some people speculate that some people with tinnitus are picking up somatic brain sounds due to a broken filter mechanism. So this is a completely different theory than the brain filling in the missing gaps in the ear (maladaptive neuroplasticity). It's a valuable theory. This broken filter theory is fully aligned with why people have visual snow. Visual snow is not created by an issue in the visual periphery. It is purely caused by a brain anomaly. Some scientists who research visual snow syndrome say that all the symptoms (including tinnitus) are caused by this brain dysfunction, so it could be the case for some people with tinnitus as well.

I have bilateral and symmetrical, moderately severe hearing loss above 7 kHz. I don't know how long I have had hearing loss because there was no clear trigger (I never exposed myself to loud sound, and I don't think I took ototoxic drugs). My tinnitus appeared when I was in a stressful period. I also have VS but fortunately it is mild, so this gating theory makes sense to me.
I don't have hyperacusis and hearing distortion.

 

[FGG]

It's just speculation on my part. I cannot imagine this having no effect. I suspect it would be most noticeable when your hearing is challenged and this will happen more likely with music as it's a complex mix of different frequencies and loudness and requires your hearing to work harder. So that would require a lot of potassium for a prolonged period of time. To be clear, I think it could affect anything though, including speech, but basic sounds might not create enough challenge for the hair cells. I suspected it may create a situation where you can hear something, but when potassium levels are becoming low it will start to create distortions as some sounds may no longer be processed or not well enough. I could obviously be wrong, it's just my laymen opinion, based on my current understanding.

Maybe it's a bad analogy, but perhaps it is somewhat comparable to a racing car that requires high potency fuel for top performances. If the potency of the fuel is reduced it would no longer allow for top performances.

Again, I don't know for sure and I don't know to what extent the stria vascularis cells are redundant. Some damage may have zero effect, but if the stria vascularis doesn't work at all, there is no hearing. Of course that situation is probably highly exceptional or non-existent.

I have not read anything specific on it in terms of actual impact on hearing. It is purely based on my understanding of cochlear physiology. So feel free to disregard what I said in regards of impact on hearing.

I didn't know it actually leads to OHC loss. That is very interesting and worrying at the same time. Did you read any specific theory on why this is the case?

There is even a hearing loss pattern evident on audiograms called "Strial pattern" (tends to be more low frequency in age-related at least). It seems related to loss of EP. Interesting, acute ototoxic damage seems to result in temporary reduction of EP, then recovery (even when stria is permanently damaged--compensation?) but ototoxins lead to thickening where's age-related is due to atrophy and the effects seem more severe in terms of EP in the later.

There is lots on this, but here is one paper:

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168953

Anecdotally, though, I haven't met a single age-related hearing loss individual who has the severe degree of music distortion I do (while i have 100% normal speech hearing in quiet) so I can't help but think it has to be something else. For the most part, age-related hearing loss individuals can enjoy music with hearing aids. Hearing aids do not help me in the least.

 

[Christopher805]

@brokensoul

So if the hairs cells are successfully regenerated will this correct the dysfunction of the auditory cortex and other parts of the brain as they relate to tinnitus?

 

[brokensoul]

There is even a hearing loss pattern evident on audiograms called "Strial pattern" (tends to be more low frequency in age-related at least). It seems related to loss of EP. Interesting, acute ototoxic damage seems to result in temporary reduction of EP, then recovery (even when stria is permanently damaged--compensation?) but ototoxins lead to thickening where's age-related is due to atrophy and the effects seem more severe in terms of EP in the later.

There is lots on this, but here is one paper:

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168953

Anecdotally, though, I haven't met a single age-related hearing loss individual who has the severe degree of music distortion I do (while i have 100% normal speech hearing in quiet) so I can't help but think it has to be something else. For the most part, age-related hearing loss individuals can enjoy music with hearing aids. Hearing aids do not help me in the least.

I have read your thread to have a better understanding of your hearing loss symptoms (how exactly music is distorted for you). My knowledge is not advanced enough to give you any decent or reliable input on your specific (complex) case, other than you certainly have a mix of issues going on. I will keep it in mind though as I learn more about cochlear physiology specifically and the auditory system in general. There is so much to be studied if you want to understand the whole system and I'm not aware of great (online and free) sources that cover everything in great detail.

Are there no specialists that could tell you what is perhaps ongoing for you?

I wish we had an actual ENT and audiologist on Tinnitus Talk to help us out.

 

[brokensoul]

@brokensoul

So if the hairs cells are successfully regenerated will this correct the dysfunction of the auditory cortex and other parts of the brain as they relate to tinnitus?

It seems that many people think it will. If tinnitus is generated as a consequence of cochlear damage leading to maladaptive neuroplasticity, then it will likely reverse the maladaptive neuroplasticity as soon as the missing frequencies are present again. If this hypothesis is correct of course.

 

[Christopher805]

@brokensoul
Thank you for the information. Your response leads me to be believe that these progenitor cells once regenerated will carry the same frequency as the damaged or dead cells they replace. It is fascinating to thank that the progenitor cells that are dormant in the cochlea will not only regenerate but replicate the exact frequency as well. I hope you feel better today. Again thank you for your response.

 

[FGG]

I have read your thread to have a better understanding of your hearing loss symptoms (how exactly music is distorted for you). My knowledge is not advanced enough to give you any decent or reliable input on your specific (complex) case, other than you certainly have a mix of issues going on. I will keep it in mind though as I learn more about cochlear physiology specifically and the auditory system in general. There is so much to be studied if you want to understand the whole system and I'm not aware of great (online and free) sources that cover everything in great detail.

Are there no specialists that could tell you what is perhaps ongoing for you?

I wish we had an actual ENT and audiologist on Tinnitus Talk to help us out.

ENTs and otologists can't figure it out but irreversible Azithromycin toxicity is very, very rare. I did find a study showing that, in Guinea Pigs, topical Azithromycin delivered in the middle ear causes severe widespread IHC loss at the base of the cochlea (along with support cells at the points closest to the round window) but relatively spares OHCs. All the IHCs in the cochlea were effected but it was more mild at the apex.

In that particular study, weirdly the stria was mostly completely spared whereas severe strial edema is suspected with most of the reversible Macrolide IV and Oral toxicity cases. It's so confusing but my dominant theory is that bizarre hearing distortions might be due to areas of severe IHC destruction in areas of more normal OHCs which is a very rare cochlear damage pattern from what I can tell.

This is why I'm particularly obsessed with FX-322 atm and I really hope it can give me some real genuine hope. If somehow I have a very unique strial damage and that's my problem, I think I would honestly be close to giving up completely.

 

[brokensoul]

ENTs and otologists can't figure it out but irreversible Azithromycin toxicity is very, very rare. I did find a study showing that, in Guinea Pigs, topical Azithromycin delivered in the middle ear causes severe widespread IHC loss at the base of the cochlea (along with support cells at the points closest to the round window) but relatively spares OHCs. All the IHCs in the cochlea were effected but it was more mild at the apex.

In that particular study, weirdly the stria was mostly completely spared whereas severe strial edema is suspected with most of the reversible Macrolide IV and Oral toxicity cases. It's so confusing but my dominant theory is that bizarre hearing distortions might be due to areas of severe IHC destruction in areas of more normal OHCs which is a very rare cochlear damage pattern from what I can tell.

This is why I'm particularly obsessed with FX-322 atm and I really hope it can give me some real genuine hope. If somehow I have a very unique strial damage and that's my problem, I think I would honestly be close to giving up completely.

FX-322 will improve your hearing. Both IHC and OHC will be regenerated at the cochlear base. We already have proof that it works. I suspect there will already be a significant improvement for you. Hopefully that improvement can give you the energy to hold on for the other or improved solutions that are coming afterwards.

FX-322 Challenges Recap:
- We don't know how effective it really is. Awaiting data from phase 2a that shows high efficacy in the treated region. This is still the big question. Good early results given the fact that they only used a small dose, but currently nothing that really confirms it's pure gold. Hopefully phase 2a shows close to maximum efficacy in the treated region (close to all missing and damaged hair cells repaired, as in full restoration for those particular frequencies). September will tell us what we want to know. Tinnitus Talk will be at the edge of their seats when they present their results, including tinnitus efficacy. Hopefully it reduces high pitched tinnitus as well.
- The current solution does not get far into the cochlea. 8kHz is still the base of the cochlea. Higher doses will hopefully get to the projected target of 3.5kHz. To get all the way to the apex Frequency Therapeutics needs to develop a better hydrogel, which means new trials to validate the new solution again (FX-322 2.0). Hopefully the higher dose already makes a big difference.
- It requires supporting cells, so if they are completely missing in some areas this may be a blocking factor to regenerate hair cells in that particular area. I'm wondering if it wouldn't be better to first cover this by injecting a supporting cell duplicator to repair the epithelium. Perhaps it's not a big concern and FX-322 may even be capable of overcoming this issue. Would be a good question to ask them though.

 

[FGG]

FX-322 will improve your hearing. Both IHC and OHC will be regenerated at the cochlear base. We already have proof that it works. I suspect there will already be a significant improvement for you. Hopefully that improvement can give you the energy to hold on for the other or improved solutions that are coming afterwards.

FX-322 Challenges Recap:
- We don't know how effective it really is. Awaiting data from phase 2a that shows high efficacy in the treated region. This is still the big question. Good early results given the fact that they only used a small dose, but currently nothing that really confirms it's pure gold. Hopefully phase 2a shows close to maximum efficacy in the treated region (close to all missing and damaged hair cells repaired, as in full restoration for those particular frequencies). September will tell us what we want to know. Tinnitus Talk will be at the edge of their seats when they present their results, including tinnitus efficacy. Hopefully it reduces high pitched tinnitus as well.
- The current solution does not get far into the cochlea. 8kHz is still the base of the cochlea. Higher doses will hopefully get to the projected target of 3.5kHz. To get all the way to the apex Frequency Therapeutics needs to develop a better hydrogel, which means new trials to validate the new solution again (FX-322 2.0). Hopefully the higher dose already makes a big difference.
- It requires supporting cells, so if they are completely missing in some areas this may be a blocking factor to regenerate hair cells in that particular area. I'm wondering if it wouldn't be better to first cover this by injecting a supporting cell duplicator to repair the epithelium. Perhaps it's not a big concern and FX-322 may even be capable of overcoming this issue. Would be a good question to ask them though.

Just want to add that <3500Hz is still well within the speech range. No way they would just stop with the first formulation.

 

[mrbrightside614]

I can't find anything regarding support cell loss in response to acoustic trauma (save for Avian test subjects) but since they lack sensory input I would think they're more likely depleted in ototoxic cases. I'll look into this more later today.

 

[brokensoul]

Just want to add that <3500Hz is still well within the speech range. No way they would just stop with the first formulation.

I expect them to be competitive enough to want the jackpot and the hiring information you posted proves that they are looking for a better "carrier/transporter" for their small molecules that can actually reach all the way down to the apex. It's a matter of time.