Inner Ear Hair Cell Regeneration — Maybe We Can Know More

[Vinnitus]

Not tinnitus, hearing loss. We are in the inner ear hair cell regeneration thread, but Yeah good point. No one cares about T. Hair cell regeneration could help or cure T though as a side affect if the T is caused by loss of hair cells. That is probably a ways out though. I'm thinking the first treatments will get people from severe/profound to moderate. Even that won't cure T since even moderate is at least 50db away from perfect hearing and you can get T with as little as a 10db loss.

I think Tinnitus is not directly related to the amount of hearing loss you have like you propose here. I think hearing loss can be a TRIGGER for T in any kind of severity (hence the correlation), just like a gazillion other things can be a trigger for Tinnitus (notably any kind of trauma or overload to the brain/nervous system). After that the Tinnitus lives separate from the hearing loss and is sustained elsewhere.

This would implicate, among others, the following things (which I think might be true):

• People can have T without hearing loss, which might be true seeing there are so many possible causes for T (stress for example).
• Tinnitus might stay regardless of your hearing loss being reversed totally.
• Somebody with 10dB hearing loss can experience more severe Tinnitus than someone with 50dB hearing loss.

Seeing there are so many variables in Tinnitus, I think the above might be true and Tinnitus is sustained somewhere else, like for example the central nervous system, the auditory cortex or the dorsal cochlear nucleus as a direct consequence of any kind of trauma.

 

[Reinier]

Tinnitus might stay regardless of your hearing loss being reversed totally.

It would surprise me when hearing loss (damage) is repaired, tinnitus remains. So much tinnitus is noise induced.
Also with ototoxicity, inner ear damage can start tinnitus. What could be the reason if this damage is repaired, tinnitus remains?

Although there are many variables in tinnitus, I read that the wide majority is noise induced.

 

[Pleasure_Paulie]

Although there are many variables in tinnitus, I read that the wide majority is noise induced.

It's mostly is and all relates to hearing loss; however that may occurred due to cumulative noise damage, sudden threshold shift, ototoxicity of drugs or infections for example.

 

[Aaron123]

Or is this too simple or even complete rubbish?

I think that is basically right though it might over simplify the stem cell side of things a bit.

My understanding of where we are has been influenced by a recent paper by Lewis, Rubel, and Stone in Acoustics Today (http://acousticstoday.org/regenerat...becca-m-lewis-edwin-w-rubel-jennifer-s-stone/).

For me, one of the key takeaways is "As discussed above, we now know several powerful genes or signaling pathways that, when manipulated in very young rodents, cause supporting cells to divide and form new hair cells. But these same manipulations have very little effect or even deleterious effects in mature rodents." I had not been aware of this, and it is something I will pay more attention to. My guess is that most pre-clinical work is done on young rodents. This may well be successful, but if it doesn't translate to older rodents, it may well be unlikely to work on older humans.

They make a number of other points:

• They discuss over expression of ATOH1 (e.g., the Genvec trial) and point out that in contrast to the promising earlier work "recent studies are less encouraging".
  
• They discuss inhibition of Notch signalling (something Audion and probably Decibel are working on) which shows promise though they point out that studies have come to conflicting conclusions about its effectiveness: "One study suggests that infusion of Notch inhibitors into live mice can promote supporting cells to convert into hair cells in the organ of Corti of adult mice after hair cell damage (Mizutari et al., 2013). However, another study clearly describes a precipitous loss of efficacy of Notch inhibitors to stimulate hair cell regeneration (Maass et al., 2015). Hopefully, these apparently conflicting interpretations of Notch inhibition will be resolved in future studies."
  
• for both of these approaches, they say "Although Atoh1 misexpression and/or Notch inhibition appears to encourage supporting cells to form hair cell-like cells in mature animals, neither treatment has a significant effect on supporting cell division. Therefore, as a therapy alone, either manipulation would likely deplete supporting cells, which would almost certainly reduce the function of the organ of Corti." Thus the concern is what are the consequences of a depleted population of supporting cells? This is unknown at present.
• They discuss the small molecule p27kip1 as a possibility to induce supporting cells to divide which could solve the problem of a depletion of supporting cells. I think Sound Pharmaceuticals is working with p27kip1.
  
• Promising new approaches include attempting to manipulate multiple pathways simultaneously (I posted a link to a paper that was working with Notch and Wnt a while back) or by attempting to recreate the dynamics of gene expression during development. The latter is likely to be much harder but more promising. This appears to be what was done to grow the "ear-in-a-dish". Doing this clinically seems very challenging at the present.
  
• There's less discussion of stem cells, but they do point out the challenge of transplanted stem cells surviving in the inner ear. An additional challenge with stem cells is the lack of inner ear stem cells and thus the need to guide iPSCs to become hair cells.
  
• Finally, the "Clinical Considerations" section is interesting. Here is most of it "For instance, we do not know how many hair cells of each type must be regenerated to adequately restore hearing in impaired individuals. Although we know that inner hair cells are critical, we can only guess how well they will restore hearing in the absence of outer hair cells. Many forms of hearing loss are caused by selective destruction of outer hair cells; regeneration of outer hair cells alone could be helpful in such patients. Furthermore, we lack the capability to accurately test which type of cells need repair in patients. This assessment requires development of more cell-specific and noninvasive diagnostic procedures. In addition, high-resolution imaging of the inner ear, enabling quantitative assessment of each cell type, would be very helpful and is currently under investigation." Thus, separate from the basic science side of things, exactly what is required for restored hearing is unknown at present. I think the need for non-invasive imaging and diagnostic procedures is key and is currently under investigated.

After reading the paper, I am a bit less optimistic about what is in the pipeline and perhaps a bit more realistic about what to expect. I'm hopeful that one of these approaches will show meaningful results but definitely not expecting a breakthrough any time soon.

 

[Vinnitus]

It would surprise me when hearing loss (damage) is repaired, tinnitus remains. So much tinnitus is noise induced.
Also with ototoxicity, inner ear damage can start tinnitus. What could be the reason if this damage is repaired, tinnitus remains?

Although there are many variables in tinnitus, I read that the wide majority is noise induced.

Like I said, when Tinnitus is sustained elsewhere independent of the initial trigger, it might be sustained even though the initial trigger has been restored to former function. Else how would one explain the case where people have noise-induced Tinnitus for months or years and it disappears? Such cases have been reported.

It can't be said their hearing has been restored to full function in such cases, as hearing does not recover according to current studies. Same is the case with deaf people experiencing no Tinnitus. They might have lost a lot of hair cells, yet they don't experience Tinnitus. This might mean the Tinnitus is not caused by the absence of hair cells in itself, but maybe rather the traumatic event itself causing the loss of the hair cells.

Personally (and at the current moment) I think the Tinnitus is more a consequence of sudden trauma of some kind, i.e. the loss of a lot of hair cells at once (during impulse sounds or rock concerts) or sudden physical damage to brain structures after an accident, etc. The sustaining part therefore might have more to do with the central nervous system than anything peripheral.

But of course, this is just my speculation. I keep having wild thoughts about this still mysterious condition we all have to deal with. My views might change again though.

 

[RB2014]

I think that is basically right though it might over simplify the stem cell side of things a bit.

My understanding of where we are has been influenced by a recent paper by Lewis, Rubel, and Stone in Acoustics Today (http://acousticstoday.org/regenerat...becca-m-lewis-edwin-w-rubel-jennifer-s-stone/).

For me, one of the key takeaways is "As discussed above, we now know several powerful genes or signaling pathways that, when manipulated in very young rodents, cause supporting cells to divide and form new hair cells. But these same manipulations have very little effect or even deleterious effects in mature rodents." I had not been aware of this, and it is something I will pay more attention to. My guess is that most pre-clinical work is done on young rodents. This may well be successful, but if it doesn't translate to older rodents, it may well be unlikely to work on older humans.

They make a number of other points:

• They discuss over expression of ATOH1 (e.g., the Genvec trial) and point out that in contrast to the promising earlier work "recent studies are less encouraging".
  
• They discuss inhibition of Notch signalling (something Audion and probably Decibel are working on) which shows promise though they point out that studies have come to conflicting conclusions about its effectiveness: "One study suggests that infusion of Notch inhibitors into live mice can promote supporting cells to convert into hair cells in the organ of Corti of adult mice after hair cell damage (Mizutari et al., 2013). However, another study clearly describes a precipitous loss of efficacy of Notch inhibitors to stimulate hair cell regeneration (Maass et al., 2015). Hopefully, these apparently conflicting interpretations of Notch inhibition will be resolved in future studies."
  
• for both of these approaches, they say "Although Atoh1 misexpression and/or Notch inhibition appears to encourage supporting cells to form hair cell-like cells in mature animals, neither treatment has a significant effect on supporting cell division. Therefore, as a therapy alone, either manipulation would likely deplete supporting cells, which would almost certainly reduce the function of the organ of Corti." Thus the concern is what are the consequences of a depleted population of supporting cells? This is unknown at present.
• They discuss the small molecule p27kip1 as a possibility to induce supporting cells to divide which could solve the problem of a depletion of supporting cells. I think Sound Pharmaceuticals is working with p27kip1.
  
• Promising new approaches include attempting to manipulate multiple pathways simultaneously (I posted a link to a paper that was working with Notch and Wnt a while back) or by attempting to recreate the dynamics of gene expression during development. The latter is likely to be much harder but more promising. This appears to be what was done to grow the "ear-in-a-dish". Doing this clinically seems very challenging at the present.
  
• There's less discussion of stem cells, but they do point out the challenge of transplanted stem cells surviving in the inner ear. An additional challenge with stem cells is the lack of inner ear stem cells and thus the need to guide iPSCs to become hair cells.
  
• Finally, the "Clinical Considerations" section is interesting. Here is most of it "For instance, we do not know how many hair cells of each type must be regenerated to adequately restore hearing in impaired individuals. Although we know that inner hair cells are critical, we can only guess how well they will restore hearing in the absence of outer hair cells. Many forms of hearing loss are caused by selective destruction of outer hair cells; regeneration of outer hair cells alone could be helpful in such patients. Furthermore, we lack the capability to accurately test which type of cells need repair in patients. This assessment requires development of more cell-specific and noninvasive diagnostic procedures. In addition, high-resolution imaging of the inner ear, enabling quantitative assessment of each cell type, would be very helpful and is currently under investigation." Thus, separate from the basic science side of things, exactly what is required for restored hearing is unknown at present. I think the need for non-invasive imaging and diagnostic procedures is key and is currently under investigated.

After reading the paper, I am a bit less optimistic about what is in the pipeline and perhaps a bit more realistic about what to expect. I'm hopeful that one of these approaches will show meaningful results but definitely not expecting a breakthrough any time soon.

You have done a great job of summing up a lot of the ideas that have been discussed and a lot of ups and downs that I have read over the years, mostly downs. You are correct in all of your statements. At the end of the day though, there are 5 or 6 startups that now think that it is possible to restore hearing and they have funding available. I don't believe that they would have funding if there was not a strong belief that it was possible to restore hearing, at least up to a certain degree. Now that the research is in the hands of private companies we are no longer going to be privy to their advancements and information. It is now a race by privately funded companies to get something that works. The first one that does will make millions if not billions of dollars. I think this is a reason to remain optimistic.

On the 10 year forecasts that were made in 2012, private funding was not supposed to start until the 10 year mark. The 10 years was never a cure, but it was enough research to begin clinical trials. These companies have jumped on the bandwagon on year 4. That is in itself incredible and says a lot about how possible it must be to restore hearing at least up to a certain degree.

I'm also confused about the optimistic comments Genvec made concerning the Novartis trial. They must know something we don't or they are lying, or maybe they now have more information on how to tweak the formula, which is supported by evidence found by some of the group members. Either way Genvec still remains optimistic and they have a huge funding source in Novartis who has taken over the trials. I'm not sure how serious Novartis still is about this, but they committed to quite a bit of research and funding several years ago and we have heard nothing ever since they did. This might be a good or bad sign. I'm not really sure at this point what to think, but it could be an indication that they want to be the first to get something to the market and don't want to share any more information than they have to.

At the end of the day I think it looks a little brighter than the information you have pictured, which is all of course true and it is the information that we have access to. I really believe the research is ahead of what they are currently publishing to the general public, but that they are now keeping it secret due to monetary reasons.

 

[Mricha37]

As a business owner, if these companies smelled a flop for even a second, they would pull funding especially if they have a lot of eggs in that basket. I mean, there's less main stream soda companies than research labs trying to cure deafness. My father, a biomedical engineer for 34 years from Duke University, has stated that he foresees hearing loss treatment is within 10 years time.

 

[spingee]

As a business owner, if these companies smelled a flop for even a second, they would pull funding especially if they have a lot of eggs in that basket. I mean, there's less main stream soda companies than research labs trying to cure deafness. My father, a biomedical engineer for 34 years from Duke University, has stated that he foresees hearing loss treatment is within 10 years time.

Have your father hearing loss? Becouse if he has i could believe him.

 

[Mricha37]

He has 2 kids with hearing issues. Which is even worse I think.

 

[Reinier]

@Aaron123 Thanks.
We have a sort of "blueprint" how regeneration works in birds. This is how this master gene ATOH1 was discovered if I am not mistaken. If I remember correct, it is Harvard (and probably others too) that is in the process of looking for all the genes that are involved in this regeneration process. I am not sure if blueprint is the correct word, but I think you know what I mean. Reverse engineering is the plan.
I know I make it sound easy, but what I am trying to say is that perhaps initially we do not have to understand every single step in the process of building (regenerating) an inner ear.

Also what I think is an indicator that something could be happening "soon" (soon is still a relative term!) is that some researchers are starting companies, or liaison with companies that want to commercialise the research findings.

Investors invest in different companies. I am sure investors take risks, but still want to make this risk as small as possible by getting all the information they can get.
These are some reasons why I am positive regarding treatments.

By the way: my background is electronics engineer. So I do not have any biology education. Perhaps it shows

 

[Reinier]

My father, a biomedical engineer for 34 years from Duke University, has stated that he foresees hearing loss treatment is within 10 years time.

I find this a very inspiring statement.

 

[Nick Pyzik]

Like I said, when Tinnitus is sustained elsewhere independent of the initial trigger, it might be sustained even though the initial trigger has been restored to former function. Else how would one explain the case where people have noise-induced Tinnitus for months or years and it disappears? Such cases have been reported.

There are many factors to be said for the brain can do to compensate for the damage that's taken place.

It can't be said their hearing has been restored to full function in such cases, as hearing does not recover according to current studies. Same is the case with deaf people experiencing no Tinnitus. They might have lost a lot of hair cells, yet they don't experience Tinnitus. This might mean the Tinnitus is not caused by the absence of hair cells in itself, but maybe rather the traumatic event itself causing the loss of the hair cells.

The deaf can have ringing and the deaf can have no ringing. I link the ringing to damage in the central nervous system. Either a malfunction that took place in the brain at birth or in ones life time from acoustic trauma. The CNS cannot repair itself. Hair cells are not what allow one to process sound more clearly and loudly. I've come to realize that the brain needs chemicals to hear sound in a certain way.

 

[Eliot333]

Shout out to Aaron123. Always brings in those great technical posts

 

[Mricha37]

What if it is as simple as just repairing the stereocilia after noise or age induced hearing loss? I know for a fact if I got some hearing back the tinnitus would be reduced if not completely gone. So it's completely possible I've had it all my life I just slowly eroded away at my hearing to where I'm at today. I don't understand how T can get worse if you need to "damage" cns for T to happen.

 

[GregCA]

I know for a fact if I got some hearing back the tinnitus would be reduced if not completely gone.

How do you know this for a fact?
My belief system has this statement as a strong assumption too, and would love to turn that into a fact, but I need scientific evidence for that. Is there any?

 

[Mricha37]

Well when I wear ear plugs I hear my T more then when I'm not. So I'm basically wearing invisible ear plugs right now with my hearing loss. And I recently did something stupid that lead to more hearing loss which lead to my T being more present. Seems pretty simple to me.

 

[Mricha37]

Or maybe I'm completely wrong. I'm just throwing stuff out there.

 

[GregCA]

Well when I wear ear plugs I hear my T more then when I'm not. So I'm basically wearing invisible ear plugs right now with my hearing loss. And I recently did something stupid that lead to more hearing loss which lead to my T being more present. Seems pretty simple to me.

OK, but anecdotal evidence is different from scientific evidence... but thank you for clarifying.

In your case when you wear your ear plugs, what may be happening is that the sounds that used to drown your T disappear, making T more prominent (the brain focuses on the little it can hear). It happens to me too.
The conclusion from that is that if you regain hearing, natural sounds will mask T more, making it less intrusive (people who wear hearing aids report this). That's different from reducing T or making it go away completely. Don't get me wrong: it's a good step.

One of my assumptions along this line is that, if there was maladaptive brain plasticity in play creating T due to loss of hearing, then regaining hearing may trigger the reverse plasticity move, which actually lowers the T volume (it's not just drowned by other noise, it's actually a smaller intensity T stimulus perceived by the brain). And that is what I would love to know for a fact (things like ACRN rely on a similar hypothesis, but they want to trigger the neuronal reconfiguration through stimulation in spite of existing hearing loss, while the things we're talking about here is recovery of hearing creating the natural stimulation).

 

[Mricha37]

I agree with reverse plasticity. To me the brain right now is trying to work with faulty equipment. Until we fix that equipment, we will never know.

 

[Nick Pyzik]

What if it is as simple as just repairing the stereocilia after noise or age induced hearing loss? I know for a fact if I got some hearing back the tinnitus would be reduced if not completely gone. So it's completely possible I've had it all my life I just slowly eroded away at my hearing to where I'm at today. I don't understand how T can get worse if you need to "damage" cns for T to happen.

We'll find out somewhat soon if hair cells actually allow one to "hear better". I stand behind the research regarding acoustic trauma to the nerve fibers/spiral ganglion neurons causing hearing loss and also which can even be connected to tinnitus with the latest documents uploaded online. Hearing is a sense. It's all about processing. Chemicals are needed in that process.

I blame the excitable neurons involved in the damage that cause your ringing to become louder. The brain will try its absolute best to function like it did before when given the ability to create neurogenesis plus neurotransmitters like dopamine are involved. Your senses will become heightened and since I believe the ringing is coming from your auditory system (plus other regions), your brain will try to hear with the damaged auditory pathways. Not necessarily involving any sort of sensory hair cell damage.

Anything that raises your brains' neurotransmitter levels, like caffeine in coffee for instance, is a good example of what I'm trying to explain.

 

[Nick Pyzik]

Well when I wear ear plugs I hear my T more then when I'm not. So I'm basically wearing invisible ear plugs right now with my hearing loss. And I recently did something stupid that lead to more hearing loss which lead to my T being more present. Seems pretty simple to me.

It's all about your brains processing. The nerve fibers involved are what allow sound to be processed. There are two types of nerve fibers involved that sprout out from what are called spiral ganglion neurons. These two nerves can be termed as "in-going" and "out-going". The more "out-going" nerve fibers or logical processing nerve fibers you have, the less the brain will rely on trying to still hear with its damaged "in-going" nerve fibers/spiral ganglion neurons. The brain can use its plasticity to try and repair the peripheral nervous system, but it can't repair the central nervous system. You therefore have ringing which will always be there if damaged almost completely or even completely.

I believe those times where your hearing goes out for a few seconds or more is when your brain sends out "out-going" nerve fibers in attempt to repair itself. As they attach to any sort of sensory hair cell, you get the loud ringing and strange change in your hearing.

 

[RB2014]

Just from my own experimenting this is what I think/know. I'm pretty sure there is a link between T volume and hearing loss. My left ear has more loss than my right and it is louder in my left most of the time. The brain is plastic and regaining hearing will either lower T or eliminate it. In order to eliminate T completely I'm pretty sure you have to get perfect hearing again. Once you have found T it won't go away unless its gone, but you can spend years with T and not know you have it if the volume is low enough and you are not aware of its existence.
I play with hearing aides all the time and I can vouch for just having them in reduces T volume vs taking them out and thats not just masking sounds, but thats hearing T loudness.
Now this applies to someone that has T because of hearing loss. There are many forms of T and H and not one size fits all from what I have learned on this forum.

 

[Reinier]

Just from my own experimenting this is what I think/know. I'm pretty sure there is a link between T volume and hearing loss.

My experience is different.
Hearing loss in my right ear is much greater than in my left ear. Yet, sometimes my tinnitus in my left ear is louder.
I actually sometimes wonder if the tinnitus sensation in my left ear does not originate from my right ear, but from my more damaged right ear.
This "mix-up" must happen in my brain.

 

[Marlino]

Hearing loss in my right ear is much greater than in my left ear. Yet, sometimes my tinnitus in my left ear is louder.

I think its to simple to expect T to be correlated with plain hearing loss.

A study showed that no so much the absolute hearing loss in high frequencies is important but the gradient (steepness of the slope on the audiogram).

That T emerges might be due to fact that a) the brain tries desperately to fill up the gaps/ correct the steep slope
b) gaps or high gradients increase the coincidence of 'zombie hearing cells', firing randomly.
c) gaps or high gradients increase the coincidence of malfunctioning of in ear amplification (IHC OHC feedback). This is what Jastreboff suggests, I think.

 

[Reinier]

I think its to simple to expect T to be correlated with plain hearing loss.

I am not exactly sure If I understand you correct.
But my inner ear is damaged because of noise. This damage gives me hearing loss, tinnitus, etc...
I accept there is no correlation between severity of hearing loss and loudness of tinnitus. At least that is how I experience it. There are plenty people that have loud tinnitus with excellent audiograms. So no steep gradients and no gaps in hearing ability.

 

[Marlino]

There are plenty people that have loud tinnitus with excellent audiograms. So no steep gradients and no gaps in hearing ability.

You got it corecct. I just meant that level of HL is not proportional to T volume, rather seems the gradient to be important. If the people with excellent audiogramms have hidden hearing loss, I don't know. But I would love to know.
In theorie everybody could just get a linear head phone and a sine frequency generator. Set it to barely audible volume and continously swipe through all the frequencies. If you don't hear the tone at a specific frequency you have HHL there.

I did that and I found dips in my hearing. But the don't necessarily match my T frequency.

So there must be something more in my opinion. Actually I'm pretty much for the zombie hair cell (ZHC) theorie.

 

[bill 112]

The CNS is most certainly involved that I can quarantee.Ever since I got T and H I've noticed my brain doesn't work like it use to,controlling my thoughts and concentrating have become problems when they never were before.Its not depression or anything like that,it's rather hard to explain but when I get stressed I just can't control my thoughts anymore,I can feel my brain going crazy causing me to twitch and no matter how hard I try I can't control it.

 

[Mricha37]

That's called PTSD. I don't believe tinnitus effects your CNS in the way you're thinking. I got tinnitus 8 years ago. Since then I've gotten a degree in finance, started 2 construction businesses, ride motorcycles, drive a lifted straight piped diesel truck, and go to concerts at my church.

The only time my CNS goes crazy is when I get a permanent spike, which hasn't happened in 4 years until a few weeks ago. Takes me a few months to get back on that horse but I climb out and keep on chugging. It's not the T that holds me back, it's the sound sensitivity. Argh what a pita!

(P.s.) for reference, my T is so loud I hear it while riding my motorcycle.

 

[Vinnitus]

It's all about your brains processing. The nerve fibers involved are what allow sound to be processed. There are two types of nerve fibers involved that sprout out from what are called spiral ganglion neurons. These two nerves can be termed as "in-going" and "out-going". The more "out-going" nerve fibers or logical processing nerve fibers you have, the less the brain will rely on trying to still hear with its damaged "in-going" nerve fibers/spiral ganglion neurons. The brain can use its plasticity to try and repair the peripheral nervous system, but it can't repair the central nervous system. You therefore have ringing which will always be there if damaged almost completely or even completely.

I believe those times where your hearing goes out for a few seconds or more is when your brain sends out "out-going" nerve fibers in attempt to repair itself. As they attach to any sort of sensory hair cell, you get the loud ringing and strange change in your hearing.

Interesting thoughts. Maybe this can explain why for some people the ringing ceases after a while if their damage is only of peripheral nature. Maybe their nerve fibers connect in the right way, compared to the people who don't have their fibers connecting in the right way and consequently don't improve?

I read the PNS (peripheral nervous system) can recover itself over time to some extend. If I'm not wrong, the auditory nerve is not part of the CNS (central nervous system) but part of the PNS. This would mean some recovery can take place, maybe in the way like described above, but maybe its a matter of chance if this recovery happens in the right way (the nerve fibers connect in the right way). This would also explain why "fleeting tinnitus" appears more prevalent when there's some kind of hearing damage... It could be the brain trying to make new connections to the peripheral equipment (cochlea) and either succeeding in it or failing.

 

[tomytl]

Hi,
there is a new player in town. It's founded by one of the leading inner ear researcher in Switzerland.
http://www.strekin.com/