Inner Ear Hair Cell Regeneration — Maybe We Can Know More

[weab00]

I am getting quite interested in SPI-1005 as well now. It may be out sooner than FX-322 and looks like it could help some of the symptoms of noxacusis especially if cochlea inflammation has anything to do with it. I'm not sure it could do anything with the loudness part of hyperacusis because I'd say that is down to cochlea physical damage, but if the consequential reaction to the noxious sound is to generate cochlear inflammation that then leads to the delayed pain then it could well bring that under control. I'm thinking that if it was taken when a setback was anticipated it could stop it in its tracks. (In the same way someone might very quickly be given predisone for sudden hearing loss).

If it does come out first, it might be good in the meantime while we wait for FX-322. Whether it would be something you could obtain and use 'as needed' would be another thing.

Interesting. Weird that there doesn't seem to be nearly as much buzz about that on these forums. Maybe that's the nature of bandwagons. What is the timeline for SPI-1005 looking like as of now?

 

[tommyd87]

Interesting. Weird that there doesn't seem to be nearly as much buzz about that on these forums. Maybe that's the nature of bandwagons. What is the timeline for SPI-1005 looking like as of now?

SPI-1005 has been a bit all over the place with release estimates. Currently I believe it is in some stage of the clinical trials, however it has been a bit all over the place because it has actually had other indications added to the clinical trial too, such as COVID-19.

 

[100Hz]

Interesting. Weird that there doesn't seem to be nearly as much buzz about that on these forums. Maybe that's the nature of bandwagons. What is the timeline for SPI-1005 looking like as of now?

It looks like its in phase 3 for menieres.

I actually wonder if OTO-104 could help some forms of cochlear inflammation as well and be used off label for it (would love to see it studied for it). That drug should be out and available to the public around next fall, which would make it the first available.

Thanks. I forgot about that one. It's Otividex right? Do you think they are very similar drugs?

 

[FGG]

It looks like its in phase 3 for menieres.

View attachment 40732

Thanks. I forgot about that one. It's Otividex right? Do you think they are very similar drugs?

View attachment 40733

Otividex is a long acting, extended release steroid (Dexamethasone) in a hydrogel for much better sustained dosing and penetrance. They aren't similar drugs other than both being anti-inflammatory.

Sound Pharmaceutical's drug (Ebselen) seems to be better for neuroinflammation than Dexamethasone. Specifically, it can help address the glutamate problem:

"Ebselen may be neuroprotective due to its ability to neutralize free radicals upon NMDA receptor activation thus, reducing lipoperoxidation mediated by glutamate-induced excitotoxicity."

https://pubchem.ncbi.nlm.nih.gov/compound/Ebselen

Otividex is being tested for and appears very effective for the "vertigo attacks" in Meniere's which are caused by hydrops in the ear (essentially pressure and volume changes). The general effects that corticosteroids have on inflammation is that they reduces the volume of inflammation and decrease the migration of inflammatory cells into the inflamed area.

Most people here will benefit much more from Sound Pharmaceutical's drug but I think there could be some effect from Otividex for many people and a much larger effect for those with an ongoing primary inflammatory cause or contributor (autoimmune disease for instance).

As others have pointed out though, Sound Pharmaceuticals may have a reason for rushed approval of their drug:

https://www.technologynetworks.com/...-weapon-against-key-coronavirus-enzyme-338631

 

[100Hz]

@FGG

I read your link and then did some more searches on Ebselen. Am I reading it correctly that this is already being used by doctors to treat bipolar and hearing loss? I'm a bit confused, is Sound Pharmaceuticals reformulating or doing anything different with it for its acute NIHL and Meniere's trials and if not, what's stopping it being used off label already?

https://www.medicalnewstoday.com/ar...drug-shows-promise-and-other-hopeful-findings

 

[FGG]

I have come across an additional mechanism of action for Ebselen (yay insomnia).

It appears that Ebselen also has voltage dependent calcium channel blocking activity. This explains why it might be especially useful as another "bomb blast pill", which they are recruiting for now.

Apparently, with acute ototoxic or noise exposure the neuro excitability contributes to an influx of calcium ions into the OHC that is large enough to overwhelm the buffering. This can damage the mitochondria and, ultimately, the cell. So, the theory goes, if you can block the influx and attenuate it, you can prevent permanent damage.

This goes into more detail about calcium's role in acute hearing damage:

Tonotopy in calcium homeostasis and vulnerability of cochlear hair cells

Anyway, this does make me wonder about side effects in certain people. For example, Amlodipine blocks similar channels and lowers blood pressure. So if someone already had hypotension or were already on that drug (not sure how much cross reactivity there is) maybe there could be excessive hypotension, for instance or a bradycardia (which is uncommon with Amlodipine and reversible when stopped). The blood pressure / vasodilation effects also might help blood flow in the ear (which is is an additional reason it might help Meniere's).

The drug (Ebselen) has thus far had a good safety profile in phases 1 and 2 of the Meniere's study but I would wonder about certain cardiovascular conditions.

If only there were a good way to determine how much inflammation someone had in more chronic cases (acutely I would assume everyone has a big inflammatory component), they would know how much they could (or not) benefit from this. But if the safety data holds up, I think it would be absolutely worth a try to reduce whatever percentage is inflammatory and if it was relatively negligible, discontinue to concentrate on structural damage.

Incidentally, Sound Pharmaceuticals published an aminoglycoside study less than a week ago, but I will stick that in the Sound Pharmaceuticals thread.

 

[GBB]

You will never have 100% guarantee that a treatment works. Even if there are effective treatments in the near future there will always be a risk you will not be helped by it, tinnitus is too subjective and too complex for a "one pill fits all" solution.

I've spent the equivalent of 8,000 USD on various treatments and drugs and achieved only around 20% reduction in tinnitus volume but consider myself lucky because of that.

What actually worked for you?

 

[FGG]

@FGG

I read your link and then did some more searches on Ebselen. Am I reading it correctly that this is already being used by doctors to treat bipolar and hearing loss? I'm a bit confused, is Sound Pharmaceuticals reformulating or doing anything different with it for its acute NIHL and Meniere's trials and if not, what's stopping it being used off label already?

https://www.medicalnewstoday.com/ar...drug-shows-promise-and-other-hopeful-findings

As far as I know, it's being researched for bipolar. It's not been approved and marketed for it.

Unless it has in another country?

 

[tommyd87]

You will never have 100% guarantee that a treatment works. Even if there are effective treatments in the near future there will always be a risk you will not be helped by it, tinnitus is too subjective and too complex for a "one pill fits all" solution.

I've spent the equivalent of 8,000 USD on various treatments and drugs and achieved only around 20% reduction in tinnitus volume but consider myself lucky because of that.

This tends to be true, although I believe that the treatments that are being investigated now are actually going to have higher chances of success. I believe this because they try to actually treat the underlying causes.

 

[serendipity1996]

Some recent research has emerged that may have implications for pain hyperacusis, investigating the interaction of auditory and pain pathways.

"Finally, we tested the hypothesis that hearing loss could alter pain sensitivity by exposing rats to an intense noise leading to hearing loss. Three and four weeks after the noise exposure, pain sensitivity significantly increased. To our knowledge, these results show for the first time that noise-induced hearing loss can lead to increased thermal pain sensitivity."

"Taken together, our results suggest that auditory and pain pathways interact in ways that depend on intensity, hearing loss, and opioid pain signaling, data that may be relevant to better understanding pain hyperacusis. "

https://hearinghealthfoundation.org...the-interaction-of-auditory-and-pain-pathways

 

[Lucifer]

Some recent research has emerged that may have implications for pain hyperacusis, investigating the interaction of auditory and pain pathways.

"Finally, we tested the hypothesis that hearing loss could alter pain sensitivity by exposing rats to an intense noise leading to hearing loss. Three and four weeks after the noise exposure, pain sensitivity significantly increased. To our knowledge, these results show for the first time that noise-induced hearing loss can lead to increased thermal pain sensitivity."

"Taken together, our results suggest that auditory and pain pathways interact in ways that depend on intensity, hearing loss, and opioid pain signaling, data that may be relevant to better understanding pain hyperacusis. "

https://hearinghealthfoundation.org...the-interaction-of-auditory-and-pain-pathways

I do hope the theory of the OHCs causing pain hyperacusis is true and that once FX-322 comes out it will help our pain hyperacusis and we can get back to our daily lives again with the exception of protecting our ears when we are exposed to loud noises.

I can't see what else could be causing pain and loudness hyperacusis other than OHCs, IHCs or synapses. It has to be one of these 3.

 

[serendipity1996]

This article is from November 2019 but it shares some exciting research developments which are new to me - it's about the Fuchs' lab at Johns Hopkins. There's discussion about modifying the efferent neurons which regulate sound sensitivity, potentially using gene therapy.

"Activated by sound, efferent neurons provide negative feedback from the brain to regulate the sensitivity of the cochlea, actually protecting the ear from the damaging effects of loud sound," he explains. "When sound gets louder, they produce stronger negative feedback."

Through their research, Fuchs and his team have pinpointed a particular molecule that could be altered to increase the strength of this modulation even more and consequently prevent damage, and they are experimenting with gene therapy to create this change. Another possible tool would be treatments through small-molecule pharmacology."

He also stated at the end that we are 'on the cusp' of applying this to real-world problems.

https://giving.jhu.edu/story/Paul-Fuchs

 

[GBB]

This article is from November 2019 but it shares some exciting research developments which are new to me - it's about the Fuchs' lab at Johns Hopkins. There's discussion about modifying the efferent neurons which regulate sound sensitivity, potentially using gene therapy.

"Activated by sound, efferent neurons provide negative feedback from the brain to regulate the sensitivity of the cochlea, actually protecting the ear from the damaging effects of loud sound," he explains. "When sound gets louder, they produce stronger negative feedback."

Through their research, Fuchs and his team have pinpointed a particular molecule that could be altered to increase the strength of this modulation even more and consequently prevent damage, and they are experimenting with gene therapy to create this change. Another possible tool would be treatments through small-molecule pharmacology."

He also stated at the end that we are 'on the cusp' of applying this to real-world problems.

https://giving.jhu.edu/story/Paul-Fuchs

So this is about preempting damage in the first place, if I understand correctly?

 

[Aaron91]

This article is from November 2019 but it shares some exciting research developments which are new to me - it's about the Fuchs' lab at Johns Hopkins. There's discussion about modifying the efferent neurons which regulate sound sensitivity, potentially using gene therapy.

"Activated by sound, efferent neurons provide negative feedback from the brain to regulate the sensitivity of the cochlea, actually protecting the ear from the damaging effects of loud sound," he explains. "When sound gets louder, they produce stronger negative feedback."

Through their research, Fuchs and his team have pinpointed a particular molecule that could be altered to increase the strength of this modulation even more and consequently prevent damage, and they are experimenting with gene therapy to create this change. Another possible tool would be treatments through small-molecule pharmacology."

He also stated at the end that we are 'on the cusp' of applying this to real-world problems.

https://giving.jhu.edu/story/Paul-Fuchs

It seems like the main point being driven on the website is that this discovery could help in preventing damage through gene therapy - i.e. if one is exposed to an abnormally loud sound, one doesn't experience hearing damage. I don't understand why one would pursue something like this as a point of research/interest though. One can never know when they might be exposed to acoustic trauma (other than soldiers, perhaps), but for all other relevant industries, surely ear protection is the way to go? If anything, such a drug could give people a false sense of security and not wear protection at all. Any thoughts on why they are pursuing this?

My BIG takeaway from this though is that the efferent neurons regulate the sensitivity of the cochlea. This is news to me, but what does it mean? Do they regulate how sensitive the cochlea is to damage, or how do they regulate dB levels when it comes to perception of sound? If it's the latter, does that mean that they've essentially developed a potential pathology model for understanding loudness hyperacusis - namely, misfiring efferent neurons leading to a hypersensitive cochlea?

Edit: it's occurred to me that the gene therapy thing could be a potential market for people who rely heavily on their hearing for their work - sound engineers, musicians, call-centre workers - but I can't imagine this market being big enough to warrant such research unless there are wider implications here.

 

[weab00]

This article is from November 2019 but it shares some exciting research developments which are new to me - it's about the Fuchs' lab at Johns Hopkins. There's discussion about modifying the efferent neurons which regulate sound sensitivity, potentially using gene therapy.

"Activated by sound, efferent neurons provide negative feedback from the brain to regulate the sensitivity of the cochlea, actually protecting the ear from the damaging effects of loud sound," he explains. "When sound gets louder, they produce stronger negative feedback."

Through their research, Fuchs and his team have pinpointed a particular molecule that could be altered to increase the strength of this modulation even more and consequently prevent damage, and they are experimenting with gene therapy to create this change. Another possible tool would be treatments through small-molecule pharmacology."

He also stated at the end that we are 'on the cusp' of applying this to real-world problems.

https://giving.jhu.edu/story/Paul-Fuchs

Isn't the model for noxacusis that the OHCs, which are normally only activated for people at noxiously loud/damaging noises (120 dB+) are hyperactive for people with noxacusis, which of course are connected to the pain efferents and the brain/ear are acting out of self-defense.

 

[Lucifer]

Isn't the model for noxacusis that the OHCs, which are normally only activated for people at noxiously loud/damaging noises (120 dB+) are hyperactive for people with noxacusis, which of course are connected to the pain efferents and the brain/ear are acting out of self-defense.

That is the current theory. We believe that the OHCs are causing pain hyperacusis. Since FX-322 does restore OHCs, there is a good chance that we will get some relief from pain hyperacusis.

What I want to know is when do you start noticing improvements after having FX-322? Do you believe you will notice a difference the next day or would it be weeks or months later?

 

[weab00]

That is the current theory. We believe that the OHCs are causing pain hyperacusis. Since FX-322 does restore OHCs, there is a good chance that we will get some relief from pain hyperacusis.

What I want to know is when do you start noticing improvements after having FX-322? Do you believe you will notice a difference the next day or would it be weeks or months later?

Does the current theory account for synapse loss as well?

I asked the same question in the FX-322 thread but didn't get a clear answer since no one is 100% sure. I know that people with temporary tinnitus due to infections or ear wax sometimes don't experience full fading for up to a year, so I wonder if it would be a similar case. Although, it stands to reason that the sound would stop as soon as all input was restored much like how unplugging a speaker immediately ceases the electrical flow.

Anyone know how long FX-322 takes to act on the hair cells?

@FGG?

 

[Diesel]

That is the current theory. We believe that the OHCs are causing pain hyperacusis. Since FX-322 does restore OHCs, there is a good chance that we will get some relief from pain hyperacusis.

What I want to know is when do you start noticing improvements after having FX-322? Do you believe you will notice a difference the next day or would it be weeks or months later?

Based on the quantifiable improvements from the Phase1/2, it seems like about 2 weeks from injection.

 

[Lucifer]

Based on the quantifiable improvements from the Phase1/2, it seems like about 2 weeks from injection.

Maybe those with pain hyperacusis will notice improvement once the hair cells start the regrowing process. It may be possible to notice improvements in pain hyperacusis the very next day after getting a FX-322 shot.

 

[weab00]

Maybe those with pain hyperacusis will notice improvement once the hair cells start the regrowing process. It may be possible to notice improvements in pain hyperacusis the very next day after getting a FX-322 shot.

I agree. And I think hyperacusis is most likely a simpler issue than tinnitus because it mainly boils down to OHCs and inflammation.

 

[frpp]

Maybe those with pain hyperacusis will notice improvement once the hair cells start the regrowing process. It may be possible to notice improvements in pain hyperacusis the very next day after getting a FX-322 shot.

Hoping so man. I have hyperacusis AND TTTS and I'm hoping that as the hearing comes back, it stops the spasms (which in theory should also give some conductivity back as well).

 

[weab00]

Hoping so man. I have hyperacusis AND TTTS and I'm hoping that as the hearing comes back, it stops the spasms (which in theory should also give some conductivity back as well).

Just imagine if regenerative medicine gave us our lives back. We should all write a book. And meet up at a bar or something.

 

[Lucifer]

Just imagine if regenerative medicine gave us our lives back. We should all write a book. And meet up at a bar or something.

I'll be definitely keen to meet some of you once I get my life back. If I do recover I want to be able to raise awareness about hyperacusis and tinnitus by making a YouTube video one day.

 

[tommyd87]

Just imagine if regenerative medicine gave us our lives back. We should all write a book. And meet up at a bar or something.

It will. Stay completely confident.

 

[serendipity1996]

https://www.mdpi.com/2076-3425/10/10/756/htm

New journal article - Perspectives on Human Hearing Loss, Cochlear Regeneration, and the Potential for Hearing Restoration Therapies.

 

[weab00]

https://www.mdpi.com/2076-3425/10/10/756/htm

New journal article - Perspectives on Human Hearing Loss, Cochlear Regeneration, and the Potential for Hearing Restoration Therapies.

These data demonstrate that while HC loss is sufficient to drive hearing loss [137], it is only one mechanism that permanently increases thresholds after noise damage. Other mechanisms could include HC intrinsic damage, strial and supporting cell damage, changes in efferent function, and changes in spiral ganglion neuron responses.

Meaning that HC/synapse regeneration may not be enough?

 

[FGG]

Meaning that HC/synapse regeneration may not be enough?

I read the whole thing and the "changes in spiral ganglion response" appear to refer to losses of "spiral ganglion synapses", aka "cochlear synaptopathy.

Strial inflammation can cause acute noise induced threshold changes in some people who get secondary endolymphatic hydrops from it (this usually shows up as a fluctuating hearing loss). Secondary hydrops is something an ENT would usually suspect though and it generally effects the lower frequencies.

As far as support cell damage, I was told by one researcher that any cause that results in profound (over 90 dB) SNHL loss results in support cell damage at that frequency so I guess it wouldn't be surprising for noise to be on that list.

For most people though, hair cells and synapses are the main issue.

 

[Diesel]

Meaning that HC/synapse regeneration may not be enough?

No, meaning there are underlying causes for broadly defined "hearing loss" besides just hair cell/synapse loss.

This research article and other recent ones seem to generally agree that SNHL/NIHL share an underlying cause: cochlear hair cell damage/death.

The coverage on progenitor cell regeneration acknowledges the work being done by Will McLean with FX-322, which is promising.

 

[tommyd87]

I read the whole thing and the "changes in spiral ganglion response" appear to refer to losses of "spiral ganglion synapses", aka "cochlear synaptopathy.

Strial inflammation can cause acute noise induced threshold changes in some people who get secondary endolymphatic hydrops from it (this usually shows up as a fluctuating hearing loss). Secondary hydrops is something an ENT would usually suspect though and it generally effects the lower frequencies.

As far as support cell damage, I was told by one researcher that any cause that results in profound (over 90 dB) SNHL loss results in support cell damage at that frequency so I guess it wouldn't be surprising for noise to be on that list.

For most people though, hair cells and synapses are the main issue.

No, meaning there are underlying causes for broadly defined "hearing loss" besides just hair cell/synapse loss.

This research article and other recent ones seem to generally agree that SNHL/NIHL share an underlying cause: cochlear hair cell damage/death.

The coverage on progenitor cell regeneration acknowledges the work being done by Will McLean with FX-322, which is promising.

Thanks for clarifying. I thought that the article was referring to everything for completeness only. Overall I feel that research largely points to hair cell/synapse issues.

 

[frpp]

My thoughts on the timeline for the next few years.

2021: Good news and trial results. FX-322, OTO-413, and SPI-1005 (might even be released by then).

2022: More results/good news. Possibly some news from Hough Ear Institute regarding their pill and maybe Dr. Shore's device will be released (have my doubts though).

2023: OTO-413 should be released, SPI-1005 will definitely be released if not already released, all Trobalt variants should be out or really close. FX-322 should be either done or close to done with phase 3 (provided they don't have a phase 2b) and possibly available for compassionate use.

2024: Everything released or very close to being released.

2025: Freedom for almost all of us.