Inner Ear Hair Cell Regeneration — Maybe We Can Know More

Discussion in 'Research News' started by Hopeful, Sep 6, 2013.

    1. Mentos

      Mentos Member Benefactor

      Location:
      Cracow, Poland
      Tinnitus Since:
      03/2015
      Cause of Tinnitus:
      Noise induced, loud rock concert
      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.
       
    2. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      I'd be interested in knowing whether SPI-1005 would be best to take as soon as it is available or at the time of another treatment like when you are getting the injection for a synapse repair for example.
       
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    3. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

      Tinnitus Since:
      01/2019
      Cause of Tinnitus:
      Multi-factorial
      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.
       
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    4. weab00
      Alone

      weab00 Member Benefactor

      Location:
      depression-ville
      Tinnitus Since:
      04/2019
      Cause of Tinnitus:
      noise, whiplash; 08/20 H
      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?
       
    5. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      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.
       
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    6. 100Hz

      100Hz Member Benefactor

      Tinnitus Since:
      2015
      Cause of Tinnitus:
      Noise exposure
      It looks like its in phase 3 for menieres.

      upload_2020-9-24_11-28-1.png
      Thanks. I forgot about that one. It's Otividex right? Do you think they are very similar drugs?

      upload_2020-9-24_11-31-3.png
       
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    7. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

      Tinnitus Since:
      01/2019
      Cause of Tinnitus:
      Multi-factorial
      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
       
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    8. 100Hz

      100Hz Member Benefactor

      Tinnitus Since:
      2015
      Cause of Tinnitus:
      Noise exposure
      @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
       
    9. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

      Tinnitus Since:
      01/2019
      Cause of Tinnitus:
      Multi-factorial
      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.
       
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    10. GBB

      GBB Member

      Location:
      NYC
      Tinnitus Since:
      2020
      Cause of Tinnitus:
      Microsuction / Additional Acoustic Trauma in Close Proximity
      What actually worked for you?
       
    11. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

      Tinnitus Since:
      01/2019
      Cause of Tinnitus:
      Multi-factorial
      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?
       
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    12. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      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.
       
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    13. serendipity1996
      No Mood

      serendipity1996 Member Podcast Patron

      Tinnitus Since:
      2011
      Cause of Tinnitus:
      Unknown but suspect noise-induced
      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
       
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    14. Lucifer

      Lucifer Member Podcast Patron Benefactor

      Tinnitus Since:
      2017
      Cause of Tinnitus:
      Ear Infection
      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.
       
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    15. serendipity1996
      No Mood

      serendipity1996 Member Podcast Patron

      Tinnitus Since:
      2011
      Cause of Tinnitus:
      Unknown but suspect noise-induced
      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
       
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    16. GBB

      GBB Member

      Location:
      NYC
      Tinnitus Since:
      2020
      Cause of Tinnitus:
      Microsuction / Additional Acoustic Trauma in Close Proximity
      So this is about preempting damage in the first place, if I understand correctly?
       
    17. Aaron91

      Aaron91 Member

      Tinnitus Since:
      2007
      Cause of Tinnitus:
      Loud music/headphones/concerts
      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.
       
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    18. weab00
      Alone

      weab00 Member Benefactor

      Location:
      depression-ville
      Tinnitus Since:
      04/2019
      Cause of Tinnitus:
      noise, whiplash; 08/20 H
      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.
       
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    19. Lucifer

      Lucifer Member Podcast Patron Benefactor

      Tinnitus Since:
      2017
      Cause of Tinnitus:
      Ear Infection
      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?
       
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    20. weab00
      Alone

      weab00 Member Benefactor

      Location:
      depression-ville
      Tinnitus Since:
      04/2019
      Cause of Tinnitus:
      noise, whiplash; 08/20 H
      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?
       
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    21. Diesel

      Diesel Member Benefactor

      Location:
      Ohio
      Tinnitus Since:
      1-2019
      Cause of Tinnitus:
      20+ Years of Live Music, Motorcycles, and Power Tools
      Based on the quantifiable improvements from the Phase1/2, it seems like about 2 weeks from injection.
       
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    22. Lucifer

      Lucifer Member Podcast Patron Benefactor

      Tinnitus Since:
      2017
      Cause of Tinnitus:
      Ear Infection
      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.
       
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    23. weab00
      Alone

      weab00 Member Benefactor

      Location:
      depression-ville
      Tinnitus Since:
      04/2019
      Cause of Tinnitus:
      noise, whiplash; 08/20 H
      I agree. And I think hyperacusis is most likely a simpler issue than tinnitus because it mainly boils down to OHCs and inflammation.
       
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    24. frpp

      frpp Member

      Tinnitus Since:
      2010
      Cause of Tinnitus:
      Tmj, Nihl, ototoxic drugs, nerve/ vascular issues
      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).
       
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    25. weab00
      Alone

      weab00 Member Benefactor

      Location:
      depression-ville
      Tinnitus Since:
      04/2019
      Cause of Tinnitus:
      noise, whiplash; 08/20 H
      Just imagine if regenerative medicine gave us our lives back. We should all write a book. And meet up at a bar or something.
       
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    26. Lucifer

      Lucifer Member Podcast Patron Benefactor

      Tinnitus Since:
      2017
      Cause of Tinnitus:
      Ear Infection
      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.
       
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    27. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      It will. Stay completely confident.
       
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    28. serendipity1996
      No Mood

      serendipity1996 Member Podcast Patron

      Tinnitus Since:
      2011
      Cause of Tinnitus:
      Unknown but suspect noise-induced
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    29. weab00
      Alone

      weab00 Member Benefactor

      Location:
      depression-ville
      Tinnitus Since:
      04/2019
      Cause of Tinnitus:
      noise, whiplash; 08/20 H
      Meaning that HC/synapse regeneration may not be enough?
       
    30. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

      Tinnitus Since:
      01/2019
      Cause of Tinnitus:
      Multi-factorial
      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.
       
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