Inner Ear Hair Cell Regeneration — Maybe We Can Know More

I need to take a break from Tinnitus Talk lol. The seed of doubt this study has planted in our minds for regenerative medicine is stressful. I would be pissed if I spent 10s of thousands on these drugs and it didn't do anything for noxacusis, although hopefully type II pain fibers can be desensitized once the cochlea is regenerated. Guess we'll find out soon enough.

 

Yeah, it's just speculation - sort of piqued by this excerpt from the 2015 study from the same authors: "Alterations in the relative contributions of type II and type I afferents’ activity after hearing loss might contribute to both tinnitus and noxacusis."

So maybe the increase in silent ribbon synapses, which increase in number after acoustic trauma, is a sort of maladaptive plasticity in response to hearing loss? Who knows though.

Unmyelinated type II afferent neurons report cochlear damage

And yeah, I'm wondering how ATP fits into all of this - I think the next thing we need is an animal model of how fresh acoustic traumas affect a damaged cochlea.

It's interesting that in the latest paper on the OHC ribbon synapses, mentioned at the end that "The model presented assumes that OHCs retain normal sensitivity." So I'm guessing they are saying that their model assumes that there is no sensitisation occurring after damage? Not quite sure, what is your reading of it?

 

Personally, I think we should consider what @FGG mentioned about the difference between human adults and neonatal rats; the myelination makes a huge difference imo.

 

I'm thinking if these findings could potentially amplify my fears of FX-322 fixing my hearing strength while not improving my hyperacusis, but actually making it worse because of all the new amplification happening from the newly created hair cells and input to the brain.

Then again, I'm sure at least a few of the 100+ patients they've had on the trials so far must have had some level/form of hyperacusis, and if it went completely through the roof for them, it would have been flagged as a negative side effect / safety issue. Or?

 

Still planning to hiatus more and drop by less for a bit, but I did want to comment on this reply to make my original post more clear.

The myelination difference is not in the OHC afferents BUT it still illustrates the point I was making with the differences in the auditory systems of rodents and humans.

Liberman originally described a degradation of the SGN after injury to synapses/hair cells because in rodents that happens over weeks to months. In humans, based on autopsies, that happens from decades to never (Liberman now says "many years" in recent papers). In fact people in their 80s who have been deaf most of their life, still have normal SGNs often. This is why cochlear implants don't have to be given right away but if they were used on rodents, they would need to be.

Anyway... I suspect researchers will now do autopsy studies specifically in people with acute noxacusis and those who improved over time to see if the extra afferent synapses are a issue once they get enough donated for research post mortem cochleas.

And if they aren't present both acutely and chronically (then rodents are different than people here). If they are acutely but not chronically, then the body decreases them on its own after time. I suspect if OHC afferent synaptogensis occurs in people, the later happens because a lot of people with noxacusis improve quite a lot over time.

I can't find it now but someone also asked what ATP has to do with it. The (over)stimulation at the purine receptors might be the impetus for these changes (again if they occur in people at all).

But we are back to the same question, does the sensitization resolve with a more normalized ear (in terms of neuroexcitability, structure etc)? I think it very well could since noxacusis improves in many people with time.

Logging off for a bit again. Been frequenting the research section for more than a year. Just tired.

 

I feel you - I don't think this study necessarily spells doom for regenerative medicine though. I'm just trying to keep in mind the bigger picture - that noxacusis ultimately is a consequence of an underlying problem - noise-induced hearing loss. Hopefully this paper will be presented an at upcoming conference or something so we can put it into context and what it means for hyperacusis sufferers.

 

I believe I'm dead before 2025. Any chance you could adjust the timeline?

 

Yeh I just had another look at that. I think what's confusing now is, is this type II synapse increase upon noise trauma the actual act of sensitization? Or is sensitization something yet again different?

The part about OHCs retaining normal sensitivity would suggest to me that that they don't yet suffer synapse disconnection.

Then it goes on to say that type IIs are excited by and could become sensitized by ATP.

So is it like a 2 point attack on the type IIs? First they become hyper-connected to the OHC with the new synapses, and then they become sensitized by a flood of ATP? Or a combination of the 2 that causes sensitization.

'Here, we have examined OHC ribbon synapses 7 days after noise exposure. The model presented assumes that OHCs retain normal sensitivity. Also, it is known that acute tissue damage initiates spreading waves of activity among supporting cells via the release of ATP. Type II afferents are excited by ATP, and could become sensitized in the presence of ATP as is observed in somatic nociceptors. Tissue damage caused by acoustic trauma also induces a prolonged inflammatory response.'

I think there's a couple of pieces of research that can be linked together quite well in a new experiment. First the research with the deaf mice that still showed type II sensitization due to noise trauma (I'm not sure if anyone ever uncovered the paper for this but its mentioned here), then there's the latest one that you found on the extra ribbon synapses here. I'll spend some time reading them over the next couple of days to see how they could collaborated together in a possible 'setback' experiment.

 

The Anoveros finding is really interesting -one thing I am confused about, however, is that they found that the Type 2s still respond to noxious noise even if they're deaf. How do they define noxious noise? Since we know that even in a healthy cochlea the type 2s will show activity once you hit 120 dB+. So is that study demonstrating how type 2s respond in a damaged cochlea? If so that's a really interesting find.
I'm not sure if I made any sense.

 

I just feel so sad this whole thing happened to me.

 

Not sure. Could they know this already from a previous study where this level damaged OHC's?

I'd like to know how if these studies could actually determine that pain was being felt. If it can be proven that type II's gets sensitized and respond to ATP, even grow extra synapses etc. I'm guessing that this happens for lots of people that might not necessarily get pain.

You see quotes such as 'Type II afferent sensitization could be attributed to noxacusis" etc. but I don't think I've ever seen a study that proves that pain is being felt due to these particular damages.

 

This is also something I wonder especially given how common hearing damage is yet noxacusis is frightfully rare in comparison.

Like, there are many people who have far more severe hearing loss than we do, or decades of excessive noise exposure. Surely their cochleas would show a greater level of damage than ours? We know ATP is involved in pain though but then if ATP is released upon cell death, how come there are so many people with bog-standard hearing loss and no noxacusis?

This again brings me back to wondering if it's down to genetic susceptibility and stuff like gene expression differing in the Type IIs for different people.

 

I wonder if this is what Hough Ear Institute is using as a method of measuring tinnitus? (I believe it was Hough Ear Institute but correct me if I’m wrong).

Published today. Loving all these new research papers coming out!

Objective measurement of tinnitus using functional near-infrared spectroscopy and machine learning

Quote from the abstract:

“Naïve Bayes classifiers were able to classify patients with tinnitus from controls with an accuracy of 78.3%. An accuracy of 87.32% was achieved using Neural Networks to differentiate patients with slight/ mild versus moderate/ severe tinnitus. Our findings show the feasibility of using fNIRS and machine learning to develop an objective measure of tinnitus”

 

I wish they could come up with some injectable substance like Gentamicin that specifically targets type 2 afferents.

 

I also had a similar question some time ago. I'd need to find the study, but it had something to do with mice exhibiting some very obvious behaviours which are known in lab research to be associated with mice experiencing pain, and these knock out mice were exhibiting those behaviours in that noxacusis study. Now you could say that perhaps something else was triggering some other kind of pain upon exposure to noxious sound, but that seems quite a stretch to me.

 

Go to the French hyperacusis Wikipedia page on Chrome and translate it to English. This article is one of the best summaries of the condition and its mechanisms I've yet to see.

 

An upcoming webinar on the emerging hearing medicines landscape will be held this Thursday (4pm GMT) - this is the 3rd webinar in their series. I managed to catch the first one, not caught up on the second one yet. This webinar will be on 'How and Why to Commercialise Your Hearing Research.'

You can register to view it here:

https://go.md.catapult.org.uk/how-why-commercialise-hearing-research/

The previous webinars are available here:

https://md.catapult.org.uk/syndicat...g-hearing-medicines-landscape-webinar-series/

 

The final webinar in 'The Emerging Hearing Medicines Landscape' series will be taking place this Tuesday, 8 December. This one is on The Challenges and Opportunities for Emerging Cell and Gene Therapy Approaches to Address Hearing Loss.

It may be of interest as Professor Marcelo Rivolta, who founded Rinri Therapeutics, will be speaking. Hopefully we will get some more information about what he and his company have been up to!

https://go.md.catapult.org.uk/emerging-approaches-address-hearing-loss/

Also, these webinars are recorded and made available for watching later.

 

A new article demonstrating that Trk agonist drugs can regenerate cochlear synapses and could potentially be used to treat hidden hearing loss. Some of the authors of this paper include Albert Edge and Sharon Kujawa (who has collaborated extensively with Charles Liberman and together they discovered hidden hearing loss).

https://insight.jci.org/articles/view/142572

 

Things seem to be getting more promising with research.

 

Interesting that Amitriptyline is one of the drugs they infused IT.

Some people here have reported success with it, while it has made others worse or no change.

Efficacy of amitriptyline in the treatment of subjective tinnitus

Of course it has strong neurotransmitter effects when taken systemically (which is of course the primary reason it is taken). I wonder if IT injections would prevent some of these effects.

 

To add to this, it looks like BDNF is a TRK agonist and Otonomy is way ahead of the game (this is their study):

BDNF, NT-3 and Trk receptor agonist monoclonal antibodies promote neuron survival, neurite extension, and synapse restoration in rat cochlea ex vivo models relevant for hidden hearing loss

 

Great find and good news because in true scientific spirit this is another team replicating another team's results (Otonomy's), which is exactly what we need.

It seems that in this study though NT-3 was more critical than the BDNF but maybe I'm reading wrong. Either way it appears both are needed. I was taking high dose cocoa and turmeric a couple of months ago for 2 weeks as I read they were good for BDNF, and I must say that although it didn't do much for my ears at the time I did feel healthier and had more positive energy. I've since read that to get a noticeable benefit/increase in BDNF from cocoa it needs to be taken every day for 12 weeks straight. I'm thinking again of trying and curcumin it but adding Astaxanthin and Lion's Mane to the mix, which I've been taking but intermittently. Add some intermittent fasting, meditation and HIT exercise (ears permitting) and hopefully one can accelerate the BDNF production even more. I think it's worth a shot.

Has anyone on here done anything similar before?

 

I really doubt you can do it without a direct injection but worth a shot.

 

7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders

Nootropics Depot: 4’-DMA-7,8-DHF Capsules | 8mg | 4'-DMA-7,8-Dihydroxyflavone

 

Very interesting. Has anyone ordered or tried this before?

 

I haven’t but I do want to point out this is the supplier that sells me my Phenibut and they’ve been pretty reliable.

 

Just came across this on the Hyperacusis Research Facebook page - the Johns Hopkins Department of Otolaryngology-Head and Neck Surgery has received a $15 million gift to support their research. Paul Fuchs is also quoted in this article, on how this gift will help (although he doesn't mention hyperacusis specifically here, this is definitely encouraging.

Johns Hopkins Department of Otolaryngology-Head and Neck Surgery receives $15M contribution

 

This study was supposed to be finished in early February 2020. Since then, there has been no update and there have been no further news about STR001. Because of that I wrote an e-mail to Strekin AG whether they could provide me with some information about the current status of STR001. It has been 10 days and I haven't received an answer.

I now have Googled Strekin AG again and found out that they filed for bankruptcy in August 2020. We can assume that this is because STR001 failed (there are still no results to be found).

I guess that's just too bad. But on the positive side, if 90% of new drugs fail to get through all trials it better be drugs like these rather than FX-322 or OTO-413.

 

This just showed up in Google News.

Protein Discovery in the Development of New Hearing Hair Cells Could Lead to Treatments for Hearing Loss

Seems like early research, but still intriguing.