Inner Ear Hair Cell Regeneration — Maybe We Can Know More

Some exciting research about sensory hearing cells regeneration:

https://www.sciencedaily.com/releases/2020/07/200701134242.htm

 

I hope they rush

 

And further in the future, it could become possible to directly reprogram supporting cells in the inner ear of a deafened individual, as a way to restore hearing.

Isn't this what FX-322 already is supposed to be doing? Seems like these researchers are a bit behind.

 

Yeah lol it's so weird I see so many of these papers mention hearing regeneration like it's way off in the distant future or something. Seems kind of incongruous given we have the likes of FX-322 in phase 2.

 

I don’t think FX-322 actually directly ‘reprograms’ the hair cells. Frequency and its people are from the science community, so I take it scientists know about it.

 

Frequency induces a subset of support cells that are progenitor cells (LGR5+) to divide into a hair cell and a replacement for itself (support cell).

 

New article (1 July) on the Development of Nanoparticle Drug-Delivery Systems for the Inner Ear

https://www.futuremedicine.com/doi/10.2217/nnm-2020-0198

 

I don't think this has been posted but apologies if it has and I missed it.

More work from the ubiquitous Albert Edge.

https://stemcellsportal.com/article...neural-regeneration-and-hearing-loss-reversal

 

This isn't technically latest news (Sept 2019) but an interesting study nonetheless.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759357/

"Further experiments showed that instead of acting like amplifiers, outer hair cells seem to monitor the loudness of sound and adjust the level accordingly before passing the vibrations on to the inner hair cells."

Perhaps this could also have something to do with loudness hyperacusis?

 

FX-322 is a propriety drug. They certainly won't share their actual drug info and data and we don't know if FX-322 is even effective. Sure they passed Phase 1 but Phase 1 is focused solely on human safety and not efficacy. Phase 2 is when they prove if the drug has any definitive and positive effect with double blind, placebo-controlled, and etc for a small group of people. For all we know, and I don't want to be a downer, FX-322 can make claims all they want but could just be another fluke. There have been so many flukes throughout the years it's quite disheartening.

So kudos to other researchers for finding different drugs to induce hair cell recovery on the cochlea. Perhaps these different drugs are better or actually works on humans, rather than just animals.

 

This could also help with pain hyperacusis as well. I have a theory that those with loudness hyperacusis may also have pain hyperacusis as well but they only experience pain at a higher decibel. But also their tolerance to sound will be below 120 decibel so they will experience pain at lower decibel levels compared to normal people without hyperacusis but still loudness hyperacusis will have better sound tolerance than people who experience pain hyperacusis.

That’s why I believe that fixing the OHCs could help with both pain and loudness hyperacusis.

 

Doubling word scores is unheard of. Definitely not a fluke.

 

So Fx-322 has had phase 1/2 results showing improvement on the 8khz range of 10 decibels. Further, they have shown on human cochlea that they are regenerating the hair cells ex vivo. That's why people are so hyped about fx-322. The concern I have is that if fx-322 works, which I think it will, it only works on the ranges that you have support cells on. Flat epithelials, and it can't help unless it turns out kicking off the signal for replicating with the support cells causes the body to begin to regenerate support cells in the other areas too. Which if it does, resolves most issues of the ear. We don't really expect that, though.

 

@WillBeNimble I tried searching for actual research articles and data, do you have any link to them? Articles that describe how they measure cochlea hair cell recovery as hard data in human because as far as I know the current imaging techniques aren't good enough to just scan the ear to look at cellular level resolution for hair cells. They usually have to dissect to look at the cochlea.

I'm not trying to be a downer and I pray something will work, but I'm confused how they can show definitively at the cell level in live humans.

The only thing I can find are their press releases stating how their drug work but never published any methodologies and hard data results (not just claims and summaries).

 

In addition to the reply below, you should check out their recent interview with Tinnitus Talk Podcast where they discuss their Phase 1/2 results more and the very stringent measures they took to ensure placebo-controlled double-blind studies.

Another thing that stood out to me was they had several patients whose word scores in fact doubled - they said that they have shown these results to the world's experts in the field who said that this is completely new, nobody has ever seen ears do this before. Yes, it is still early days and it's prudent to remain cautious but I would say they are far from being a fluke.

 

Yeah, it's interesting because for me at least I definitely also have some degree of loudness hyperacusis. It's not as intrusive as my pain hyperacusis (which has improved but still... it's slow lol) but certain sounds, e.g. a dog barking in an enclosed space sounds like a gunshot! In my case, I also find that my loudness discomfort level isn't necessarily uniform and can vary according to the 'type' of sound e.g. I find that with noise coming from radios, TV etc it doesn't take much for me to reach the threshold where I find it 'too loud' compared to face-to-face talking and walking down a city street which doesn't register as too loud.

It's unfortunate that noxacusis is so poorly understood but at least research has started to pick up. Paul Fuch's theory about how when OHC are damaged it takes less for the type 2 fibers to be activated is pretty compelling. He and his colleagues are continuing work on this etc with animal models so hopefully we will get more insights into this in the not-so-distant future.

 

Have you seen their Germany perilymph analysis study? This demonstrated that the drug successfully reached its destination in the cochlea at a therapeutically active dose.

Improvements in hearing function are measured audiometrically and via tests such as word-in-noise test. There's no way to scan the cochlea and like quantify exactly how many hair cells you've gained/lost in a living human but that's not really clinically significant in the sense that if patients demonstrate audiogram improvements etc it surely function as proof that the drug works. They've also done numerous tests on explanted human cochleas where they observed hearing regeneration with their drug.

 

I also suspect hyperacusis has more to do with a really damaged OHC or batch of OHCs sending overdriven signals to the nerve in the form of loudness or pain. The reason it improves for some is the auditory system adapts to the bunk hair cells to some extent, quieting down the response. This would also explain the loudness discomfort that some feel, the damaged OHC don’t have enough “resolution” to handle a range of normal loudness. This also explains recruitment with hyperacusis, as the damaged or adjacent damaged OHC are overcompensating.

I'm not a scientist, but more normal/new OHC in the damaged area may be enough to silence or replace the underlying cause of hyperacusis.

 

I still really hope that’s the case. I don’t really believe in drugs such as Trobalt to silence the nerve fibres to stop the pain. You need to fix the underlying issues in the ear such as OHCs to fix the problem with hyperacusis.

 

There's definitely been discussion about this so that's food for thought. I've posted this link before I think but, for example, at the 2017 ARO conference hosted by Hyperacusis Research there's a pretty detailed write-up of all the presentations. It's mostly oriented around pain hyperacusis.

https://hyperacusisresearch.org/wp-content/uploads/2017/03/ARO-2017-Technical-Summary.pdf

On pages 7-8 there's some discussion about whether hair-cell regeneration could potentially improve hyperacusis. There's an interesting part where it says this (page 8):

"These strategies may sound various degrees of futuristic, but I wouldn’t be surprised to hear that some of them are farther along than we might think, or that technologies other than these are (or will be!) in development and improve the lives of people with hyperacusis, as suggested by several speakers in a symposium on studying the inner ear via ingenious ‘models’ in vitro (outside the body)."

This makes me wonder whether it would be possible to somehow create a model of a damaged cochlea and pain hyperacusis to see what effect regeneration could have. (My lack of scientific knowledge is probably showing here lol). But it's really interesting that there some presentations on studying how organs respond to changes in the environment.

 

I really wonder what mechanisms are at play in the facial pain that many of us experience as part of pain hyperacusis and whether this will become clearer as more research unfolds. In my case, it's very peculiar as I haven't had prolonged ear pain in months yet I still have facial pain/pressure in my forehead mainly. This is my most distressing and prolonged symptom. It definitely worsens with noise but also seems to flare up of its own accord which worries me. I've wondered if this could be TTTS but I don't really experience any fluttering or ear spasming at all which seem to characterise it.

Jaime Garcia-Anoveros, who's done a lot of research into the possible mechanisms behind pain hyperacusis, did some experiments a few years ago to try and determine what mechanisms are integral to it.
https://hyperacusisresearch.org/an-md-summary-of-the-2016-aro-hyperacusis-symposium/

"They did not find responses to noxious noise in the trigeminal (5th cranial nerve) or vestibular (part of the 8th cranial nerve serving balance) nuclei."

"His conclusion: The response to noxious noise starts in the cochlea—not in middle ear or vestibule, and information about it is transmitted from OHCs via Type II auditory neurons."

I'm not sure if I'm reading this correctly tbh, but this finding seems to suggest that the damage is ultimately stemming from the cochlea and inner ear. So I wonder if the facial symptoms I get are a result of widespread inflammation/referred pain from cochlear damage? My ears still don't feel back to normal but it's odd how I haven't really had proper ear pain for months but the face pain has remained. Granted, it fluctuates wildly. I know that there's still so much we don't really know about hyperacusis. Dr Megan Wood, a researcher in the Fuchs lab, is apparently doing research into cochlear inflammation and type 2 activity on the prolonged pain from sound. I'm just desperate for answers.

 

Yes, probably widespread inflammation. When I first had my injury and the hyperacusis was relentless, I had shooting pains into my jaw and neck. As the hyperacusis got better, those symptoms went away along with them. The source for me was hearing damage. So if the damage is regenerated in some way, it stands to reason the nerves that are getting inflamed may begin to function pre-damage again.

 

Yeah, it seems to be some form of secondary hyperalgesia where surrounding areas get inflamed as a response to cochlear damage. Hopefully if our cochleas get repaired then this maladaptive processing will 'readjust' back to normal. I'd like to think that our bodies are always trying to get better and if we can fix the underlying damage hopefully that will take care of the rest.

 

Dam right Maam! Docs and pharmacists both suck! But there are still some good Docs.

 

Stem cells cam do wonders wherever they are used or whatever kind they are. I know a fair few people who have had them done in other areas such as their leg/knees and it has changed them.

 

Otonomy Announces Exclusive License Agreement with Kyorin for Novel Compound in OTO-6XX Hearing Loss Program

https://pipelinereview.com/index.ph...Compound-in-OTO-6XX-Hearing-Loss-Program.html

 

Good find! They have to be at least reasonably close to filing an IND if they already have a partnership for this drug.

 

It talks about anti-inflammatory and preventing neutrophile migration. How does this generate new hair cells?

 

Sorry I cannot understand what you are talking about and I could not see anything about this on that link.

 

Where did you get that information? It's not in that article nor is there any info on the Otonomy website.