Inner Ear Hair Cell Regeneration — Maybe We Can Know More

https://www.eurekalert.org/pub_releases/2020-07/sfn-hcl071420.php

“Both the hair cells and the stria vascularis, the cellular battery powering them, degrade with age. For 60 years, scientists attributed noise-induced hearing loss to hair cell death and age-related hearing loss to stria vascularis damage. But a new study from Wu et al. proves otherwise: age-related hearing loss in humans stems from hair cell death, not stria vascularis damage.

The research team counted surviving hair cells, auditory nerve fibers, and stria vascularis area in cochlea samples from 120 people and compared the damage to hearing test scores. Hair cell death predicted the severity of hearing loss, while stria vascularis damage did not. This contradicts findings in animal models, where the opposite is true. But animals do not experience the same auditory abuses as humans, which may mean that much of age-related hair cell loss is noise-induced, and therefore avoidable.”

 

At least they are working on inner ear regeneration and not on other research topics the world does not need.

 

That is true. I think that they will succeed in it too, although how long it will take is the question. The thing we should be thankful for is that there's tonnes of work being done in this area currently.

 

I wonder if they have already started a study looking at tinnitus ears as well. Would be nice to have further proof of it being hearing loss so they'll have less reason to treat it as nothing to be worried about.

 

We’ll find out if tinnitus is related to hair cell loss after the FX-322 Phase 2A.

 

Well, true, but I meant as in even "stress" induced tinnitus. You are right though, the FX-322 trial should clear it up.

 

Some new proteins identified for hair cell development:

https://www.genengnews.com/news/protein-identified-for-new-hearing-hair-cell-development/

 

So, Action on Hearing Loss will be hosting a webinar on the 28th of September on 'The Emerging Hearing Medicines Landscape'. According to the link this is:

"A monthly webinar series developed by the Hearing Medicines Discovery Syndicate, exploring hearing drug discovery in the context of an emerging area for medicines development and a growing market. The first webinar will be on 'addressing an unmet need'."​

Further information about this:

"Through this series of webinars, we will explore the emerging hearing medicines landscape by inviting leading clinicians, academics and industry representatives along with people with lived experience of hearing loss, to share their expertise and insight.

Over 4 webinars we will provide a 360-view of the field covering the patient need, the key challenges faced by innovators, how to commercialise your hearing research and why regenerative approaches could be a game-changer for hearing medicines discovery."​

I've registered for it - speech to text will be available as well.

One of the speakers, Anne Schilder, was involved in the Regain trial and will be discussing 'the hearing therapeutics timeline'. Regain seems far less promising in comparison to, say, Frequency Therapeutics, so it will be interesting to hear her take on this topic...

https://go.md.catapult.org.uk/emerging-hearing-medicines-landscape-addressing-an-unmet-need/

 

This is an English organisation, right? While I think this will be interesting and beneficial, I wonder how much they actually know about the stuff going on in America? Especially when the American companies have been guarded with their info due to the reporting rules and requirements. Or do you think they’ll comment only from a general perspective.

 

There's a Q&a session at the end of the webinar.

Sign up, ask, and witness for yourself how much they know.

 

Yes, it's a British organisation. Honestly I would be slightly disappointed if they're not aware of recent developments with Frequency Therapeutics etc. I mean, I'm British and this stuff is not hard to find out about. Although if you mean perhaps they might know something we don't? Not sure. I think it would be a glaring omission if they failed to discuss Frequency Therapeutics.

 

That is a option, however I am more interested in what they can show us in their talk. It is not always the case, however just like there are some links between hearing loss and tinnitus there is often a link between what is presented at a seminar or the like and what someone presenting things knows. However there are exceptions.

I agree that it would seem rational to discuss these US firms like Frequency Therapeutics and Hough Ear Institute, especially when they are highly relevant to the topic that they are discussing.

I think finding out about Regain would be interesting, however having a look at what is happening with the company and what we know about the medicine, it seems to be very different to FX-322 both in terms of treatment and also how it worked.

 

Yeah, there's been considerably less buzz about Regain and their results weren't much to write home about. Carl LeBel was pretty critical of their approach because it doesn't turn the correct genes on and depletes supporting cells.

 

I saw some stuff about Regain and actually understood why it inevitably wasn't going to be a good treatment option in its current form. I think that was why we have seen much more upside with FX-322 though because it is actually targeting the right stuff, it is not very risky and also seems to be getting results to date.

 

I mean, their own CEO was notably lackluster when asked about their drug and said they hadn't had their Eureka moment yet. And as @FGG pointed out, the hair cells produced using their approach are more similar to vestibular hair cells.

 

I wish I was more organized and had all the studies in one place but this is the initial study that soured me on Audion's approach:

https://www.frontiersin.org/articles/10.3389/fncel.2018.00073/full

 

I think that the science and the biological outcomes of Regain were quite ineffective and poor overall, especially when you look at the outcomes they achieved. Yes, we saw them attain an outcome from their treatment but it was the wrong outcome based off of the fact that they enabled people to regain cells but they weren't necessarily the best type of cells to regain. Furthermore, other treatments like FX-322 have a much lower risk overall and are not going to deplete stuff which would be useful for future regrowth. Thus I think that the benefit of treatments like FX-322 will be far and above what Regain can produce in its current format.

There is a possibility that Regain may even abandon their treatment redevelopment as well if other options like FX-322 surpass it. I cannot see Regain and its managers believing that it is going to be viable to redevelop something which mightn't even achieve its goal, if it has already been surpassed by another treatment option.

If I am correctly looking at what Audion was wanting to do, it seems that their treatment, their treatment's mechanism of action and their outcomes are chalk and cheese to what Frequency Therapeutics is doing. It seems that the only thing which was the same was the fact that they are aiming to regrow cells.

There just seems to be so many positives with Frequency Therapeutics' approach such as theoretically regrowing the same types of cell and also it just seems to be so low risk that you would have no qualms at all about using it. Audion's approach seems very risky and the cell types do seem more like what you'd want to see from a balance cell medicine.

Like you I'd think I'd pass too .

 

You seem to be knowledgeable. So what regenerative treatments do you think will show efficacy for noxacusis/hyperacusis in general?

 

Hyperacusis is the mystery box that we still seem to be working out how to open. We neither know what causes hyperacusis nor can we establish causal links like we can with tinnitus. However, what we do know is that treating ear conditions will probably have a reasonable effect on resolving hyperacusis. This is because most people who have hyperacusis also have ear related problems like damaged synapses and hair cells. Therefore using logic we can deduce that if issues like broken synapses and hair cells are theoretically what led to the hyperacusis, then repairing the damage should theoretically make the hyperacusis go away.

Furthermore, it should be noted that hyperacusis is yet to show the same response that tinnitus has to the presently available treatment options such as hearing aids. Therefore, the fact that hyperacusis does not react to the current treatment options tells us three important facts about hyperacusis:

1. The reason we cannot determine the cause or causes of hyperacusis is because hyperacusis does not respond to currently available treatment options like a hearing aid in the same way tinnitus does. This is because we cannot establish a causal link for hyperacusis (like broken synapses), whereas with tinnitus we can establish that a causal link is the reduced auditory input through hair cells.

2. Hyperacusis probably will need to be treated anatomically to resolve the issues associated with it because it doesn't respond to current treatment options like hearing aids.

3. Hyperacusis is very likely caused by multiple conditions together such as hair cell damage, synapse damage and an inflamed cochlear(s) or any combination of these conditions. This is because most people who are found to have hyperacusis tend to present with symptoms of both hair cell and synapse damage. Furthermore, there are indications that an inflamed cochlear is likely to be a symptom of hyperacusis. Also treating the issues related to hyperacusis with available treatments like hearing aids is ineffective. Therefore once again, until we have a medicine treatment for these conditions, we won't know what is causing the hyperacusis and won't be able to pinpoint how to treat it because we cannot play around with the medicine and cannot trial treat to see what may help.

Therefore, while we do not have any specific information that enables us to determine and identify what will treat hyperacusis at present, I am fairly confident that the medicines are getting developed will assist with this because they will treat the appropriate areas.

If I was going to suggest which ear medicine would assist with hyperacusis treatment, I would probably suggest all of them because hyperacusis isn't necessarily caused by just one issue.

However, what I think would be a better question for you to ask and for me to answer would be what areas would I try and treat first to try to hopefully work out what is causing hyperacusis and what could also treat hyperacusis ?

The answer is trying inflammation and synapse medicines first. The reason that I would focus on synapse damage and cochlear inflammation first is because I have understood that a common trait of people who have got hyperacusis seems to be exposure to loud noise(s).

Thus as both synapse damage and also cochlear inflammation are caused by a single and also repeated subjection to loud noise, it would seem somewhat logical that this could therefore result in hyperacusis.

The reason I suggest treating synapses first is based off of what we we know, the role of synapses is to allow somebody to regulate the sound(s) around them to hear the noise they want to hear. This includes things like being able to block out sounds around them at night to hear an animal such as an owl or to block out the ambient noises in a place like a cafe so they can hear someone speak.

Interestingly from what we know about those with hyperacusis, two common complaints are:

- that they often usually have issues with being able to filter out the sound that they want to hear in a noisy place like a cafe.

and

- they also have issues with this ambient noise being not just overpowering but also intolerable and irritating.

Therefore based off of the reading and investigating that I have done, my contention is that the role of the synapses is to regulate the volume of sounds around oneself and also to allow oneself to filter these out. Damaged synapses simply mean someone has a reduced ability to do this.

However, what I think damaged synapses also do is cause sounds around someone to seem artificially louder and overpowering because they are unable to get rid of or ignore/regulate the irrelevant noise(s). This means that a person do not have the subconscious capability to simply block out sounds like a coffee machine or plates dropping in a cafe as they did previously when they had functioning synapses. This therefore means that these noises seem artificially louder.

Thus the thinking that the sounds are louder is actually somewhat false, it is actually just the busted synapses not being able to regulate the sound as effectively like they would if they were functioning normally.

Therefore I think that restoring synapses should quite likely have a positive effect on those who have hyperacusis, as an appropriate number of synapses will enable people to actually regulate sounds again.

I also believe that treating cochlear inflammation is necessary in people with hyperacusis because those with hyperacusis often have had repeat exposure to loud noise(s). This in turn is likely to inflame the cochlea.

This ear inflammation happens in exactly the same way as when people have chafing on their thighs for example. The constant rubbing causes the skin on the thighs to get irritated and thus they end up with the skin getting contusions and becoming inflamed as well. Thus this skin inflammation needs to be treated in order to eliminate the various problems caused by the inflammation and allow the skin to return to a normal state without issues like pain.

Hence the same scenario is likely to play out in the ear. The ear gets inflamed after exposure to loud noise(s) repeatedly and subsequently results in the cochlea becoming irritated and inflamed. While the cochlea remains inflamed, things like the irritation and pain associated with certain sounds hitting the ear will remain. Thus the ear won't return to a normal state until this inflammation is treated.

Furthermore, the inflammation is possibly going to cause sounds to seem distorted too, because the cochlear is not going to be working properly and normally while it is inflamed, much the same why your thigh skin remains red and painful while it is inflamed. Therefore I feel that the inflamed nature of the cochlea is actually also something which might cause sounds to be distorted because while it is inflamed it is unable to pick up sounds in a normal manner.

Thus I believe that by treating the cochlear inflammation, you will overcome the issues associated with this like the pain in the ear when hearing certain noises as this inflammation is no different to the problems associated with inflammation in other areas of the body such as skin on the thighs. Thus I think this will be a very prudent area to treat and also understand when ear inflammation medicine is available.

 

I agree with this. One thing to add though is that recent research indicates that the outer hair cells also play an important role in regulating the ear's sensitivity to sound instead of simply acting as 'amplifiers' as has traditionally been thought. I can imagine hyperacusis could arise from a combination of hair-cell and synapse damage.

https://elifesciences.org/for-the-p...air-cells-regulate-ear-s-sensitivity-to-sound

 

Thanks. That is what I thought might have been the case too. I think it is why you are probably going to have to take three medicines to get benefit for hyperacusis.

However, I think that the work indicates that outer hair cells could be treated with some of the synapse medicines. This may mean that people don't need a hair cell medicine if the synapse medicine is effective enough.

Essentially I expect that there is going to be a lot of trial and error in treating hyperacusis initially.

 

That's interesting so it may not always be "central gain" after all.

I find it interesting that loudness hyperacusis often dramatically improves even when tinnitus doesn't so it may be a case where inflammation often causes the decreased hair cell function (because of the resistance the inflammation would cause to the normal movement) leading to loudness hyperacusis.

I had pretty substantial loudness hyperacusis early on when the Azithromycin was still retained in my cochlea (about 6 months), so it fits in my case at least. It completely resolved while my tinnitus has not changed past the first few months (and my hearing still sucks).

Noxacusis of course is a different animal.

 

Of the synaptopathy drugs, only PIPE-505 reportedly has any effect on outer hair cells and they are still enrolling for phase 1 so they are the "slowest" unfortunately.

 

So there is no OTC compound that can affect this inflammation? Because of the blood barrier in the cochlea? How are upcoming treatments planning to cross that barrier?

 

Not OTC but it's possible some of the current Rx biologics that inhibit TNF Alpha (e.g. Embrel) might (that's a big if and I believe there is a study now recruiting using these drugs for tinnitus).

Sound Pharmaceuticals has an oral drug in phase 3 that's super promising for this and Otonomy has an extended release Dexamethasone which seems many times more effective and penetrating (based on how well it treats Meniere's patients). Otonomy's drug will have results Q1/2021 and they have said they will immediately submit an NDA if positive. They seem pretty confident as they have relayed that they already have manufacturing ready and will have the drug available about 6 months after submission.

The Hough Ear Institute pill is reportedly excellent for this but their time line is more unknown.

Some people have success with supplements and dietary means of lowering inflammation more generally but that's very hit or miss and seems very individual.

 

There are two elements to your comment:

1. I think that the blood barrier issue in the cochlear has been well and truly overcome now.

2. I might be mistaken, however I feel that Sound Pharmaceutical's inflammation treatment is a pill. Hough Ear Institute's synapse repair medicine is also a pill too.

This indicates you can treat in the ear issues with oral medicines.

 

I thought that was the the medicine. I also note that PIPE-505 is very limited in its criteria for phase 1 candidacy too. They have allowed people with 'normal hearing' on a standard audiogram to enroll for their phase 1 trial and are going to expand the criteria after this trial.

Therefore while we will see results, we will only see it in the synaptic part of the treatment most probably.

 

Is inflammation not going to go down once the underlying synaptic/hair cell damage is fixed? Once both components are restored, there's no reason for the cochlea to continue being inflamed, right?

 

I've wondered about the Hough Ear Institute pill being a pill, and what it is doing differently to be able to get over the hurdle of the blood labyrinth barrier. And I understand that SPI1005 is a pill as well.

It's probably been answered before why FX-322 can't be delivered via pill, I've read the Frequency Therapeutics thread so probably forgotten if it has been mentioned already. It's fairly obvious that it can't because of some molecular level highly scientific reason. Would be nice to know what it is though.

 

It is interesting. I was seeing some stuff about other issues caused by the ear which also attempted to make out the causes much more complex when in fact they were just something simple like hair cell loss.

Looking at what we have found out about ear conditions recently and especially since this hearing medicine stuff started to get discussed it is becoming quite a lot more obvious that the way the ear works is actually also a lot more simple than these experts thought it was or had been telling us it is.