Inner Ear Hair Cell Regeneration — Maybe We Can Know More

The reason why FX-322 can’t be taken orally is that when they tested it on rats it caused cancer whereas with IT injection they found no issues with it.

 

Good question and I don't know the answer to it. I know that many inflammation issues can be treated through a tablet. For example you can take a tablet to treat skin inflammation.

I actually wonder whether there is something special with Sound Pharmaceutical's inflammation tablet that enables it to breach the blood labyrinth barrier or is this not necessary to actually achieve?

I wonder whether @FGG knows more about this?

 

Like all regenerative drugs, FX-322 is not safe to give at the very high doses you need to give systemically.

SPI-1005 is a synthetic organoselenium drug that acts as a glutathione peroxidase inducer. It's appears very safe to give at very high doses.

The Hough Ear Institute Pill combines NAC with a proprietary potent free radical trapping agent that also can be given at large doses.

 

Indeed - It seems that there are a limited number of structures in the ear that can be damaged through noise and hearing loss.

 

Thanks, interesting. I think I did read something like that quite a while back.

 

Assuming you have no underlying reason for continued inflammation (e.g., Autoimmunity, ototoxin exposure etc), I think that's a fair assumption.

Inflammation is always self limiting (it's designed that way) in the body unless you have autoimmunity or something continuing to stimulate the immune system.

 

This is incredibly interesting and I wonder whether targeting the specific section of the body such as hair cells in the ear is a key component of getting targeted and also effective hair cell growth with the progenitor cell activation technique. I wonder, when taken orally, if it causes cancer type growth because of targeting the body widely. Do you know the specific reason?

Also I must say that this rat cancer comment is interesting because this gives merit to the post someone made saying that there was a comment going around that FX-322 was dangerous because it gave some rats cancer. It is now clear that this is true when it was consumed in tablet form. However their comment is completely disingenuous because it simply failed to acknowledge that this was caused not by FX-322 per se but by the method used to consume it.

 

I think, but I could be wrong, that they gave the drug as a parenteral injection and not as a tablet. The point still remains though.

And yes, the cancer problem appears to be a widespread off-target problem with very high systemic administration.

Part of any phase 1 study is gathering pharmacokinetic data, and for them to determine the drug was safe, it had to have a low rate of systemic absorption/clearance. I think if we get another Tinnitus Talk Podcast chance, details about their pharmacokinetic data would be a great thing to ask!

 

That’s what I think too. If FX-322 targets the right area such as hair cells then it shouldn’t cause cancer as it only regrows hair cells.

 

Plus aside from making it ineffective it gives another reason to not want to swallow while it's being administered. (Though I'm guessing the dose in this case would be much lower and therefore wouldn't carry much risk).

 

So there isn’t any readily available substance that’s a uhhhhh... “glutathione peroxidase inducer?” I’ve taken NAC with no results, and I was kinda under the impression that the whole “free radical” thing was supplement mumbo jumbo.

 

Not to any meaningful extent that I am aware of.

Hough's pill is an extremely potent "free radical trapping agent" that was accidentally to their happy surprise apparently found to also regrow synapses, something they were reportedly not expecting.

Free radicals and oxidative stress are real and are both directly damaging and pro inflammatory.

I have a feeling NAC doesn't do a whole lot on its own for the cochlea, though. Maybe acutely.

 

I think this is why targeting the right area (in FX-322's case ears by intratympanic injection) makes it quite safe as proven by the results to date.

 

You really believe in this Hough n' Puff pill? Give me a break... An extremely potent antioxidant... So what? Antioxidants don't regenerate anything.

It's a Bomb Blast Pill.

 

Does anyone have experience with this Serbian clinic?

https://www.startstemcells.com/new-tinnitus-treatment-with-stem-cells.html

Any testimonials? Cost and duration of treatment?

 

Their product isn't technically a standard antioxidant. It's a free radical trapping agent that has been shown to a) penetrate the cochlea in amounts to have been shown to have a therapeutic effect, and b) in rodents, shown to regrow synapses.

The synapse regrowth was an accident/unplanned effect. Uncommon and "off target" effects are common, hence why side effects are a thing. Occasionally those things can be positive. A famous example is Rogaine which was a blood pressure medicine that unexpectedly grew hair. They are proposing that's what happened with their drug.

Hough Ear Institute have been published many times in peer reviewed journals and I don't believe they fake their pre clinical or clinical work (independent of this, Hough Ear Institute has a reputation in the field, they were one of the first in the whole country to put in cochlear implants).

I think where people lose faith in Hough Ear Institute is that they don't appear to be completely transparent about some of the behind the scenes goings on but this doesn't mean the drug isn't effective. But it still needs way more testing on humans.

Either way, Hough Ear Institute isn't vital because Sound Pharmaceuticals and Otonomy have drugs both in phase 3 for inflammation.

For synapse regeneration, there is also OTO-413 and PIPE-505.

With the exception of PIPE-505, these drugs are further in the process anyway.

 

Ok fair enough, I'll buy the Hough Ear Institute story for now...

Also, may I ask, what does curing inflammation do?

 

Tinnitus is ridiculously complex and multi factorial. I feel like you and everyone on the forum knows this and it is almost akin to a stoner saying "woaaahhh, the universe is deep, man" but anyway bear with me because this is going to be kinda long...

It seems to me that T = x + y + z.

x is structural damage or hearing impedance. Structural damage would be things like hair cell loss, synapse damage, etc and what I am calling "impedance" without permanent structural damage would be things like hydrops or TMJ.

y is inflammation

z is intrinsic factors like having a more "predictive brain" or neurotransmitter effects.

All of these contribute to tinnitus.

Complicating it further, everyone's equation is probably different (for instance, if your tinnitus was caused by benzos you would have an equation with a higher "z" value. For most people though, the most important of these factors is probably "x", so the equation might look like T = x + xy + y + z.

You get the idea.

Chronic cochlear inflammation has a long list of differentials including: viral or rickettsial / Lyme infection, TMJ, auto immune, toxic exposure (usually medications) etc but *acutely* anything that causes the death of hair cells or synapses does so through primarily through inflammation and oxidative damage. This is why many times, if you treat hearing loss very early, you can prevent some or all of the damage from becoming permanent. That's the theory behind steroids (which have such a variable penetrance into the cochlea that they don't work for everyone, unfortunately but for some it's very significant), the "Bomb Blast Pill", antioxidants given acutely etc.

There is also a subtype of inflammation which seems to be a big component of this also which is more of a "neuroinflammation" from a glutamate surge. This often especially happens with noise induced injury (and is the theory behind OTO-313 blocking the glutamate NMDA receptor acutely to prevent tinnitus).

My take is that most people will have a pretty big "y" component acutely but inflammation is self limiting unless you have a continued stimulus.

Since "y" is so variable, this is why some people have better responses to things like anti oxidants and an anti inflammatory diet ("y" was a bigger part of their tinnitus). There things help by lowering the mediators of inflammation in the whole body.

For others, structural damage probably can potential neuro inflammation on its own (one mechanism is that IHCs control the flow of glutamate across the synapse).

A bit of a tangent too but this is important. Just because you have noise induced hearing loss, do not assume you don't have cofactors that can make your tinnitus much worse. Some of you probably have TMJ making your tinnitus louder (for instance) and don't realize this because it started with a noise injury.

Tl;dr: Addressing inflammation addresses the "y" component of a really complex issue.

 

Presumably there is debris from cell death in the cochlea as a result of noise exposure/ototoxic meds etc. It sticks around for a LONG time which is why H is so persistent. This irritates the cochlea which sends signals to the trigeminal nerve/brain which somehow turns into noise sensitivity/pain/fullness/TTTS/other middle ear issues. So if you clean up the cochlea/calm the inflammation you should stop the source of the bad signals.

Tinnitus seems to be different but I bet reducing inflammation in the inner ear will help there too. But ultimately synapse/OHC repair is probably what is needed to totally eliminate tinnitus. Unless some of the upcoming meds like Thanos' treatment can brute force the erroneous tinnitus signals.

I have a really hard time believing there isn't SOMETHING out there that can get to the cochlea in therapeutic quantities and reduce inflammation. Obviously regrowing complicated hair cells will need exotic stuff like FX 322 but geez... How is inflammation so hard to reduce?

 

Wowzers! Dead hair cell debris!

Did you come up with this theory yourself or do you have a source for this?

 

I'd like to ask how far does everyone think research is realistically away from a cure?

I hate my tinnitus. Despite doing TRT at the moment, which does help, but if I could be rid of tinnitus forever, I'd jump at the chance.

I'd like to be sure that it works 100% first. There'd be nothing worse than paying for a cure and not have it work.

 

Interestingly, finding ways to control inflammation has been proposed as a possible treatment for pain hyperacusis (or at least a way of calming the symptoms) - this was discussed at the 2016 ARO symposium.

"In addition, to the extent that pain represents dysfunctional signaling from a chronically inflamed cochlea, perhaps emerging treatments for controlling out-of-proportion inflammation could be very helpful as well. Such treatments are currently used—or under investigation—with patients who have overachieving mast cells, the primary initiators and perpetrators of allergic and many intolerance-type responses."​

More excerpts:

"Important phenomenon: If inflammation is present, sympathetic activity can activate undamaged nociceptors.

This raises the question of whether inflammation—with its release of inflammatory chemicals—may be important to initiating and maintaining pain in hyperacusis and whether hyperacusis pain is neuropathic. Experiments showing that Type II cochlear neurons can be activated by very intense sound were conducted in animals and humans free of hyperacusis; but perhaps in hyperacusics, the initiating processes and chronic inflammation result in sensitization with the transmission of pain signals with relatively low-intensity sounds—especially sounds of certain qualities that are difficult for the damaged or inflamed cochlea to process—such as tearing paper, leaf-blowers or electrical equipment."​

https://hyperacusisresearch.org/an-md-summary-of-the-2016-aro-hyperacusis-symposium/

 

Hyperacusis sufferers will be waiting a decade and spend $15k+ for hair cell, synaptic, and inflammation treatments. Not that the money is a problem but it's sounding like we'll be waiting a while especially for inflammatory treatments like Prof Thanos's. I am optimistic but maybe we should curb our expectations.

 

I'd say potentially within the next five years, although it could be sooner.

There seems to be two major barriers which need to be overcome to getting a cure for tinnitus.

> Getting treatments to pass FDA clinical trials.

When this will happen is very much unknown because there are a number of variables that can influence the duration of a clinical trial. These include things like the time taken to report results, how long it takes to get enough enrollees, COVID-19 delays etc etc.

> Trying to determine which treatment(s) treat tinnitus.

While we know some causes of tinnitus now, we don't definitively know if these are the only causes of tinnitus. Therefore this is likely to mean that there will be a number of people who may need to attempt various treatments to resolve their tinnitus.

I inevitably think that there is going to be a fair idea that either the pharma companies and/or doctors will know whether a medicine being used to treat you is going to work before they use it. However if the companies wish to be savvy they could offer a money back guarantee on failed treatment

 

If it turns out pain and loudness hyperacusis are caused by OHC loss then FX-322 should allow us to regain our lives. This will be the best outcome since FX-322 will be the first drug to come out to restore hearing.

 

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.

 

Most definitely. I’m just glad that companies are working on treatments which targets different areas in the ear such as hair cells and synapses so we can find out which treatments work for hyperacusis, tinnitus and hearing loss.

I personally believe that if we fix the physical problem by restoring hair cells and synapses then hyperacusis, tinnitus and hearing loss should resolve. I wouldn’t have a clue if these issues are caused by something else.

 

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.

 

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.

 

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.