Frequency Therapeutics — Hearing Loss Regeneration

[Jorge1984]

Is there a difference between hearing loss and SSHL?

 

[Mentos]

Have you ever wondered what your reaction would be if the FX-322 worked?

I would read hundreds of books in silence.

 

[FGG]

Is there a difference between hearing loss and SSHL?

Hearing loss is much more broad and can include things like conductive hearing loss (a problem with the bones in the inner ear).

SSHNL is a specific type of hearing loss that effect the sensory cells of sound perception. The first "S" in SSNHL stands for sudden, so it's different than gradual losses. "SNHL" with one "S" is sensorineural loss that isn't necessarily sudden. Here is the wiki on sensorineural hearing loss:

https://en.wikipedia.org/wiki/Sensorineural_hearing_loss

 

[grate_biff]

Per Liberman, the synapses are the most susceptible to noises but it has been known for awhile that the OHCs are sensitive as well. It may even depend on the individual and the specific exposure. IHC damage seems more prevalent with certain Ototoxins but sometimes noise can damage IHCs more selectively than other structures too for unknown reasons (there was a rabbit study I found awhile ago).

Both OHC and IHCs work together to produce sound at each frequency, so one isn't further away functionally from the noise. "Outer" doesn't mean higher frequency hair cells. It means it is a hair cell on the outer row that exists throughout the whole cochlea (from 20Hz to 20000Hz just like the IHCs).

Ototoxins can damage any structure in the cochlea depending on the individual toxin. It is unfortunately very poorly researched what each toxin effects except for Aminoglycosides, Loop diuretics and platinum based chemotherapeutics. Keep in mind that blood also flows from outside the cochlea in so there is a higher concentration of toxin to bind at the base (vs the apex) too generally.

I think it's also confusing because there is no diagnostic test except when it comes to outer hair cells so no one really can tell anyone what they have specifically damaged apart from OHCs evident on an abnormal audiogram.

Regenerative technology seems to be beating diagnostic technology. I really think people will have to "trial treat" with both a hair cell regeneration drug and a synaptopathy drug unless that changes. Even Otonomy have said in their last presentation that they think their synapse drug will work even better with their upcoming hair cell regeneration drug (OTO-6xx, in pre clinical for severe hearing loss) and vice versa. A lot of people will need one or both and unless they have an abnormal audiogram and/or speech in noise issues (would indicate synaptopathy at the important speech frequencies), they won't know what category they are in.

Re: Antidepressants that effect neurotransmitters. GABA and Glutamate both exists in the cochlea as well as the brain. Serotonin modulates the effects of both GABA and Glutamate.

Glutamate is needed to travel across the IHC/SGN synapse to transmit sound but too much of it results in neuroinflammation which can cause damage to structures in the cochlea due to oxidative stress.

There are GABA receptors on the efferent nerves of OHCs as well (I could be wrong but I think mainly in the base of the cochlea so this would be more relevant to higher pitched sounds).

Basically anything that alters the GABA/Glutamate homeostasis can directly affect the cochlea.

It's also why I believe GABA potentiating drugs (e.g.. Benzos) are helpful at reducing tinnitus at first but when tolerance happens or with withdrawal they can make it so much worse because Glutamate has been increased and the receptor is now less sensitive to GABA.

So, you are basically saying that benzo withdrawal is ototoxic?

I´m in the middle of this hell right now and the noxacusis has never been worse, but the tinnitus is a bit better.

Confusing.

 

[all to gain]

Per Liberman, the synapses are the most susceptible to noises but it has been known for awhile that the OHCs are sensitive as well. It may even depend on the individual and the specific exposure. IHC damage seems more prevalent with certain Ototoxins but sometimes noise can damage IHCs more selectively than other structures too for unknown reasons (there was a rabbit study I found awhile ago).

Both OHC and IHCs work together to produce sound at each frequency, so one isn't further away functionally from the noise. "Outer" doesn't mean higher frequency hair cells. It means it is a hair cell on the outer row that exists throughout the whole cochlea (from 20Hz to 20000Hz just like the IHCs).

Ototoxins can damage any structure in the cochlea depending on the individual toxin. It is unfortunately very poorly researched what each toxin effects except for Aminoglycosides, Loop diuretics and platinum based chemotherapeutics. Keep in mind that blood also flows from outside the cochlea in so there is a higher concentration of toxin to bind at the base (vs the apex) too generally.

I think it's also confusing because there is no diagnostic test except when it comes to outer hair cells so no one really can tell anyone what they have specifically damaged apart from OHCs evident on an abnormal audiogram.

Regenerative technology seems to be beating diagnostic technology. I really think people will have to "trial treat" with both a hair cell regeneration drug and a synaptopathy drug unless that changes. Even Otonomy have said in their last presentation that they think their synapse drug will work even better with their upcoming hair cell regeneration drug (OTO-6xx, in pre clinical for severe hearing loss) and vice versa. A lot of people will need one or both and unless they have an abnormal audiogram and/or speech in noise issues (would indicate synaptopathy at the important speech frequencies), they won't know what category they are in.

Re: Antidepressants that effect neurotransmitters. GABA and Glutamate both exists in the cochlea as well as the brain. Serotonin modulates the effects of both GABA and Glutamate.

Glutamate is needed to travel across the IHC/SGN synapse to transmit sound but too much of it results in neuroinflammation which can cause damage to structures in the cochlea due to oxidative stress.

There are GABA receptors on the efferent nerves of OHCs as well (I could be wrong but I think mainly in the base of the cochlea so this would be more relevant to higher pitched sounds).

Basically anything that alters the GABA/Glutamate homeostasis can directly affect the cochlea.

It's also why I believe GABA potentiating drugs (e.g.. Benzos) are helpful at reducing tinnitus at first but when tolerance happens or with withdrawal they can make it so much worse because Glutamate has been increased and the receptor is now less sensitive to GABA.

Thanks for the in-depth reply. I misunderstood what OHCs are and their relationship to higher frequencies.

I still don't really understand really what an abnormal audiogram means? Does it just mean more hearing loss for one's age than is the normal? For example, I have mild to moderate hearing loss at 50 years old, and have big dips at 4000 Hz in one ear and 6000 Hz in the other. I can't hear much of anything past 9000-10000 Hz (going by online sound generators). An ENT told me that maybe my tinnitus is at 4000 Hz and 6000 Hz as I couldn't hear the sounds on the audiogram in those ranges, but I feel like my tinnitus is higher pitched. But I find it hard to pin down my tinnitus using an online sound generator, so who knows, maybe she was right.

Also, I still don't understand in what order, and if it makes any difference, a person would need to get FX-322 and OTO-413 if they need both?

How far away is OTO-6xx from possibly hitting the market? I know nothing about it.

Thanks for your patience. You must get bored of answering such questions

 

[Am92]

I got tinnitus from a physical trauma to the ear. Could FX-322 potentially be beneficial to me?

I have no visible hearing loss.

 

[Jorge1984]

@FGG, how did you get your tinnitus?

I'm not sure if I asked you this question already.

In what ways will FX-322 help you?

 

[Momme]

What does "phase 1/2" mean? Is it phase 1 or both phase 1 and 2?

 

[FGG]

So, you are basically saying that benzo withdrawal is ototoxic?

I´m in the middle of this hell right now and the noxacusis has never been worse, but the tinnitus is a bit better.

Confusing.

As far as I have read, benzos are not directly ototoxic (i.e.. they don't directly lead to the death of hair cells and synapses) so their neurotransmitter effects and the consequence of those would be a lot more unpredictable.

I have no idea why benzos and their withdrawal seems to have an effect on noxacusis but I have read that many times. I wonder if it's related to the GABA receptors on the OHC efferent nerves?

 

[FGG]

Thanks for the in-depth reply. I misunderstood what OHCs are and their relationship to higher frequencies.

I still don't really understand really what an abnormal audiogram means? Does it just mean more hearing loss for one's age than is the normal? For example, I have mild to moderate hearing loss at 50 years old, and have big dips at 4000 Hz in one ear and 6000 Hz in the other. I can't hear much of anything past 9000-10000 Hz (going by online sound generators). An ENT told me that maybe my tinnitus is at 4000 Hz and 6000 Hz as I couldn't hear the sounds on the audiogram in those ranges, but I feel like my tinnitus is higher pitched. But I find it hard to pin down my tinnitus using an online sound generator, so who knows, maybe she was right.

Also, I still don't understand in what order, and if it makes any difference, a person would need to get FX-322 and OTO-413 if they need both?

How far away is OTO-6xx from possibly hitting the market? I know nothing about it.

Thanks for your patience. You must get bored of answering such questions

Based on your description, you have an abnormal audiogram and very likely have some OHC loss.

"Normal for age" just means some OHC loss in the highest frequencies are expected with age. If we lived in a quiet world, there wouldn't be a "normal for age." Tinnitus is sometimes very hard to pin down. Especially in areas where you have a lot of hearing loss.

I can't imagine why the order of the drugs would matter. Anyone else have a different idea?

OTO-6xx is pre-clinical which means only Otonomy has any info about it at this time.

 

[FGG]

I got tinnitus from a physical trauma to the ear. Could FX-322 potentially be beneficial to me?

I have no visible hearing loss.

If the trauma affected the cochlea, I would say it's likely. If it affected the middle ear or the ear drum (or the jaw and you have undiagnosed TMJ), then no.

 

[FGG]

@FGG, how did you get your tinnitus?

I'm not sure if I asked you this question already.

In what ways will FX-322 help you?

High dose Azithromycin. FX-322 will only partially help me unfortunately as Macrolide antibiotics are unique in that they also can poison the KV3.1 ion channels in the brainstem.

 

[FGG]

What does "phase 1/2" mean? Is it phase 1 or both phase 1 and 2?

https://www.cancer.gov/publications/dictionaries/cancer-terms/def/phase-i-ii-clinical-trial

 

[Pink Noise]

What does "phase 1/2" mean? Is it phase 1 or both phase 1 and 2?

Study that tests the safety, side effects, and best dose of a new treatment. Phase I/II clinical trials also test how well the condition responds to a new treatment. In the phase II part of the clinical trial, patients usually receive the highest dose of treatment that did not cause harmful side effects in the phase I part of the clinical trial. Combining phases I and II may allow research questions to be answered more quickly or with fewer patients. Also called phase 1/phase 2 clinical trial.

 

[F-u-T]

Have you ever wondered what your reaction would be if the FX-322 worked?

Dance around naked.

I also bought a bunch of stock that hopefully turns out well too.

 

[all to gain]

Based on your description, you have an abnormal audiogram and very likely have some OHC loss.

"Normal for age" just means some OHC loss in the highest frequencies are expected with age. If we lived in a quiet world, there wouldn't be a "normal for age." Tinnitus is sometimes very hard to pin down. Especially in areas where you have a lot of hearing loss.

I can't imagine why the order of the drugs would matter. Anyone else have a different idea?

OTO-6xx is pre-clinical which means only Otonomy has any info about it at this time.

Thanks.

It looks like I'm going to need both FX-322 and OTO-413 then. Just hope they both hit the market, but the latter seems quite a long way off. Then there is the Hough Ear pill, but I don't really understand how that differs from OTO-413, except that it is a pill and that it may help with the auditory nerve. If I have auditory nerve damage as well I feel a bit doomed to be honest.

 

[FrontRoomFanatic]

Newly generated hair cells will attach to the auditory nerve, but preexisting hair cells will not reattach. Drugs by other companies address the nerve endings that attach to the auditory nerve (Hough pill, OTO-413, PIPE-505), they have their own threads.

I have a mild form of pain hyperacusis (also have tinnitus). Which one of these drugs should I be focused on to reduce the hyperacusis element? And will a combination of one or more be relevant to having both hyperacusis and tinnitus? Thanks.

 

[WickedCarnival]

I've been thinking about microdosing too! Let me know how it goes.

I have experience with LSD, magic mushrooms, MDMA, and edible cannabis (THC oil) at different doses and they all have different effects on my tinnitus:

Micro/low doses: Both LSD and magic mushrooms are variable for me, so when the day of the microdose goes well, I can focus on things other than tinnitus more easily. It's like being in a more flowing, meditative state. The tinnitus is still there, but very manageable. I don't take MDMA or THC oil at low doses by the way as both haven't had beneficial effects at that dose for me

Moderate doses: With shrooms or LSD, I seem to either have to take very low doses, or high doses, as moderate doses ramp up anxiety and I just don't feel comfortable most of the time. THC oil allows me to completely forget about tinnitus and have a good experience, but the next day the tinnitus is back to it's old grating again. With MDMA, tinnitus is both attenuated during and after the experience, usually for the day after. I can feel quite depleted the day after MDMA, but at least the tinnitus is not that bothersome.

High doses: I don't take magic mushrooms at high doses as they end up causing me bad trips and severe depression. LSD on the other hand has very beneficial affects for me at high doses; spiritual/peak experiences, ego dissolution and feeling of oneness, profound personal insights, and the week after I have a beautiful afterglow in which my tinnitus is reduced to a satisfying level. Not completely gone, but enough that I feel great. As for THC, I don't like high doses as it feels like "my brain is about to break and go crazy." With MDMA, I get a good reduction of tinnitus for the day of and day after the experience. But high doses leave me with potential low-grade depression for a week after.

The brain is very complex and highly affected by different chemicals. LSD seems to work best with my brain chemistry in the right set and setting. Everyone will react differently so please be very careful and educate yourselves with good quality information and harm-reduction practices. Erowid, and several channels on YouTube are very helpful. These are potentially very promising drugs, and continuing research is revealing that. But I can't stress this enough, please, please be very careful. There's a reason they have been used only under supervision with Shamans for thousands and thousands of years.

 

[MrCrybaby]

I have a mild form of pain hyperacusis (also have tinnitus). Which one of these drugs should I be focused on to reduce the hyperacusis element? And will a combination of one or more be relevant to having both hyperacusis and tinnitus? Thanks.

Pain hyperacusis is poorly understood by science, so no one really knows what will fix it. Most people here will probably benefit from both a hair cell regenerating drug and a synapse regenerating drug (FX-322 and Hough pill for example).

 

[Fanny1]

Um sorry, but what is the last update for a projected release for FX-322?

 

[Lucifer]

Um sorry, but what is the last update for a projected release for FX-322?

If you are talking about when the Phase 2a clinical trial results will be released they stated September 30th this year.

I have no idea when the actual release date for FX-322 is but they did receive Fast Track status last year and could possibly get Breakthrough Therapy status if Phase 2a results are positive.

I really hope they release it in 2021 but with the coronavirus that date seems unlikely.

 

[Mentos]

Thanks.

It looks like I'm going to need both FX-322 and OTO-413 then. Just hope they both hit the market, but the latter seems quite a long way off. Then there is the Hough Ear pill, but I don't really understand how that differs from OTO-413, except that it is a pill and that it may help with the auditory nerve. If I have auditory nerve damage as well I feel a bit doomed to be honest.

I suppose OTO-413 is based on BDNF and should regenerate synapses only, while HEI pill should regenerate both synapses and the nerve. And HEI pill is a different compund.

 

[Ozwel]

If you are talking about when the Phase 2a clinical trial results will be released they stated September 30th this year.

I have no idea when the actual release date for FX-322 is but they did receive Fast Track status last year and could possibly get Breakthrough Therapy status if Phase 2a results are positive.

I really hope they release it in 2021 but with the coronavirus that date seems unlikely.

"Breakthrough Therapy status"? What do you mean?

What is fast track doing anyway? Having shorter test periods? Skipping some phases?

Not sure if skipping phases is a good thing honestly. I'm dealing with tinnitus for years and years, I can wait for one more year if they make sure it works better and it is safer.

If it's just about speeding up the admin side on the FDA side, then ok.

 

[BBakkers]

If you are talking about when the Phase 2a clinical trial results will be released they stated September 30th this year.

I have no idea when the actual release date for FX-322 is but they did receive Fast Track status last year and could possibly get Breakthrough Therapy status if Phase 2a results are positive.

I really hope they release it in 2021 but with the coronavirus that date seems unlikely.

I hope you are right in general and about the Breakthrough Therapy status. But a Wikipedia search gave me this hit:

"Requests are reviewed by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). CDER receives approximately 100 requests per year for breakthrough designation. Historically, about one third were approved. CBER receives 15–30 requests per year. Sponsors must apply for breakthrough status separately for each indication they intend to label the drug for. Breakthrough designation applications are submitted as an amendment to the IND applications, usually prior to end of Phase II meeting."

Just thinking out loud: pompous:?
-So if we are optimistic, there's a 33% chance of getting Breakthrough tatus, only if the results are showing a lot of promise in September?
-And for which indication would they need to label FX-322 to get the Breakthrough status? Tinnitus or restoring hearing?

 

[FGG]

I hope you are right in general and about the Breakthrough Therapy status. But a Wikipedia search gave me this hit:

"Requests are reviewed by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). CDER receives approximately 100 requests per year for breakthrough designation. Historically, about one third were approved. CBER receives 15–30 requests per year. Sponsors must apply for breakthrough status separately for each indication they intend to label the drug for. Breakthrough designation applications are submitted as an amendment to the IND applications, usually prior to end of Phase II meeting."

Just thinking out loud: pompous:?
-So if we are optimistic, there's a 33% chance of getting Breakthrough tatus, only if the results are showing a lot of promise in September?
-And for which indication would they need to label FX-322 to get the Breakthrough status? Tinnitus or restoring hearing?

The indication would have to be for hearing I would imagine since that's what their IND submission was for and their trial reflects that (tinnitus is only in the experimental arm).

 

[Sevv]

I hope you are right in general and about the Breakthrough Therapy status. But a Wikipedia search gave me this hit:

"Requests are reviewed by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). CDER receives approximately 100 requests per year for breakthrough designation. Historically, about one third were approved. CBER receives 15–30 requests per year. Sponsors must apply for breakthrough status separately for each indication they intend to label the drug for. Breakthrough designation applications are submitted as an amendment to the IND applications, usually prior to end of Phase II meeting."

Just thinking out loud: pompous:?
-So if we are optimistic, there's a 33% chance of getting Breakthrough tatus, only if the results are showing a lot of promise in September?
-And for which indication would they need to label FX-322 to get the Breakthrough status? Tinnitus or restoring hearing?

It has probably a good chance of getting breakthrough status since the US army has a vested interest in improving the hearing of its soldiers (just not in developing a fix for it).

 

[PhoenixAcademy]

Are we even sure that tinnitus is from hair cell and synapse damage?

What about people with tinnitus that is on and off and have normal hearing? I even used to get tinnitus for a few minutes here and there as a child. Wouldn't it make more sense that this is more like brain damage?

 

[F-u-T]

Are we even sure that tinnitus is from hair cell and synapse damage?

What about people with tinnitus that is on and off and have normal hearing? I even used to get tinnitus for a few minutes here and there as a child. Wouldn't it make more sense that this is more like brain damage?

My tinnitus is 100% from hearing loss. Developed right after an acoustic trauma event.

 

[MrCrybaby]

Are we even sure that tinnitus is from hair cell and synapse damage?

What about people with tinnitus that is on and off and have normal hearing? I even used to get tinnitus for a few minutes here and there as a child. Wouldn't it make more sense that this is more like brain damage?

"Normal hearing" does not mean no hearing damage, audiograms are severely outdated. There are scientists who know and understand more than we do that think this could impact tinnitus, that's why it's an experimental arm of the study.

 

[FGG]

Are we even sure that tinnitus is from hair cell and synapse damage?

What about people with tinnitus that is on and off and have normal hearing? I even used to get tinnitus for a few minutes here and there as a child. Wouldn't it make more sense that this is more like brain damage?

Read the Dr. Sedley thread, he goes into it a bit more. Tinnitus brains are not damaged brains, they are normal brains (and possibly even more efficient brains at prediction of sound) reacting to damage.