Frequency Therapeutics — Hearing Loss Regeneration

[AtlasFainted]

FX-322 repairs hair cells and will re-synapse to the ganglions of the nerve once repaired. If you have synapse damage without hair cell damage or auditory nerve damage (pretty uncommon and due to certain systemic immune conditions) you will need different drugs.

OTO-413, Hough Pill and Pipeline Therapeutics for synapse.

Rinri is working on auditory nerve damage (things like Guillian Barre or genetic conditions can affect the nerve).

This is good news to me. Before I thought that FX-322 doesn't repair, it only regrows.

I previously thought hair cells that were damaged but not lost completely wouldn't be helped by the drug.

 

[Ben S]

It's a new month, which means we're one month closer to getting this stuff!

 

[FGG]

This is good news to me. Before I thought that FX-322 doesn't repair, it only regrows.

I previously thought hair cells that were damaged but not lost completely wouldn't be helped by the drug.

They have said "damaged or destroyed hair cells" before though it would be nice to get an exact clarification from them. I think most of the time damaged cells would be subject to apoptosis over time anyway so you could do those cells with later dosing i suspect anyway.

I also think (based on Liberman) that a lot of people who suspect they might have "minor" hair cell damage may have more of an issue with synaptopathy instead (at least with noise induced) since the synapses are much more susceptible to damage. Just my opinion.

 

[Danad]

FX-322 repairs hair cells and will re-synapse to the ganglions of the nerve once repaired. If you have synapse damage without hair cell damage or auditory nerve damage (pretty uncommon and due to certain systemic immune conditions) you will need different drugs.

OTO-413, Hough Pill and Pipeline Therapeutics for synapse.

Rinri is working on auditory nerve damage (things like Guillian Barre or genetic conditions can affect the nerve).

Unless I've misunderstood the process, FX-322 causes clonal expansion of Lgr5 cells (progenitors) and then converts them into IHC and OHCs with full synapse machinery. There is no repair of existing hair cells.

 

[PhoenixAcademy]

If the hair cells are just damaged then can they eventually heal on their own? I think they are classified as types of nerves, and if nerves can sometimes heal couldn't hair cells too?

 

[AtlasFainted]

They have said "damaged or destroyed hair cells" before though it would be nice to get an exact clarification from them. I think most of the time damaged cells would be subject to apoptosis over time anyway so you could do those cells with later dosing i suspect anyway.

I also think (based on Liberman) that a lot of people who suspect they might have "minor" hair cell damage may have more of an issue with synaptopathy instead (at least with noise induced) since the synapses are much more susceptible to damage. Just my opinion.

Apoptosis over time for damaged cells seems like it could make sense. I read an interview with Liberman where he talked about his research (I think @Tweedleman posted it).

Most of my hearing damage I suspect is from gunfire, most of it as a child (my super smart dad always told me I didn't need hearing protection) but exacerbated by an infection which is when my tinnitus showed up.

I'm deaf in my right ear when it comes to ultra high frequencies 10kHz+, and I have tinnitus in both ears. I'm leaning towards thinking I've probably lost a lot of hair cells in the upper frequencies... what are the chances in your opinion that this is actually mass synaptopathy? I know this is all speculation but its all we can do at this point...

 

[FGG]

Unless I've misunderstood the process, FX-322 causes clonal expansion of Lgr5 cells (progenitors) and then converts them into IHC and OHCs with full synapse machinery. There is no repair of existing hair cells.

One of the presentations said "damaged or destroyed cells" which makes me wonder if it's a similar process as other cellular repair. Ie whether you damage or destroy skin cells, your skin gets remodeled and damaged cells get displaced.

But you are right I should have used "replaced" instead of repaired.

I would love to get the company's exact position on this.

 

[FGG]

If the hair cells are just damaged then can they eventually heal on their own? I think they are classified as types of nerves, and if nerves can sometimes heal couldn't hair cells too?

They can recover from acute inflammation sometimes but don't heal from chronic injury on their own. Peripheral nerves can heal on their own but central nerves (e.g..cranial nerves, spinal cord) and hair cells do not.

Regenerative medicine is trying to bridge this gap.

 

[Ben S]

Unless I've misunderstood the process, FX-322 causes clonal expansion of Lgr5 cells (progenitors) and then converts them into IHC and OHCs with full synapse machinery. There is no repair of existing hair cells.

I really hope that it repairs damaged cells, because there's no way you can have only destroyed cells and completely healthy cells with nothing in between...

 

[FGG]

Apoptosis over time for damaged cells seems like it could make sense. I read an interview with Liberman where he talked about his research (I think @Tweedleman posted it).

Most of my hearing damage I suspect is from gunfire, most of it as a child (my super smart dad always told me I didn't need hearing protection) but exacerbated by an infection which is when my tinnitus showed up.

I'm deaf in my right ear when it comes to ultra high frequencies 10kHz+, and I have tinnitus in both ears. I'm leaning towards thinking I've probably lost a lot of hair cells in the upper frequencies... what are the chances in your opinion that this is actually mass synaptopathy? I know this is all speculation but its all we can do at this point...

If you can't hear anything over 10kHz in one ear, I think you should get an extended audiogram. You almost definitely have measurable OHC damage and might see it to a certain extent in your "good" ear too.

 

[FGG]

I really hope that it repairs damaged cells, because there's no way you can have only destroyed cells and completely healthy cells with nothing in between...

I think replaces might have been a better word than repairs.

 

[Diesel]

I really hope that it repairs damaged cells, because there's no way you can have only destroyed cells and completely healthy cells with nothing in between...

I'd like to pose a theory on damaged vs destroyed, since we're all about speculating in this thread...

Let's classify "destroyed" cells as those that have been replaced with a support cell "scar" that, from what we know so far citing other sources here; those support cells may be LGR5+ cells. So in a round-about way, a "destroyed cell" that is really a support cell is replaced with a a fresh new hair cell when FX-322 is applied.

Now let's talk about "damaged" cells. I pose three scenarios to consider:

1. There's some way that damage cells are replaced with new cells because FX-322 can pass through/around them and be "absorbed" by the underlying/surrounding progenitor support cells.
2. Somehow the organ/surrounding support cells "knows" what is damaged/not functioning and "ejects" the damaged hair cells. This part of the video shared above; McLean mentions that the cell creation is throttled; which may imply that the body somehow knows max capacity; so it may not be getting a signal from damaged cells and replaces them.

See: 18:30 in the video.


3. I suspect, as shown in many of Frequencies' "Damaged" rows of hair cell images, that hearing loss, (potentially tinnitus), involves consolidated regions of hair cells that are damaged/destroyed. So, it might be that in a region where there are 100 cells that are missing/damaged, causing hearing loss at a certain frequency range, that restoring a fraction, let's say 50 to new, leaving 50 damaged, may be enough for the system to begin functioning at an acceptable level again.

 

[PhoenixAcademy]

They can recover from acute inflammation sometimes but don't heal from chronic injury on their own. Peripheral nerves can heal on their own but central nerves (e.g..cranial nerves, spinal cord) and hair cells do not.

Regenerative medicine is trying to bridge this gap.

Do you think they are close?

 

[PhoenixAcademy]

So my tinnitus changes A LOT!!!!!!!! Sometimes it is a combination of 3-5 tones anywhere from about 1,500 Hz all the way up to above 15,000 Hz. It changes, almost day to day. Sometimes it is loud, sometimes it is not very loud and I can live normally that day with a clear mind.

I get the theory about damaged hair cells and restoring input but with me, it just changes and is all over the spectrum all the time and I am wondering if a treatment like FX-322 would help people like me?

 

[Tweedleman]

I found a recent article that might shed some light on this, but of course it's behind a paywall. Anybody here already have it?

https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(19)30040-2

From the abstract:
"This damage can manifest in many forms, from dysfunction of the hair cell mechanotransduction complex to loss of specialized ribbon synapses, and may even result in hair cell death."

and:
"Given that mammalian hair cells do not regenerate, the repair of hair cell damage is important for continued auditory function throughout life. Here, we discuss how several key hair cell structures can be damaged, and what is known about how they are repaired."

 

[serendipity1996]

I found a recent article that might shed some light on this, but of course it's behind a paywall. Anybody here already have it?

https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(19)30040-2

From the abstract:
"This damage can manifest in many forms, from dysfunction of the hair cell mechanotransduction complex to loss of specialized ribbon synapses, and may even result in hair cell death."

and:
"Given that mammalian hair cells do not regenerate, the repair of hair cell damage is important for continued auditory function throughout life. Here, we discuss how several key hair cell structures can be damaged, and what is known about how they are repaired."

I may be able to get institutional access to this, will check!

 

[annV]

I found a recent article that might shed some light on this, but of course it's behind a paywall. Anybody here already have it?

https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(19)30040-2

From the abstract:
"This damage can manifest in many forms, from dysfunction of the hair cell mechanotransduction complex to loss of specialized ribbon synapses, and may even result in hair cell death."

and:
"Given that mammalian hair cells do not regenerate, the repair of hair cell damage is important for continued auditory function throughout life. Here, we discuss how several key hair cell structures can be damaged, and what is known about how they are repaired."

Here's the full paper, you're welcome.

 

[FGG]

Here's the full paper, you're welcome.

Thank you! And here is a link to the paper they referenced about the stereocilia bundles:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795320/

What I gleaned (I think):

In frogs and birds the stereocilia bundles self repair even when fully removed.

In mammals, they don't self repair in the cochlea but do in the vestibular hair cells (which means mammals have the capability but the gene isn't switched on in the cochlea).

This was done in vitro and in culture which would prevent apoptosis. They referenced a previous study which showed regeneration of these bundles in mammals but argued against that study saying they must not have damaged the stereocilia (or enough/properly). In order to destroy the bundles, this study used mechanical suction (totally real world scenario).

The point of the study seems to be to show that hair cells could survive in neonatal mice (which have cells that still can mature and still regenerate in a limited basis) without stereocilia for 2 weeks. The author concludes that if you could repair stereocilia in that time you could save the hair cell from dying, which means in my interpretation, in vivo this cell would likely die.

The study came out in 2009, so my guess is also the goal was to highlight a need to save the cell from dying with methods of regenerating the bundle that frogs and birds use. Which makes sense since hair cell regeneration wasn't possible in 2009.

Other thoughts?

 

[AtlasFainted]

I'd like to pose a theory on damaged vs destroyed, since we're all about speculating in this thread...

Let's classify "destroyed" cells as those that have been replaced with a support cell "scar" that, from what we know so far citing other sources here; those support cells may be LGR5+ cells. So in a round-about way, a "destroyed cell" that is really a support cell is replaced with a a fresh new hair cell when FX-322 is applied.

Now let's talk about "damaged" cells. I pose three scenarios to consider:

1. There's some way that damage cells are replaced with new cells because FX-322 can pass through/around them and be "absorbed" by the underlying/surrounding progenitor support cells.
2. Somehow the organ/surrounding support cells "knows" what is damaged/not functioning and "ejects" the damaged hair cells. This part of the video shared above; McLean mentions that the cell creation is throttled; which may imply that the body somehow knows max capacity; so it may not be getting a signal from damaged cells and replaces them.

See: 18:30 in the video.


3. I suspect, as shown in many of Frequencies' "Damaged" rows of hair cell images, that hearing loss, (potentially tinnitus), involves consolidated regions of hair cells that are damaged/destroyed. So, it might be that in a region where there are 100 cells that are missing/damaged, causing hearing loss at a certain frequency range, that restoring a fraction, let's say 50 to new, leaving 50 damaged, may be enough for the system to begin functioning at an acceptable level again.

Considering your first point, I wonder if noise induced synaptopathy would damage the hair cell at all, or enough for it to be replaced by FX-322?

Also in Liberman's studies I wonder how long he waited to see how long the hair cells that had noise induced synaptopathy stuck around? It seems like there'd have to be at least some structual damage to the hair cell...

I'm really thinking a lot about how much of my hearing loss is synaptopathy based, and if the corresponding hair cells would be damaged enough for the drug to replace them.

 

[FGG]

Considering your first point, I wonder if noise induced synaptopathy would damage the hair cell at all, or enough for it to be replaced by FX-322?

Also in Liberman's studies I wonder how long he waited to see how long the hair cells that had noise induced synaptopathy stuck around? It seems like there'd have to be at least some structual damage to the hair cell...

I'm really thinking a lot about how much of my hearing loss is synaptopathy based, and if the corresponding hair cells would be damaged enough for the drug to replace them.

By definition noise induced synaptopathy damages the synapse while noise induced hair cell loss effects hair cells.

Get an extended audiogram if you want to know if outer hair cell loss is likely to be part of your clinical picture.

 

[Momme]

@FGG

If a person has tinnitus in the head and not ears, what damage is it you think or does it not matter where the tinnitus is located?

 

[Danad]

Considering your first point, I wonder if noise induced synaptopathy would damage the hair cell at all, or enough for it to be replaced by FX-322?

Also in Liberman's studies I wonder how long he waited to see how long the hair cells that had noise induced synaptopathy stuck around? It seems like there'd have to be at least some structual damage to the hair cell...

I'm really thinking a lot about how much of my hearing loss is synaptopathy based, and if the corresponding hair cells would be damaged enough for the drug to replace them.

Luckily for us, FX-322 appears to regenerate hair cells regardless of the state of existing cells.

 

[PhoenixAcademy]

in the head and not ears

Is there a difference?

 

[AtlasFainted]

By definition noise induced synaptopathy damages the synapse while noise induced hair cell loss effects hair cells.

Get an extended audiogram if you want to know if outer hair cell loss is likely to be part of your clinical picture.

Don't synapses reside within inner hair cells?

I know synaptopathy can happen without losing the associated hair cell, I'm just wondering if the hair cell can be damaged in the process, without being totally lost. It sounds like from your perspective, damaged hair cells eventually enter apoptosis.

Which I guess is good news where FX-322 is concerned.

Luckily for us, FX-322 appears to regenerate hair cells regardless of the state of existing cells.

But it only forms new hair cells where there aren't any, right?

& yes this is good news, and better news if hair cell loss is a greater problem for those who suffer NIHL than synaptopathy. (which is what I'm trying to figure out)

Obviously this varies case by case but I'm wondering if there are trends? Maybe high level acoustic trauma (gunshot) induces a higher degree of hair cell loss, where as lower level exposure over a longer period of time (construction site) induces more synaptopathy?

As I understand it, synaptopathy, not hair cell loss, could actually be the bigger problem for NIHL sufferers.

 

[Tweedleman]

Here's the full paper, you're welcome.

Thank you!!!

Thank you! And here is a link to the paper they referenced about the stereocilia bundles:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795320/

What I gleaned (I think):

In frogs and birds the stereocilia bundles self repair even when fully removed.

In mammals, they don't self repair in the cochlea but do in the vestibular hair cells (which means mammals have the capability but the gene isn't switched on in the cochlea).

This was done in vitro and in culture which would prevent apoptosis. They referenced a previous study which showed regeneration of these bundles in mammals but argued against that study saying they must not have damaged the stereocilia (or enough/properly). In order to destroy the bundles, this study used mechanical suction (totally real world scenario).

The point of the study seems to be to show that hair cells could survive in neonatal mice (which have cells that still can mature and still regenerate in a limited basis) without stereocilia for 2 weeks. The author concludes that if you could repair stereocilia in that time you could save the hair cell from dying, which means in my interpretation, in vivo this cell would likely die.

The study came out in 2009, so my guess is also the goal was to highlight a need to save the cell from dying with methods of regenerating the bundle that frogs and birds use. Which makes sense since hair cell regeneration wasn't possible in 2009.

Other thoughts?

It's still not clear to me how much damage to the hair bundle is necessary to cause the whole hair cell to die. Like you've pointed out the study is of course mainly interested in complete removal of hair bundles to gauge survival of the cell. In one instance they removed half of the V shaped hair bundle, but they don't mention the whole hair cell dying, just that the truncated half didn't repair.

I had hoped to get a sense of how prevelant these surviving "damaged" hair cells with bent/mangled/dysfunctional hair bundles might be in the average case. Do we likely have more widespread hair bundle damage/dysfunction than actual whole hair cell death responsible for our hearing problems?

In Frequency's video for FX-322 they only animated hair bundles completely sheared off and the respective hair cells subsequently dying. They don't show any surviving hair cells with damaged bundles. Only completely destroyed or untouched. Is it this black and white only to demonstrate FX-322's regenerative mechanism for dead hair cells?

 

[FGG]

@FGG

If a person has tinnitus in the head and not ears, what damage is it you think or does it not matter where the tinnitus is located?

Tinnitus is "heard" in the head regardless of where it originates because it is caused by reduced input, not an input an ear would normally "hear".

 

[FGG]

Thank you!!!

It's still not clear to me how much damage to the hair bundle is necessary to cause the whole hair cell to die. Like you've pointed out the study is of course mainly interested in complete removal of hair bundles to gauge survival of the cell. In one instance they removed half of the V shaped hair bundle, but they don't mention the whole hair cell dying, just that the truncated half didn't repair.

I had hoped to get a sense of how prevelant these surviving "damaged" hair cells with bent/mangled/dysfunctional hair bundles might be in the average case. Do we likely have more widespread hair bundle damage/dysfunction than actual whole hair cell death responsible for our hearing problems?

In Frequency's video for FX-322 they only animated hair bundles completely sheared off and the respective hair cells subsequently dying. They don't show any surviving hair cells with damaged bundles. Only completely destroyed or untouched. Is it this black and white only to demonstrate FX-322's regenerative mechanism for dead hair cells?

The paper seemed to imply at the end that they thought the cell would die if they couldn't save it by regenerating the bundle. At least that's how I read it. There seemed to be a reason they stopped at 14 days and I think it was to show that in mammals the bundle didn't regenerate and the other thought reversing that (as in frogs, chicks) might prevent that.

 

[FGG]

Don't synapses reside within inner hair cells?

I know synaptopathy can happen without losing the associated hair cell, I'm just wondering if the hair cell can be damaged in the process, without being totally lost. It sounds like from your perspective, damaged hair cells eventually enter apoptosis.

Which I guess is good news where FX-322 is concerned.

But it only forms new hair cells where there aren't any, right?

& yes this is good news, and better news if hair cell loss is a greater problem for those who suffer NIHL than synaptopathy. (which is what I'm trying to figure out)

Obviously this varies case by case but I'm wondering if there are trends? Maybe high level acoustic trauma (gunshot) induces a higher degree of hair cell loss, where as lower level exposure over a longer period of time (construction site) induces more synaptopathy?

As I understand it, synaptopathy, not hair cell loss, could actually be the bigger problem for NIHL sufferers.

Google the cochlear anatomy online. That should help clear it up. There are no synapses inside hair cells. Synapses connect inner hair cells to the spiral ganglion neurons.

 

[Juan]

Tinnitus is "heard" in the head regardless of where it originates because it is caused by reduced input, not an input an ear would normally "hear".

I think it depends on the kind of tinnitus, if it is somatosensory tinnitus, noise-induced, and also if it is reactive to sound, or perceived as a filter on top of sound, or heard at the same time of sound.

 

[FGG]

I think it depends on the kind of tinnitus, if it is somatosensory tinnitus, noise-induced, and also if it is reactive to sound, or perceived as a filter on top of sound, or heard at the same time of sound.

I'm not following you. All tinnitus is ultimately heard in the auditory cortex, no? It is not the result of external stimulus unless you have something like pulsatile tinnitus.