Frequency Therapeutics — Hearing Loss Regeneration

[JohnAdams]

From http://www.hearingreview.com/2018/10/university-rochester-researchers-regrow-sensory-hair-cells/

"The researchers found that activating the ERBB2 pathway triggered a cascading series of cellular events by which cochlear support cells began to proliferate and start the process of activating other neighboring stem cells to become new sensory hair cells. Furthermore, it appears that this process not only could impact the regeneration of sensory hair cells, but also support their integration with nerve cells."​

From memory, Frequency Therapeutics hope their drug will do something similar. I don't have the reference though.

I emailed Mr. Jeff Karp sometime ago and asked this:

"But I would like to ask you if your method will also repair/regenerate the auditory nerve/connections from nerve to hair cell?"

Mr Jeff Karp responded:

"Thank you for the note - we have some evidence to suggest the answer to that question is yes - but only time will tell as we push things forward

with warm regards,

Jeff"

 

[Don Tinny]

Phase 3 is everything. Am I wrong? Remember Auris Medical´s AM-101

 

[Enclave]

I, too, am most worried about what @Contrast said. That a healthy HC, but with retracted ribbon synapses, will not get regenerated, thus this drug will be futile for this kind of damage.

Hopefully OTO-413 will fix the issue above.

I am concerned that the cascading of chemical signals that FX-322 will initiate will cause the development of Supernumery Hair Cells, which can negatively impact hearing.

 

[Reinier]

That a healthy HC, but with retracted ribbon synapses, will not get regenerated

I read that a hair cell needs these synapses in order to survive. Likely it will survive with a smaller amount of synapses, otherwise there would not be the so called "hidden hearing loss".

Also I wonder if damaged hair cells survive or will eventually die anyway.

 

[katri]

I, too, am most worried about what @Contrast said. That a healthy HC, but with retracted ribbon synapses, will not get regenerated, thus this drug will be futile for this kind of damage.

Hopefully OTO-413 will fix the issue above.

I am concerned that the cascading of chemical signals that FX-322 will initiate will cause the development of Supernumery Hair Cells, which can negatively impact hearing.

In what way?

 

[JohnAdams]

Phase 3 is everything. Am I wrong? Remember Auris Medical´s AM-101

AM-101 is nothing like FX-322. AM-101 was not designed to restore hearing, but quieten tinnitus. FX-322 was not designed to quieten tinnitus, but restore hearing. The main ingredients of FX-322 have already been shown to restore hearing in deafened mice. This of course only holds promise for tinnitus sufferers that got their tinnitus from hearing loss.

 

[JohnAdams]

I, too, am most worried about what @Contrast said. That a healthy HC, but with retracted ribbon synapses, will not get regenerated, thus this drug will be futile for this kind of damage.

Hopefully OTO-413 will fix the issue above.

I am concerned that the cascading of chemical signals that FX-322 will initiate will cause the development of Supernumery Hair Cells, which can negatively impact hearing.

I would take Jeff Karp's opinion over Contrast's.

 

[Don Tinny]

AM-101 is nothing like FX-322. AM-101 was not designed to restore hearing, but quieten tinnitus. FX-322 was not designed to quieten tinnitus, but restore hearing. The main ingredients of FX-322 have already been shown to restore hearing in deafened mice. This of course only holds promise for tinnitus sufferers that got their tinnitus from hearing loss.

Yes, I know. And AM-101 was only for acute tinnitus.

Regarding FX-322: maybe people who have profound hearing loss feel some difference. But I wonder if it will help in cases of very specific hearing loss, like ours. I hope it works. If it becomes effective it will be a transcendental event of historical importance.

 

[Contrast]

Phase 3 is everything. Am I wrong? Remember Auris Medical´s AM-101

AM-101 would have only helped you in a few weeks of time span after tinnitus onset.

 

[Johan_L]

Hopefully OTO-413 will fix the issue above.

Otonomy's stock has plunged 90% over the last 3 years.

Anybody know why?

Makes we worried there is not much potential in OTO-413, OTO-313 or OTO-6XX.

 

[katri]

Yes, I know. And AM-101 was only for acute tinnitus.

Regarding FX-322: maybe people who have profound hearing loss feel some difference. But I wonder if it will help in cases of very specific hearing loss, like ours. I hope it works. If it becomes effective it will be a transcendental event of historical importance.

When the synapses are lost and broken, it triggers a ton of other symptoms. I say that it's worth checking out the ribbon synapses more than anything else.

In articles we see that supporting cells have the capability to move after damage. In other articles we see that we can regenerate and repair the broken synapses.

If the brain is as plastic as everyone says it is (it is), then it should help more than hurt to at least repair the broken synaptic areas.

 

[katri]

Otonomy's stock has plunged 90% over the last 3 years.

Anybody know why?

Makes we worried there is not much potential in OTO-413, OTO-313 or OTO-6XX.

Probably because they have so much going on and they are tight lipped about it.

Each project they have is explained within one paragraph and they don't make too many of their research papers public.

There has to be some kind of potential based on what we've seen from other public research in the same field, especially those relating to BDNF (or whatever it is)

 

[Rubenslash]

Otonomy's stock has plunged 90% over the last 3 years.

Anybody know why?

Makes we worried there is not much potential in OTO-413, OTO-313 or OTO-6XX.

Has to do with failed Meniere's drug in phase 3, nothing to do with its preclinical research on hearing loss.

 

[PolishSoldier87]

Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs
https://www.ncbi.nlm.nih.gov/m/pubmed/25036727/

"Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening.

Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness."

@JohnAdams
John, do you remember who is working at synapses regeneration?

 

[JohnAdams]

Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs
https://www.ncbi.nlm.nih.gov/m/pubmed/25036727/

"Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening.

Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness."

@JohnAdams
John, do you remember who is working at synapses regeneration?

"The pairing of the two delivered the breakthrough solution, the researchers said, as neurons responded to the molecule, regenerating synapses in mouse ear tissue that led to repair of the hair cells and neurons, which are essential to hearing."

https://news.usc.edu/140224/new-study-shows-hope-for-hearing-loss/

 

[grate_biff]

who is working at synapses regeneration?

Decibel Therapeutics!

 

[PolishSoldier87]

I think unless hair cells are dead, there is a possibility to repair IHC/OHC synapses.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132175/
"Although exogenous NT-3 and BDNF are equally effective in promoting SGN neurite growth and synaptogenesis in vitro, we show here that growth of SGN axons to IHCs and synaptogenesis on IHCs are greatly reduced by TrkC-IgG, a NT-3 scavenger, thus establishing a role for endogenous NT-3 in reinnervation of IHCs. As TrkB-IgG was without effect, BDNF is not necessary for reinnervation. Remarkably, TrkC-IgG inhibits SGN axon growth and synaptogenesis even when BDNF is added to the culture medium. This implies that NT-3, the principal endogenous neurotrophin in the organ of Corti, has a distinctive role in promoting SGN axon growth to IHCs and synaptogenesis on IHCs, a role for which BDNF can't substitute even when added at high concentration. Conversely, in the vestibular system, BDNF is necessary for proper innervation of hair cells by vestibular neurons and NT-3 can't substitute (Agerman et al., 2003). BDNF and NT-3 also differ with respect to physiological phenotypes they induce in SGNs (Adamson et al., 2002). The observations that NT-3 and BDNF differ in their effects on inner ear neurons imply that, in this context, TrkC signaling is functionally different from TrkB signaling, even though they are structurally similar receptor protein-tyrosine kinases."

Here is also interesting relation:
"As expected, in noise-treated animals the spiral ganglia neurites were retracted from inner hair cells by 29.5 ± 12.9 μιη 24 hr following noise exposure. The neurites remained retracted (23 ± 3.6 μιη) 14 d after noise exposure. The persistent retraction indicates a permanent loss of synaptic connectivity between hair cells and spiral ganglia neurites in vehicle-treated animals after noise exposure."
https://patents.google.com/patent/WO2014014828A1/en
In the other way:
"ribbons may persist for several days in the absence of a postsynaptic partner and that the rapid loss of presynaptic ribbons following acoustic trauma results, at least in part, from a direct effect of noise on the IHC rather than being entirely a result of loss of spiral ganglia neurites' postsynaptic terminals on the IHC."

 

[katri]

I think unless hair cells are dead, there is a possibility to repair IHC/OHC synapses.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132175/
"Although exogenous NT-3 and BDNF are equally effective in promoting SGN neurite growth and synaptogenesis in vitro, we show here that growth of SGN axons to IHCs and synaptogenesis on IHCs are greatly reduced by TrkC-IgG, a NT-3 scavenger, thus establishing a role for endogenous NT-3 in reinnervation of IHCs. As TrkB-IgG was without effect, BDNF is not necessary for reinnervation. Remarkably, TrkC-IgG inhibits SGN axon growth and synaptogenesis even when BDNF is added to the culture medium. This implies that NT-3, the principal endogenous neurotrophin in the organ of Corti, has a distinctive role in promoting SGN axon growth to IHCs and synaptogenesis on IHCs, a role for which BDNF can't substitute even when added at high concentration. Conversely, in the vestibular system, BDNF is necessary for proper innervation of hair cells by vestibular neurons and NT-3 can't substitute (Agerman et al., 2003). BDNF and NT-3 also differ with respect to physiological phenotypes they induce in SGNs (Adamson et al., 2002). The observations that NT-3 and BDNF differ in their effects on inner ear neurons imply that, in this context, TrkC signaling is functionally different from TrkB signaling, even though they are structurally similar receptor protein-tyrosine kinases."

Here is also interesting relation:
"As expected, in noise-treated animals the spiral ganglia neurites were retracted from inner hair cells by 29.5 ± 12.9 μιη 24 hr following noise exposure. The neurites remained retracted (23 ± 3.6 μιη) 14 d after noise exposure. The persistent retraction indicates a permanent loss of synaptic connectivity between hair cells and spiral ganglia neurites in vehicle-treated animals after noise exposure."
https://patents.google.com/patent/WO2014014828A1/en
In the other way:
"ribbons may persist for several days in the absence of a postsynaptic partner and that the rapid loss of presynaptic ribbons following acoustic trauma results, at least in part, from a direct effect of noise on the IHC rather than being entirely a result of loss of SGN postsynaptic terminals on the IHC."
View attachment 23526

You mean stop them from retracting? Or go back to their original placement?

 

[PolishSoldier87]

You mean stop them from retracting? Or go back to their original placement?

To stop them for retracting during therapeutic window is quite easy it seems.

https://patents.google.com/patent/WO2014014828A1/en

Thread:
Nicotinamide Riboside
"Next, spiral ganglia neurites in NR-treated animals were examined. Noise exposure in NR-treated animals resulted in minimal neurite retraction after both 24 hr"

After that window happens what I wrote about in my previous post.

However death of ribbons and synapses is also a direct result of noise impact on IHC so stopping retraction could be useless in some cases.

As @JohnAdams wrote:
Some researchers work on complex regeneration of this neural connection, even if it is broken by dead synapses, presynaptic ribbons or spiral ganglia neurities (not funny damage to one of this elements can permanently kill others).

So it could be done.

 

[JohnAdams]

To stop them for retracting during therapeutic window is quite easy it seems.

https://patents.google.com/patent/WO2014014828A1/en

Thread:
Nicotinamide Riboside
"Next, spiral ganglia neurites in NR-treated animals were examined. Noise exposure in NR-treated animals resulted in minimal neurite retraction after both 24 hr"

After that window happens what I wrote about in my previous post.

However death of ribbons and synapses is also a direct result of noise impact on IHC so stopping retraction could be useless in some cases.

As @JohnAdams wrote:
Some researchers work on complex regeneration of this neural connection, even if it is broken by dead synapses, presynaptic ribbons or spiral ganglia neurities (not funny damage to one of this elements can permanently kill others).

So it could be done.

I said that?

 

[PolishSoldier87]

I said that?

You provided a source:
https://news.usc.edu/140224/new-study-shows-hope-for-hearing-loss/

"The pairing of the two delivered the breakthrough solution, the researchers said, as neurons responded to the molecule, regenerating synapses in mouse ear tissue that led to repair of the hair cells and neurons, which are essential to hearing."

 

[JohnAdams]

Ok stop worrying about ribbon synapses. FX-322 or whatever does everything.

Will McLean of Frequency Therapeutics talks about this. Skip to 16:50:



We just have to wait.......

 

[JohnAdams]

Also in that video, the last comment seems to indicate that the length of time you have hearing damage shouldn't matter so long as you still have lgr5+cells.

 

[PolishSoldier87]

Ok stop worrying about ribbon synapses. FX-322 or whatever does everything.

Will McLean of Frequency Therapeutics talks about this. Skip to 16:50:



We just have to wait.......

Did he say that it promotes synapse regeneration in HC that are damaged and already exists?

 

[PolishSoldier87]

Also in that video, the last comment seems to indicate that the length of time you have hearing damage shouldn't matter so long as you still have lgr5+cells.

So I think on hearing loss of -60 dB it should work excellently.

 

[JohnAdams]

So I think on hearing loss of -60 dB it should work excellently.

I think so too.

Did he say that it promotes synapse regeneration in HC that are damaged and already exists?

Nope. Hopefully functioning ones will grow around them that will send better signals.

 

[Jack Straw]

Ok stop worrying about ribbon synapses. FX-322 or whatever does everything.

Will McLean of Frequency Therapeutics talks about this. Skip to 16:50:



We just have to wait.......

Very good news! Will watch when I get home!

 

[PolishSoldier87]

I think so too.

Nope. Hopefully functioning ones will grow around them that will send better signals.

Yes. And this beautiful healthy input will lead the brainstem and cerbellum out from the states of hyperactivity and cross-activity that are causing tinnitus and hyperacusis.

 

[jeff W]

Otonomy's stock has plunged 90% over the last 3 years.

Anybody know why?

Makes we worried there is not much potential in OTO-413, OTO-313 or OTO-6XX.

Potential and Otonomy?

 

[Contrast]

Potential and Otonomy?

View attachment 23542

What made investors dislike Otonomy?

It's sad knowing OTO-413 is the only confirmed up and coming treatment for cochlear synaptopathy.

Once again Decibel hasn't announced anything but they are working on it.