Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

[FGG]

Doesn't hurt to try given the lack of options for hearing loss out there. Provided the possible improvements outweigh the side effects. Who knows how many of the old people that are taking this drug are getting their hearing checked regularly. Lack of testing is one of the big issues in hearing health care isn't it?

For some people who can't wait for trials and are suffering dearly, I don't disagree with last ditch efforts.

 

[d'Wooluf]

From the link posted by @Utopia in the other thread, they are still looking at clinical trials, so probably not an immediate solution.

Edit:
https://medicalxpress.com/news/2020-07-bone-disease-medications-reverse-loss.html

 

[urgentresearch]

This research was funded in part by the Lauer Tinnitus Research Center

Funding
This work was supported by the Department of Defense grant W81XWH-15-1-0472, the National Institutes of Health grants R01 DC015824 (KS) and R01 DC014089 (AE), Nancy Sayles Day Foundation, Lauer Tinnitus Research Center, and Sheldon and Dorothea Buckler (KS). AE is a cofounder and scientific advisor to Decibel Therapeutics and Audion Therapeutics.​

 

[tommyd87]

From the link posted by @Utopia in the other thread, they are still looking at clinical trials, so probably not an immediate solution.

Edit:
https://medicalxpress.com/news/2020-07-bone-disease-medications-reverse-loss.html

I don't think that this is too far away though in terms of them being able to trial the treatment if there is evidence of positive outcomes in rats and also if it is believed to benefit humans.

While the lab trials may take time to complete all their required processes I could see something getting fast tracked should there be proof of success at that time.

 

[FGG]

I don't think that this is too far away though in terms of them being able to trial the treatment if there is evidence of positive outcomes in rats and also if it is believed to benefit humans.

While the lab trials may take time to complete all their required processes I could see something getting fast tracked should there be proof of success at that time.

If it works, it wouldn't need to be fast tracked. These drugs are already available and could be used off-label.

 

[Utopia]

Since the bisphosphonate was administered 24 hours after the noise exposure in the mice, do you think it's worth trying a prescription for tinnitus/hearing loss that has lasted months?

 

[d'Wooluf]

do you think it's worth trying a prescription for tinnitus/hearing loss that has lasted months?

It would be challenging finding a doctor that would prescribe it and administer it to you. It's commonly taken through an IV drip and there are possible serious side effects. The results I've seen from a retrospective study were interesting but not dramatic enough to warrant an off-label prescription. Mostly, people's SNHL remained stable. This was over 5 years or more, so an impressive result really (you would have expected continued loss of hearing for that particular group) but not enough for a doctor to take the risk. NB I'm not a doctor.

 

[tommyd87]

If it works, it wouldn't need to be fast tracked. These drugs are already available and could be used off-label.

Oh ok, excellent. Is it only a requirement that they get tested through the phases if it is a new drug?

 

[FGG]

Oh ok, excellent. Is it only a requirement that they get tested through the phases if it is a new drug?

If you want something labelled for an indication, i.e. so insurance will cover it, it needs to be tested for that indication whether it's old or new.

Any approved drug can be used off label by a doctor if they see a medical reason for doing so and there isn't a restriction on that.

 

[tommyd87]

Any approved drug can be used off label by a doctor if they see a medical reason for doing so and there isn't a restriction on that.

OK cheers. Currently that is different to what happens in Australia.

 

[FGG]

OK cheers. Currently that is different to what happens in Australia.

I should have clarified. That's only in the US. I have no idea what the regulations are in other countries.

 

[tommyd87]

I should have clarified. That's only in the US. I have no idea what the regulations are in other countries.

It is incredibly likely that the access will be granted in Australia if it is granted in America as long as it is proven to be safe and works.

When the trials are done in the US and as long as the results are positive it will get released in Australia ASAP after.

Almost all Europe and US based treatments get approved here in Australia

 

[Thuan]

@FGG Do you think Frequency Therapeutics is aware of this? Seeing that FX-322 is targeting hair cell regrowth (but I think they are hypothesizing that it will also regenerate neurons), wouldn't using this in conjunction with FX-322 be ideal (assuming that FX-322 is actually effective for their Phase 2)?

 

[FGG]

@FGG Do you think Frequency Therapeutics is aware of this? Seeing that FX-322 is targeting hair cell regrowth (but I think they are hypothesizing that it will also regenerate neurons), wouldn't using this in conjunction with FX-322 be ideal (assuming that FX-322 is actually effective for their Phase 2)?

I'm sure they keep up with synaptopathy drugs in general considering Dr. LeBel used to work for Otonomy and they have a synaptopathy drug in trial (OTO-413).

As far as adding Bisphosphonates to the trial of FX-322, you don't add random drugs in the middle of FDA trials, that's not really how it works.

But Otonomy has said using OTO-413 (synapse repair) with OTO-6xx (hair cell) may produce additive results in terms of hearing so if Bisphosphonates work, it is possible they could have a synergistic effect.

OTO-413 should have phase 1/2 results around the end of this year so there will be more data on at least one synaptopathy drug well before Bisphosphonates in humans.

 

[WillBeNimble]

@FGG Do you think Frequency Therapeutics is aware of this? Seeing that FX-322 is targeting hair cell regrowth (but I think they are hypothesizing that it will also regenerate neurons), wouldn't using this in conjunction with FX-322 be ideal (assuming that FX-322 is actually effective for their Phase 2)?

I am certain that Frequency Therapeutics is aware of other possible solutions to neuron growth that are in the works. There's OTO-413, the Hough Pill, and now these. Hair cell loss tends to be the primary reason for hearing loss, though, so I can understand where Frequency Therapeutics is coming from.

 

[Thuan]

@FGG, @WillBeNimble and whoever else. Are there resource links on how the various Otonomy drugs work, somewhat like in the format of the FX-322 research papers on mice?

Reading the research, the mechanisms and results in lab animals is giving me hope. It would be really wonderful if someone could stick these at the top of each respective thread.

 

[FGG]

@FGG, @WillBeNimble and whoever else. Are there resource links on how the various Otonomy drugs work, somewhat like in the format of the FX-322 research papers on mice?

Reading the research, the mechanisms and results in lab animals is giving me hope. It would be really wonderful if someone could stick these at the top of each respective thread.

In general, you can find this info on each of these company's websites. Often they have a "publications page" or reference their publications in their presentations page. Here is a link to Otonomy's presentations page:

https://investors.otonomy.com/presentations

 

[tommyd87]

I am certain that Frequency Therapeutics is aware of other possible solutions to neuron growth that are in the works. There's OTO-413, the Hough Pill, and now these. Hair cell loss tends to be the primary reason for hearing loss, though, so I can understand where Frequency Therapeutics is coming from.

I think that while what you have said is right, it is a combination of both bits. We know that the improvement in the synapses allows you to much better hear speech in noise and we know that the improvement in hair cell function gives you volume and clarity.

Currently the research shows that there is an obvious overlap between the two in terms of evidence and hypothesis.

Thus hair cells are the primary point when it comes to hearing however synapses still play a crucial and actually important role with this.

That's why I feel strongly that people are actually going to benefit from both bits of treatment. This is because they work in conjunction and unless a massive gain is demonstrated when looking at speech in noise with FX-322 then you are going to take both for the ultimate result.

 

[Jurger]

I think that while what you have said is right, it is a combination of both bits. We know that the improvement in the synapses allows you to much better hear speech in noise and we know that the improvement in hair cell function gives you volume and clarity.

Currently the research shows that there is an obvious overlap between the two in terms of evidence and hypothesis.

Thus hair cells are the primary point when it comes to hearing however synapses still play a crucial and actually important role with this.

That's why I feel strongly that people are actually going to benefit from both bits of treatment. This is because they work in conjunction and unless a massive gain is demonstrated when looking at speech in noise with FX-322 then you are going to take both for the ultimate result.

Which groups are most at risk for cochlear synaptopathy? I always assumed it's mostly the elderly because of decades of wear and tear of the cochlea, whereas patients with some sort of incident - acoustic trauma, sudden hearing loss, ototoxicity - are more likely to have mostly hair cell damage.

 

[FGG]

@Jurger

Charles Liberman (one of the top researchers on cochlear synaptopathy and the one I believe who discovered it) reports cochlear synaptopathy frequently in both noise trauma and aging populations. Really anything that causes glutamate neuroexcitability can cause the connections to break, however (including some ototoxins).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438769/

 

[Jurger]

@Jurger

Charles Liberman (one of the top researchers on cochlear synaptopathy and the one I believe who discovered it) reports cochlear synaptopathy frequently in both noise trauma and aging populations. Really anything that causes glutamate neuroexcitability can cause the connections to break, however (including some ototoxins).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438769/

Maybe it's time to get Liberman or Stefan Heller on the Tinnitus Talk Podcast to talk about neurosynaptopathy.

 

[El BUZZ]

I did participate in the AM-101 trial, receiving a total of 9 injections per ear. Doctor told me it was a pretty easy and common procedure for which most ENT doctors are trained for. Before receiving the injection they have to numb the area using some lidocaine or other form of anesthetic. Then, after 15 to 20 minutes the injection is applied which is 100% painless. After that one had to rest on their side for 30 minutes making the whole visit to last around nearly one hour.

I was scared shitless before receiving the first pair. Then I was very confident in each of the following injections.

 

[Thuan]

@FGG Do you think excessive consumption of MSG rich foods can also cause this? I think it's kind of well known that some people get headaches eating MSG rich food. I wonder if some people who has tinnitus with unknown causes have been eating MSG rich food over the years, which slowly damage their cochlea.

 

[serendipity1996]

Maybe it's time to get Liberman or Stefan Heller on the Tinnitus Talk Podcast to talk about neurosynaptopathy.

Liberman would be great - I am sure he would have lots of valuable insights into hidden hearing loss and also noxacusis.

 

[FGG]

@FGG Do you think excessive consumption of MSG rich foods can also cause this? I think it's kind of well known that some people get headaches eating MSG rich food. I wonder if some people who has tinnitus with unknown causes have been eating MSG rich food over the years, which slowly damage their cochlea.

Who knows. There is definitely a link between food sensitivities and migraines and there are types of migraines that are associated with (even peripheral, inner ear type) vertigo so there might be some sensitive individuals who could have a general inner ear reaction to it. I haven't seen any studies/evidence it's a risk factor on the population as a whole, though.

Just to be clear, I doubt it's related to synaptopathy but could be related to inflammation that makes symptoms worse.

 

[GBB]

Who knows. There is definitely a link between food sensitivities and migraines and there are types of migraines that are associated with (even peripheral, inner ear type) vertigo so there might be some sensitive individuals who could have a general inner ear reaction to it. I haven't seen any studies/evidence it's a risk factor on the population as a whole, though.

Just to be clear, I doubt it's related to synaptopathy but could be related to inflammation that makes symptoms worse.

To the best of our collective knowledge is there a therapeutic window for synapse regeneration? The text of the original study here seems to suggest therapeutic potential solely or largely because the nerve fibers remain living for months or years.

 

[tommyd87]

To the best of our collective knowledge is there a therapeutic window for synapse regeneration? The text of the original study here seems to suggest therapeutic potential solely or largely because the nerve fibers remain living for months or years.

I don't think that there is any issue of time. I think that it is simply a matter of regenerating them to then restore their functionality.

 

[GBB]

I don't think that there is any issue of time. I think that it is simply a matter of regenerating them to then restore their functionality.

But are we regenerating the synapse or the spinal ganglion neuron or both? It sounds like the SGN has a finite lifespan.

"There is potentially a long therapeutic window because cell bodies of SGNs can survive for many months (in animal models) and years (in humans) after peripheral synaptic and neurite loss."

 

[tommyd87]

But are we regenerating the synapse or the spinal ganglion neuron or both? It sounds like the SGN has a finite lifespan.

"There is potentially a long therapeutic window because cell bodies of SGNs can survive for many months (in animal models) and years (in humans) after peripheral synaptic and neurite loss."

\
I am pretty positive that the information I have said indicates that the restoration of synapses also restores the nerve function. From finding out about this through the reading I have done, the issue with this not being able to regrow is more to do with the fact that there was no way of achieving this pre-medicine research.

Here is one such research paper's abstract that indicates this is being investigated. I would also suggest that this is quite possible and also pretty probable with synapse repair since I am actually lead to believe that these are the nerve endings that have been talked about when synapse repair happens.

https://link.springer.com/chapter/10.1007/978-3-030-40413-0_4

 

[GBB]

\
I am pretty positive that the information I have said indicates that the restoration of synapses also restores the nerve function.

Here is one such research paper's abstract that indicates this is being investigated. I would also suggest that this is quite possible and also pretty probable with synapse repair since I am actually lead to believe that these are the nerve endings that have been talked about when synapse repair happens.

https://link.springer.com/chapter/10.1007/978-3-030-40413-0_4

Okay thank you for clarifying!