Frequency Therapeutics — Hearing Loss Regeneration

[Andrei90]

The short answer is no one here knows. That said, it seems as though their approach should work as long as there are Lgr5+ supporting cells. In your example, the outcome would likely depend on why there was only a 20% gain in the first place. It could be that additional rounds could improve things or it could be that there is other damage that cannot be fixed by this approach. Again, however, this is all speculation since we have only seen one paper at this point.

I remember there being some concern about these support cells not being there for some reason. Is there a possibility they might disappear at some point? Perhaps through considerable damage such as profound hearing loss? Will these people be able to be saved at all? Sorry if this has been discussed before. These threads get longer by the day and harder to find the appropriate post.

 

[parsky]

The short answer is no one here knows. That said, it seems as though their approach should work as long as there are Lgr5+ supporting cells. In your example, the outcome would likely depend on why there was only a 20% gain in the first place. It could be that additional rounds could improve things or it could be that there is other damage that cannot be fixed by this approach. Again, however, this is all speculation since we have only seen one paper at this point.

Aaron, have you seen anything in the literature about whether the Lgr5+ cells convert directly to hair cells after division or does another molecule convert them? Just wondering if any Lgr5+ cells would be left after the FX-322 treatment? I haven't seem them comment on this so far, but might have missed something.

 

[Aaron123]

Aaron, have you seen anything in the literature about whether the Lgr5+ cells convert directly to hair cells after division or does another molecule convert them? Just wondering if any Lgr5+ cells would be left after the FX-322 treatment? I haven't seem them comment on this so far, but might have missed something.

With Frequency's approach, they differentiate before conversion so supporting cells should remain.

Is there a possibility they might disappear at some point? Perhaps through considerable damage such as profound hearing loss?

Yes.

Will these people be able to be saved at all?

If there are none of the appropriate supporting cells, then this approach will not work.

 

[Apolonia]

If there are none of the appropriate supporting cells, then this approach will not work.[/QUOTE]
What if the supporting cells work out and then they die bc of another acoustic trauma, are there other supporting cells or those were the last ones? And also, let's Just stop discussing about the possible outcomes.. these questions and speculations are Just making me more anxious and I guess other People as well... Let's see first what happens and then discuss about the results.... IT is kind of sad that they only rely on these supporting cells... I kind of thought that they Will produce completely New cells... That would mean an infinite regeneration....I guess companies with hearing aids will still be very much busy.... Why can't they finally make a cochlear implant for listening to music with all this New technology?

 

[Aaron123]

Let's see first what happens and then discuss about the results..

I'm in favor of this. And yet you put forth another hypothetical

What if the supporting cells work out and then they die bc of another acoustic trauma, are there other supporting cells or those were the last ones?

IT is kind of sad that they only rely on these supporting cells... I kind of thought that they Will produce completely New cells... That would mean an infinite regeneration

It is the supporting cells that are the progenitor cells (in fact it is only a subset of the supporting cells, but that doesn't really matter for the discussion here) so without them this approach would not work. No idea what you mean by "completely New cells" or "infinite regeneration".

 

[parsky]

With Frequency's approach, they differentiate before conversion so supporting cells should remain.

I wish there was a cartoon of this. So the LGR5+ support cell divides through wnt signaling, the resulting new cell converts to a hair cell? This is different than the use of gamma secretase inhibitors which cause direct trans differentiation through notch? I'm still a bit confused because it looks like in the paper they are using a cocktail that works on both wnt and notch.

 

[Reinier]

Just wondering if any Lgr5+ cells would be left after the FX-322 treatment?

I read that part become LGR5+ cells and part become hair cells (LGR5-). So you should not "run out of" progenitor cells. After all the same happens in the intestinal tract. We don't run out of progenitor cells there.

 

[Contrast]

[USERGROUP=4]@Moderators[/USERGROUP] It would be helpful if there was a "FAQ & Updates" tab in the Frequency Thread which describes the process Frequency is using to regenerate hair cells as well as what we currently know about their success as well as updates.

This way everything is organized and it will prevent people from asking the same repetitive questions. Most post made by @Aaron123 are very informative so someone has to take on the task of scanning through the thread and finding his and other post containing important info and pin them in a separate tab.

 

[Steve]

[USERGROUP=4]@Moderators[/USERGROUP] It would be helpful if there was a "FAQ & Updates" tab in the Frequency Thread which describes the process Frequency is using to regenerate hair cells as well as what we currently know about their success as well as updates.

This way everything is organized and it will prevent people from asking the same repetitive questions. Most post made by @Aaron123 are very informative so someone has to take on the task of scanning through the thread and finding his and other post containing important info and pin them in a separate tab.

We are working on something but it will take a little bit to implement. I'm on the same page as you, these threads can become unwieldy and need a summary.

 

[jcloth]

Frequency steals Otonomy's CSO:

https://www.businesswire.com/news/h...rapeutics-Welcomes-Otonomy-CSO-Executive-Vice

"Since I've been monitoring scientific advances in hearing regeneration over the last decade, I consider Frequency's PCA Regeneration platform a game-changer that has the potential to address a multitude of diseases, starting with their most advanced program in hearing regeneration," said Dr. LeBel. "This is an exciting time to be involved with a company like Frequency, who is poised to bring a new form of regenerative medicine therapeutics to fruition and help millions of people the world over. I'm honored to join such an auspicious group of individuals and continue building on their successful therapeutic research and development."

 

[Sven]

This is good news why? (Asking because I have no clue. )

 

[IAmCalifornia]

This is good news why? (Asking because I have no clue. )

It means things are moving along

 

[jeff W]

This is good news why? (Asking because I have no clue. )

A rat fleeing a sinking ship. Lets hope he was brought in to increase speed to trial dates.

 

[Aaron123]

Frequency steals Otonomy's CSO

They didn't actually "steal" him. He left Otonomy in late 2016/early 2017 depending on the source.

 

[jcloth]

Science Magazine Recognizes Frequency Therapeutics' PCA Regeneration Technology as a Breakthrough in Regenerative Medicine

https://www.businesswire.com/news/h...izes-Frequency-Therapeutics’-PCA-Regeneration

 

[Aaron123]

Science Magazine Recognizes Frequency Therapeutics' PCA Regeneration Technology as a Breakthrough in Regenerative Medicine

The fact that Will McLean was a finalist for this award was posted a couple of weeks ago when the finalists and winner were announced. Didn't seem to get much interest though perhaps that was because it was in the inner hair cell regeneration thread....
https://www.tinnitustalk.com/threads/inner-ear-hair-cell-regeneration-—-maybe-we-can-know-more.3131/page-119#post-315347
https://www.tinnitustalk.com/threads/inner-ear-hair-cell-regeneration-—-maybe-we-can-know-more.3131/page-119#post-315375

The essay is most notable for having the first published statement that they have achieved "functional hearing improvement in animals with hearing loss". Otherwise it's just a description of what they have already published.

 

[Chad Lawton]

For those wondering about whether the dead/damaged cells would remain after treatment, it looks like/is likely that the dead/damaged cells are cleared away by the body sometime after the damage occurs, depending on the severity of the damage. In this video at the :52 second mark,



You can see images of mouse cochlea's. After they damaged the cochlea, the cells disappear. Whether this is due to the stain no longer working on the damaged cells or them actually being cleared away remains unknown.

Also, if you google "damaged hair cells ear" and look at the electron microscopy images, you can see that while some of the stereocilia are bent or broken looking, in a lot of the images the stereocilia are completely missing; indicating that they are cleared away. Here are a few examples:

https://www.google.com/search?q=dam...AUICigB&biw=1920&bih=960#imgrc=2axLc0baEnXHcM:

https://www.google.com/search?q=dam...AUICigB&biw=1920&bih=960#imgrc=MgUvqAuw-z_sIM:

https://www.google.com/search?q=dam...AUICigB&biw=1920&bih=960#imgrc=lW3xu738AZrZsM:

I think this lends credence to the tinnitus theory of "reduced input to the brain" rather than the "cell stuck in the on position" theory because there appears to be a visual reduction in stereocilia hairs in the damaged hearing examples.

Edit- Unless the cell body continues to emit neurotransmitters when there is a complete lack of stereocilia, then that would align with the "on position" theory.

 

[Contrast]

I think this lends credence to the tinnitus theory of "reduced input to the brain" rather than the "cell stuck in the on position" theory because there appears to be a visual reduction in stereocilia hairs in the damaged hearing examples.

Edit- Unless the cell body continues to emit neurotransmitters when there is a complete lack of stereocilia, then that would align with the "on position" theory.

I agree, reduced input in the auditory nerve can result in central gain and hyper neuronal activity (tinnitus and hyperacusis) It makes far more sense because it explains hyperacusis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208401/

 

[Chad Lawton]

Great video and article, hadn't seen that one yet. I completely agree.

My biggest concern with Frequency's treatment is how well the new stereocilia will anatomically form. They've proven they can grow the cells with all the functional features, but will the stereocilia lengths be correct and do they need to be facing the proper direction for the cochlear fluid to effect them properly? From what I've read, the stair step fashion of the stereocilia length plays a key role in normal hearing. From the video I posted, you can see the new cells are in quite a disorganized fashion.

I'm concerned that they've done testing on animals and have measured brain stem responses that point to a hearing improvement, but for all we know the mouse could be hearing everything all garbaled even though it can now hear noises. Time will tell.

 

[Apolonia]

Great video and article, hadn't seen that one yet. I completely agree.

My biggest concern with Frequency's treatment is how well the new stereocilia will anatomically form. They've proven they can grow the cells with all the functional features, but will the stereocilia lengths be correct and do they need to be facing the proper direction for the cochlear fluid to effect them properly? From what I've read, the stair step fashion of the stereocilia length plays a key role in normal hearing. From the video I posted, you can see the new cells are in quite a disorganized fashion.

I'm concerned that they've done testing on animals and have measured brain stem responses that point to a hearing improvement, but for all we know the mouse could be hearing everything all garbaled even though it can now hear noises. Time will tell.

I agree with you. We need to take into consideration the fact that the New hair cells May not be properly distributed.. that is what happens with Birds. They can regrow New hair cells but those cells are not organized as the original ones were...anyways, the results Will tell... But, it Will be a process. Until then we better take care of the reamaining hearing we have

 

[robertmaverick]

I agree with you. We need to take into consideration the fact that the New hair cells May not be properly distributed.. that is what happens with Birds. They can regrow New hair cells but those cells are not organized as the original ones were...anyways, the results Will tell... But, it Will be a process. Until then we better take care of the reamaining hearing we have

I think the whole idea of Frequency is to kickstart an innate proces in the human body to regenerate the hair cells. So the method Frequency uses is not a method to create hair cells per se, but to instruct the body to regenerate the cells. Our body has a perfect blue print of our most ideal body, so I am not really concerned about such issues.

 

[streeter1985]

I have a question concerning the "lost hair cells" and the connection to the auditory nerve. I for example have a T from a hearing loss and need 90db at 5000 hz and above. I have no hearing aid, but I believe in the theory that a T comes from less input in the auditory nerve (concerning hearing loss generated T). So lets say Frequency finds a cure or 50% improvement in 10 years wouldnt it be useless for hearing loss patients like me that dont need to wear a hearing aid because the auditory nerve would have disabled the availability to transport sounds around 5000hz over time? Like "use it or lose it". I hope I wrote it understandable. So the question is should hearing loss patients use hearing aids also if they dont need them 100% to keep the full functionality of the nerve up. Of course those hearing aids cant cover all frequencies...but it would at least cover the important ones.

Sorry if my question is from a lack of knowledge about the complete cure process, but that question just popped up for me reading your discussion and seemed important to me. Thank you!

 

[Contrast]

I have a question concerning the "lost hair cells" and the connection to the auditory nerve. I for example have a T from a hearing loss and need 90db at 5000 hz and above. I have no hearing aid, but I believe in the theory that a T comes from less input in the auditory nerve (concerning hearing loss generated T). So lets say Frequency finds a cure or 50% improvement in 10 years wouldnt it be useless for hearing loss patients like me that dont need to wear a hearing aid because the auditory nerve would have disabled the availability to transport sounds around 5000hz over time? Like "use it or lose it". I hope I wrote it understandable. So the question is should hearing loss patients use hearing aids also if they dont need them 100% to keep the full functionality of the nerve up. Of course those hearing aids cant cover all frequencies...but it would at least cover the important ones.

Sorry if my question is from a lack of knowledge about the complete cure process, but that question just popped up for me reading your discussion and seemed important to me. Thank you!

I don't think it works that way, I highly doubt hearing aids stimulate the auditory nerve in anyway.

Charles Liberman a leading expert on hearing loss stated that the nerve signals last decades after damage so a therapeutic window is long.

 

[Chad Lawton]

I don't think it works that way, I highly doubt hearing aids stimulate the auditory nerve in anyway.

Charles Liberman a leading expert on hearing loss stated that the nerve signals last decades after damage so a therapeutic window is long.

I disagree. While the hearing aid may not stimulate the auditory nerve directly, it does assist with sound amplifcation which in turn can cause greater stimulation to the auditory nerve via the hair cells. It is my understanding that the outer hair cells are primarily responsible for amplification while the inner hair cells actually send the afferent signal to the brain. When you have db threshold losses greater than 50db, this tends to damage the inner hair cells. If your loss is less than 50db typically only the outer hair cells are damaged.

https://www.ncbi.nlm.nih.gov/pubmed/95382

By using a hearing aid, you are assisting the outer hair cells with the amplification process and thus the inner hair cells can send a stronger signal down the nerve when they hear the amplified sound from the hearing aid. This lends credence to why many people with mild/moderate hearing loss get relief from tinnitus with hearing aids.

 

[Akk]

I don't think it works that way, I highly doubt hearing aids stimulate the auditory nerve in anyway.

Charles Liberman a leading expert on hearing loss stated that the nerve signals last decades after damage so a therapeutic window is long.

I have quite similar HL (- 60 dB) above 4 kHz in left ear and have constant T. I use hearing aid, and it reduces my T about 40-50 %. In addition it helps me hear higher frequencies and let me enjoy music listening again. But it took about three months with HA, before HF-hearing came back. So, I do belive that HA stimulates audiotory nerve somehow.

 

[Contrast]

I have quite similar HL (- 60 dB) above 4 kHz in left ear and have constant T. I use hearing aid, and it reduces my T about 40-50 %. In addition it helps me hear higher frequencies and let me enjoy music listening again. But it took about three months with HA, before HF-hearing came back. So, I do belive that HA stimulates audiotory nerve somehow.

Now that I think about it, I am wrong. Central gain decreases once higher frequencies are heard better. Therefore hearing aids should slightly or moderately reduce tinnitus and hyperacusis type 1

 

[Contrast]

The brain rewires itself again to adapt to the hearing aids enhancements

 

[Rajin]

@Contrast I got a 90 yrs old ears , I . Fuc....k screwed I think .Left ear with T very bad 70 dB loss @ 6 k Right ears not too bad 40 dB @6k . Hearing Aid do help a little in my left ears. You think I will be able to get help from frequency Hearing regeneration. Low frequency , mid are good.

 

[Contrast]

@Contrast I got a 90 yrs old ears , I . Fuc....k screwed I think .Left ear with T very bad 70 dB loss @ 6 k Right ears not too bad 40 dB @6k . Hearing Aid do help a little in my left ears. You think I will be able to get help from frequency Hearing regeneration. Low frequency , mid are good.

As far as I know (correct me if I am wrong) the progenitor cells have to exist for new hair cells to be created.
Frequency has a method of cloning progenitor cells to create the max amount of hair cells possible unlike other bio tech firms which are converting progenitor cells into hair cells with only minimal hair cell regeneration. Frequency claims they can generate 2000 fold hair cells. However the begging questions "If it works?" will not be answered until Frequency-tx's Stage 2 clinicial trial which is suppose to start mid 2018. So all we can do is wait until then.

Also remember there is more to hearing then just hair cells. This will not repair damaged auditory nerve fibers,
and take note of the post above by @Chad Lawton about the hair cells being an incorrect length which might lead into problems. Since high frequency hair cells are short and low frequency hair cells are long in design.

The ears God/Evolution gave us naturally was perfect but fragile, sciences best attempt at regenerating hearing will ofcourse have some flaws. Perhaps one day in the future it will be perfected but right now all we can do is wait for stage 2 of Frequency.

 

[Rajin]

The good thing is my T is moderate, think from all I read here. I feel I am getting better as time goes by. Hope for the best for everyone here , to get some kind of help soon. Thanks for the response.