Frequency Therapeutics — Hearing Loss Regeneration

http://www.courant.com/business/hc-...d-fri-may--5-084003-2017--20170505-story.html
Dang ear buds and ear infections!

year to 18 months

 

Another question due to a possible duration of a clinical trial. Frequency TX claims, that both involved drugs are already been used in other clinical application, so the cobination of both for the inner ear would be an off label application? I guess, one compound could be the one Albert Edge has been used (the one currently tested for Alzheimer disease)...So probably, they aren't completly untested in case of secure dosages or so.
Was just a thought.

 

Wow news to me what drug is being tested on Alzheimer's?

 

As far as I know, the drug in question is no longer being tested on Alzheimer's. The drug is LY411575. It's an Eli Lilly drug that, I believe, is also being used by Audion.

 

This is the thread that makes everyday seem better. The day this treatment is available cant come soon enough. I really hope this will be the cure.

 

A little remark about the effectivity of HA's in reducing your T sound. Probably it is due to auditory masking which is a build in feature of our beautiful brain. It is the main reason why compressed audio (like mp3's) sounds the same (well... If you are not an audiophile off course ) as uncompressed audio. Our consciousness can not handle the chaos of multiple frequency input and shuts down the unnecessary frequencies. That's why most of us don't hear the T sound while listening to music.

More info about psychoacoustics and auditory masking on wikipedia: https://en.m.wikipedia.org/wiki/Psychoacoustics

 

One more article about Frequency TX. It's the same as we already know, but the statement of
Dr. Mark Parker is interesting. He has also a very good knowledge about hair cell regeneration.

Mark A. Parker, a hearing loss researcher at the Tufts University School of Medicine who is not affiliated with the company, applauds the private venture capital funding for advancing hearing technology, rather than the traditional model of getting grants from the federal government. He said the company still likely has plenty of questions to work out, such as whether it is safe and what kinds of patients would benefit.

Parker also noted there are other companies and researchers working on similar ideas to build a drug to restore hearing. “I think the more people that invest in this, the more companies that invest in it, the better off we will be as humanity,” he said. For now, though, he’s not telling patients to hold off on hearing aids yet.


http://www.vocativ.com/427408/startup-manufacture-hearing-drug/

 

i definitely notice a diff when I try to go without masking and no noise in a room. It seems to just build up and get louder and louder. The whole idea of putting the masking sound below the T seems to work in calming it down which supports this. When i do listen to music I can pick it out if i look for it sometimes but your def right.

 

This is interesting, too (and new, I think):

"Frequency’s researchers published a paper about their scientific approach in the journal Cell Reports in February and say they have another paper coming out later this year."

 

Could this process of converting supporting cell be modified to replace dead vestibular hair cells?? I don't currently have this problem but could be useful for the elderly with balance issues.

 

I found the article again, where the 2 components of Frequency TX has been described. It's in German language:
GSK3beta-Inhibitors
and
Histon-Deacetylase-Inhibitors
and these two should be tested in the clinic right now, for another treatment.

https://www.aerzteblatt.de/nachrich...offe-koennten-Haarzellen-im-Innenohr-erneuern

 

It appears that the article is not quite correct. The quotes below are from the paper McLean et al., 2017, Cell Reports 18, 1917–1929 February 21, 2017 ª 2017 The Author(s). http://dx.doi.org/10.1016/j.celrep.2017.01.066

The two compounds they mentioned were used to expand the supporting cells ("We added the glycogen synthase kinase 3b (GSK3b) inhibitor CHIR99021 (CHIR or C) and the histone deacetylase (HDAC) inhibitor valproic acid (VPA or V) to the growth factor cocktail that was previously used for the culture of inner ear spheres..." (page 1918)). Thus it is the GSK3b inhibitor, the HDAC inhibitor and a cocktail of growth factors. They refer to this as EFICVP6.

To differentiate the supporting cells to hair cells they used an additional drug, "To test whether the expanded Lgr5+ cells were able to generate higher yields of hair cells after simultaneous Notch inhibition and Wnt activation, we treated Lgr5-GFP or Atoh1-nGFP cells, expanded by the above procedures, with LY411575, a g-secretase inhibitor previously used to differentiate inner ear progenitor cells (Jeon et al., 2011; Mizutari et al., 2013), and CHIR, the GSK3b inhibitor.(1920)".

Thus there are three separate compounds: CHIR99021, valproic acid, and LY411575 along with the other components of EFICVP6. Of these, valproic acid is available now so there is no problem with that. I have not been able to find evidence that either CHIR99021 or LY411575 are being tested in humans. I've read the same quote (that they are using drugs that are being or have been tested in humans) so I must be missing something. I'm not sure if it would be adequate that some other GSK3b inhibitor or g-secretase inhibitor has been tested in humans.

Reading the paper highlights that it will be challenging to deliver the right combination of drugs in the right order to make this work. It would be easier to just use CHIR99021 and LY411575, but that would involve the loss of supporting cells.

I'm sure Frequency knows quite a lot about these issues. We will hopefully know more with the next paper.

 

Hi,
thank you for analysis. I hope they know how to apply it in the best way.
Did they annouce about when they release their next paper?

 

No, but given when the last one was submitted, I'm assuming they have one under review now.

 

Here's an interesting exchange I recently had with Will McLean on reddit:

As I understand it, the gel you are working on is designed to activate dormant progenitor cells in the cochlea, activating them to differentiate into functioning hair cells. Will the gel only activate supporting cells that are adjacent to deceased hair cells? If not, and supporting cells next to healthy hair cells are also susceptible to activation, would that be problematic or not?

There are experiments showing that when you turn on cell cycle using transgenic mice, creating extra cells doesn't impact hearing ability. It is important to note that we are using drugs that target only a select portion of supporting cells. We have not seen any concerning results.

The findings that have been published so far involve cochleae removed from mice, primates and a human (I think?). I see that in 18 months there will be live human trials. Has there/will there be data from live animal experiments prior to that?

We have promising animal data

As I understand it, OHCs and IHCs are different types of cells, both of which you will be aiming to regenerate. But aside from this distinction, are individual hair cells unique from each other? Are they encoded with particular information to prepare them for particular frequencies, or are they all inherently identical and it is it simply their location within the cochlea that determines their relationship with frequencies? I can imagine a treatment being significantly more complicated in the former scenario…

It is some of both. Obviously creating new hair cells in the cochlea will convey the location information (tonotopy). However, an important thing to keep in mind is how development works. Along the cochlea, the progenitor cells are already "preprogrammed" to become a hair cell of the correct type in a given location. We are re-triggering this process, and believe the hair cells will also gain their specific characteristics, and showed that we can make inner and out hair cells.


He is also skeptical of synapse damage in the absence of hair cell damage, which I found interesting:

In humans, my hypothesis is that you will never have pure synaptopothy. In animals, you need a very specific sound exposure to get the effect, and any higher or lower in level fails to produce this.

 

wow, this sounds very interesting, especially that these progenitor cells seem to be preprogrammed..
thanks a lot for sharing!

 

Something what I am asking:
Researcher Albert Edge is involved in Audion Therapeutics, in Decibel Tx and also appears on papers of Frequency Tx.
So at least all 3 companies does have almost the same knowledge, at least Audion and Decibel.
Did someone read any news about Audion recently, since the partnering with Eli there has't been any public statements.

 

thanks for the info as i was genuinely curious about this. this definitely increases my optimism if they can restore or improve my hearing loss at 8k hertz and above, it could effectively reduce or eliminate my t since i believe it's related to my hearing loss at those freqs. this thread is the main reason i keep coming back here.

 

No it is very silent around Audion Therapeutics. Maybe we see an update of the progress on this site soon as the reporting period just ended so it seems:

http://cordis.europa.eu/project/rcn/193313_en.html

 

ok, the Frequency TX masterplan should be, that if transdifferention has been done, the newly generated cell from the supporting cell would be on the correct position and would know all the parameters of the damaged, or
dead orginal hair cell? Like on this illustration?
https://www.researchgate.net/figure...pporting-cell-differentiates-into-a-hair-cell

 

Here's the video:

Local company testing revolutionary hearing...

 

Good to see a report like that on Frequency

Weirdly worded statement from the voiceover though: "We are born with the exact same number of hearing hair cells as we die with" ... ummmm no!

 

If they are promoting their company on TV show it means that they are really optimistic for the future treatment.
Actually I've never seen a company working about hearing loss with such visibility !

That's really nice !

 

I saw one, her name was Genvec

 

Could we know how many recoverings would be possible witt this therapy? Only one or everytime we had a hearing loss?

 

Ideally, it would be B rather than A.

I've been thinking about these issues and re-reading some of the public statements in press releases and then re-reading parts of the paper. The goal is of course to provide a single drug treatment to restart a dormant process that will first lead supporting cells to differentiate (expand) and then for a portion of them to convert to hair cells.

To expand the supporting cells they used "the glycogen synthase kinase 3b (GSK3b) inhibitor CHIR99021 (CHIR or C) and the histone deacetylase (HDAC) inhibitor valproic acid (VPA or V)" as well as a "growth factor cocktail". They refer to this combination as EFICVP6. To differentiate the supporting cells into hair cells they use LY411575 and CHIR.

So the goal is to only have to do the first step: induce the supporting cells to divide/expand. The idea is that this will then start the differentiation process. Thus, it makes sense to look at what was and wasn't in the paper.

In the paper, they performed a number of experiments:

1) For a cell culture (with cells presumably from newborn mice), they did both steps.

2) For a cell culture from adult mice, they did both steps.

3) Cells from an adult rhesus macaques expanded using EFICVP6, but the cells did not differentiate to hair cells (they suggest this was due to contamination).

4) Cells from a human adult inner ear expanded after treatment with EFICVP6 and differentiated into hair cells after treatment with LY411575 and CHIR. Thus, both steps were used and the combined treatment lasted 22 days.

5) Finally, they used cochlear explants from neonatal mice. These were treated with CHIR, VPA, and
"2-phospho-L-ascorbic acid (pVc or P), a stable form of vitamin C" for 3 days. In this case, they only did the first (expansion) step. This is the published evidence for the idea that all that is necessary is to induce cell division in the supporting cells, and the differentiation to hair cells will follow. The caveat to this is that the mice were 2 days old. Thus, there is not yet published evidence that using only the expansion protocol leads to new hair cells in adults.

The fact that they can grow such large numbers of hair cells is a big deal for research broadly speaking (and seems to be underappreciated around here), but experiments 4 and particularly 5 seem to me to be the big deal in terms of a path to a trial. Four because it demonstrates that regeneration is possible with adult tissue and five because it demonstrates that regeneration is possible after only inducing expansion.

What should we be looking for in the next paper(s)?

a.) can/do they overcome the weaker expansion in adult tissue compared to neonatal tissue?

b.) can/do they demonstrate that inducing expansion results in differentiation in adult mice?

c.) can/do they induce expansion and differentiation in living mice? (preferably with a single administration of small molecules rather than a multi-day cell culture)

d.) for newborn mice, can/do they go beyond talking about the properties of hair cells and actually demonstrate the restoration of hearing?

e.) for adult mice, can/do they demonstrate restoration of hearing?

f.) Once those are done, can/do they show that a single administration works (i.e., restores hearing) in a living young or (ideally) adult primate?

I don't expect all of that in 1 paper, and I am assuming that they already know the answers (or have a really good idea of the answers) to a number of these outcomes. However, my guess is that they will need to get to (f) before human trials can begin.

 

Samir... at the :55 second mark the reporter states it not Luchinno