Frequency Therapeutics — Hearing Loss Regeneration

[brokensoul]

I don't get this. If support cell loss could be as common as HC loss, why would these Stanford guys decide that the support cell was their basis for hearing regeneration? Surely they're privy to information that we don't have? I'm starting to get freaked out.

It's because the whole concept was born out of looking at regeneration in animals and the gastrointestinal system in humans. They discovered progenitor cells that regenerate the entire intestine every 2 weeks or so. When studying the body they found very similar progenitor cells in the cochlea. These Lgr5+ progenitor cells are part of the whole supporting cells group in the cochlea (epithelium). As the CEO said, during initial studies there was no awareness that the first application of progenitor regeneration would turn out to be hair cells.

They need to use something as a basis to create hair cells and these Lgr5+ cells are apparently ideal for that (according to Frequency Therapeutics). This is obviously related to the specific characteristics of this particular cell and the pathways (WNT and HDAC) it provides for manipulation.

 

[brokensoul]

I don't think aminoglycosides would complete decimate support cells but i wouldn't take a support cell depleting drug (e.g.. Audion). Support cell loss, like hair cell loss is usually a gradient so if you have HF loss, you lose more support cells near the base. So FX-322 will definitely help at least some parts of y'all's aminiglycoside ototoxic cochleas. And hopefully my macrolide cochleas too.

Eventually, it looks like they will be able to (or at least they are working on) generating support cells from epithelial cells). Chen mentioned this in his paper, for instance. These therapies further out. But progress is being made. It looks like the LATS pathway Decibel just purchased the rights to may be able to help generate support cells too.

I also emailed professor Shi at the Oregon Hearing Research Center who is working on strial regeneration yesterday. He said he believes his work will result in something clinical and already some companies have expressed interest. He told me he'd keep me updated. I am not sure if this will result in just vascular regeneration or also marginal cells, etc. He also said they now have strial cell lines that will make research go much faster.

It seems odd to me that companies can buy the rights to a cellular pathway.

So this means that other biochemical companies can not use that pathway, even if they could have or work out a better solution?

Am I understanding that correctly?

I already had this thought with Frequency Therapeutics as well.

 

[brokensoul]

Venture a guess as to how problematic epithelial scarring would be to hair cell regrowth?

Do you have some good sources on this?

 

[serendipity1996]

Reading different theories of whether FX-322 will work for us or not is frightening. I just hope FX-322 will help all of us who suffer with tinnitus, hyperacusis and hearing loss.

I know it's just one anecdote but the fact that one of the participants in the Regain trail reportedly saw improvements in his tinnitus and hyperacusis which enabled him to go back on tour again (IIRC he was a musician) gives me hope.

 

[FGG]

I suspect that since tinnitus is being assessed as a secondary outcome in the Phase 2A, they probably already have some indication that it may reduce it. They don't have concrete data that can be verified with the FDA since they didn't assess tinnitus upfront in the Phase 1/2. However, any notes, for example, from the staff monitoring treatment or the the patients themselves may have indicated that tinnitus improved in some way.

I was surprised that tinnitus would be measured in a Phase 2 and not a Phase 3 given how subjective patient feedback is on the symptoms.

I recall a lawyer once saying, "don't ask an open question if you don't already know what the answer will be." I believe this may be the case for the tinnitus survey in the P2A.

This is 100% the way I see it. They have something they haven't reported yet: patient testimonials.

They didn't add tinnitus for the fun of it and if it negatively affected tinnitus they wouldn't add it to the experimental arm instead of listing it in "adverse reactions".

It is very heavily implied by the company's behavior and response at the Q and A that this drug helps tinnitus imo.

 

[FGG]

It seems odd to me that companies can buy the rights to a cellular pathway.

So this means that other biochemical companies can not use that pathway, even if they could have or work out a better solution?

Am I understanding that correctly?

I already had this thought with Frequency Therapeutics as well.

I'm no patent expert at all but it seems like different molecular approaches are patented.

 

[Lucifer]

I know it's just one anecdote but the fact that one of the participants in the Regain trail reportedly saw improvements in his tinnitus and hyperacusis which enabled him to go back on tour again (IIRC he was a musician) gives me hope.

Me too. If the Regain trial allowed the musician to have improvements in tinnitus and hyperacusis which allowed him to go back on tour surely FX-322 can do the same as well.

 

[mrbrightside614]

Do you have some good sources on this?

No. The only comparison I can make is when the heart begins remodeling in the atherosclerotic process, damaged endothelial tissue becomes non-contractile as a result of a huge cascade of events that ultimately leads to formation of a "fibrous cap," basically endothelial scarring. Non-contractile tissue can lead to necrosis, and while this mechanism is very different in the heart it could still potentially stifle input from stimulus.

Me too. If the Regain trial allowed the musician to have improvements in tinnitus and hyperacusis which allowed him to go back on tour surely FX-322 can do the same as well.

Lol all this SC talk has me shouting fuck Regain from the rooftop. YIKES

 

[Diesel]

It is very heavily implied by the company's behavior and response at the Q and A that this drug helps tinnitus imo.

Yes, at the JPM conference. I believe it was Dr Loose who was being intentionally coy about answering a few questions he could have revealed more on. Good coaching by their legal counsel on that one, I'm sure.

 

[Lucifer]

Lol all this SC talk has me shouting fuck Regain from the rooftop. YIKES

It's a shame that supporting cells get depleted with Regain but at least they are trying to get something out in the market to help people.

If Regain comes out first some people will have no choice but to take it.

 

[brokensoul]

I know it's just one anecdote but the fact that one of the participants in the Regain trail reportedly saw improvements in his tinnitus and hyperacusis which enabled him to go back on tour again (IIRC he was a musician) gives me hope.

As far as I know it was never confirmed that his tinnitus and hyperacusis improved.

 

[brokensoul]

I don't think lack of supporting cells is going to be a problem for the majority of us. I wouldn't even disregard Audion's solution because they don't duplicate supporting cells. If Audion goes to market sooner they are certainly a worthy option to consider.

I'm surprised to learn though that supporting cell reduction leads to reduction of SGNs, just like I was surprised to learn that stria vascularis damage leads to OHC loss. There does seem to be a cascade of effects possible when one element is damaged. This is valuable input to be taken into account.

 

[brokensoul]

No. The only comparison I can make is when the heart begins remodeling in the atherosclerotic process, damaged endothelial tissue becomes non-contractile as a result of a huge cascade of events that ultimately leads to formation of a "fibrous cap," basically endothelial scarring. Non-contractile tissue can lead to necrosis, and while this mechanism is very different in the heart it could still potentially stifle input from stimulus.

Lol all this SC talk has me shouting fuck Regain from the rooftop. YIKES

I remember vaguely this has been discussed long ago, but I don't know anything about this. What exactly leads to epithelial scarring?

Why did @FGG and/or others not consider this a problem?

 

[Ben S]

So I'm trying to understand is the loss of SGNs also knows as Synaptopathy? Or is it a differnet kind of pathology?

 

[FGG]

I remember vaguely this has been discussed long ago, but I don't know anything about this. What exactly leads to epithelial scarring?

Why did @FGG and/or others not consider this a problem?

I don't know anything about epithelial scaring unless it pertains to the flat denuded epithelia ("cuboidal cells" I have heard it described) that can happen with very severe to profound loss. In that case FX-322 may not apply anyway. Otonomy has a drug in pre clinical for "severe hearing loss" and I'm very curious what their approach will be.

 

[Jaysterk]

So for those of us who were affected by Neomycin and other ototoxic drugs, it does not seem like FX-322 would work if we have depleted support cells? I am no expert but this is what I've gathered from the last 20 posts?

 

[brokensoul]

So I'm trying to understand is the loss of SGNs also knows as Synaptopathy? Or is it a differnet kind of pathology?

Completely different.

People need to keep in mind that FX-322 only regenerates hair cells. So it can only resolve tinnitus for people whose tinnitus is the direct result of hair cell loss.

If tinnitus is the result of cochlear synaptopathy you will need a solution like PIPE-505 or OTO-403.

If tinnitus is the result of auditory nerve damage you will need Hough's HPN07+NAC pill or something else.

Obviously you may need all of them to completely resolve your tinnitus (and this also assumes that your tinnitus is the result of hearing damage and not something else).

 

[mrbrightside614]

I remember vaguely this has been discussed long ago, but I don't know anything about this. What exactly leads to epithelial scarring?

Why did @FGG and/or others not consider this a problem?

HC loss leads to epithelial scarring. The following passage were in regards to my concern about glial scarring, which is not an issue since stem cells don't need to be transplanted with the frequency method.

Just read something that really scared me about the efficacy of stem cells, even when administered IT.

Even if FX-322 bypasses the need to infuse stem cells with growth factors for appropriate cell differentiation... "in past experiments, transplantation of stem cells into the damaged areas has produced only varying results, and a challenging problem that prevents successful stem cell transplantation is to avoid stem cell deaths. Stem cells often die due to failure to bypass the glial scar, a hallmark of neural damage that is thought to act as a barrier for cell transplantation."

This has been addressed by a research team in Kyoto, who "discovered that applying new stem cells to the surface of the glial scar rather than underneath it helps their survival. They reported that the survived stem cells were able to grow from the damaged segment of the auditory nerve, which then travel from the cochlea to the brainstem, the part of the brain which controls flow of messages between the brain and the rest of the body – in this case, the ear - and eventually restored remarkable auditory function."

Is the idea that the slow release gel will somehow "soak" into all of the damaged areas in question, including the glial scar? Any way we could get Frequency Therapeutics on the Tinnitus Talk Podcast? Do we have any contact information besides their LinkedIn?

 

[FGG]

So I'm trying to understand is the loss of SGNs also knows as Synaptopathy? Or is it a differnet kind of pathology?

SGNs are a separate structure. It's what is on the other side of the IHC synapse.

As it turns out though, you can pretty much ignore rodent studies on SGNs because they have myelinated SGNs and ours are unmyelinated. Ours also branch differently and preserve more function when damaged because the lack of myelination affords more connectivity it seems.

As a human, you can have severe hearing loss for decades and have normal SGNs. Things that effect SGNs in humans are usually things like autoimmune neuropathies or genetic conditions not the normal things that result in tinnitus.

I posted a more recent autopsy study on humans a few pages back (I think on this thread. I can't even keep track anymore) and they found that even very deaf humans who had hearing loss for decades had normal SGNs.

 

[FGG]

So for those of us who were affected by Neomycin and other ototoxic drugs, it does not seem like FX-322 would work if we have depleted support cells? I am no expert but this is what I've gathered from the last 20 posts?

If all the LGR+ cells were fully depleted, then no. I doubt most people are in that camp though.

 

[FGG]

I don't think lack of supporting cells is going to be a problem for the majority of us. I wouldn't even disregard Audion's solution because they don't duplicate supporting cells. If Audion goes to market sooner they are certainly a worthy option to consider.

I'm surprised to learn though that supporting cell reduction leads to reduction of SGNs, just like I was surprised to learn that stria vascularis damage leads to OHC loss. There does seem to be a cascade of effects possible when one element is damaged. This is valuable input to be taken into account.

Interestingly, we will soon have data on how important support cells are and how many of certain types are needed for hair cell maintenance after the long term Regain clinical results are out.

 

[brokensoul]

HC loss leads to epithelial scarring. The following passage were in regards to my concern about glial scarring, which is not an issue since stem cells don't need to be transplanted with the frequency method.

As far as I know when a hair cell is removed from the epithelium, a supporting cell will move into that position to ensure structural integrity of the epithelium.

 

[Jack V]

People need to keep in mind that FX-322 only regenerates hair cells. So it can only resolve tinnitus for people whose tinnitus is the direct result of hair cell loss.

If tinnitus is the result of cochlear synaptopathy you will need a solution like PIPE-505 or OTO-403.

If tinnitus is the result of auditory nerve damage you will need Hough's HPN07+NAC pill or something else.

Obviously you may need all of them to completely resolve your tinnitus (and this also assumes that your tinnitus is the result of hearing damage and not something else).

...and this also assumes that these drugs will actually work.

(which we all desperately hope that they will)

 

[Diesel]

Perhaps Progenitor Cell Activation has some effect of reversing, to some extent, damage/scarring? I believe it was in the Q&A at the JPM conference, one of the members at Frequency mentioned testing PCA formulations on "a thousand" donated cochlea. I find it hard to believe that after the broad spectrum of cochlea collected, this wouldn't have surfaced in the lab, and contributed to the first 321 formulations of FX-322. Perhaps during the progenitor activation process, a new hair cell is created adjacent to scarred tissue? Maybe I don't know what I'm talking about; I can only speculate that so much of what is discussed here has been scrutinized heavily over the last 5 years of substantial R&D at Frequency in order to release a viable, profitable product.

 

[Jaysterk]

Completely different.

View attachment 36038

People need to keep in mind that FX-322 only regenerates hair cells. So it can only resolve tinnitus for people whose tinnitus is the direct result of hair cell loss.

If tinnitus is the result of cochlear synaptopathy you will need a solution like PIPE-505 or OTO-403.

If tinnitus is the result of auditory nerve damage you will need Hough's HPN07+NAC pill or something else.

Obviously you may need all of them to completely resolve your tinnitus (and this also assumes that your tinnitus is the result of hearing damage and not something else).

Very clear and useful explanation.

What about tinnitus caused by something else such as... TMJ/Neck Injuries etc?

How about Damaged Supporting Cells?

 

[mrbrightside614]

Interestingly, we will soon have data on how important support cells are and how many of certain types are needed for hair cell maintenance after the long term Regain clinical results are out.

Where'd you find this?

 

[mrbrightside614]

Very clear and useful explanation.

What about tinnitus caused by something else such as... TMJ/Neck Injuries etc?

How about Damaged Supporting Cells?

This would be more suitable for the thread on Susan Shore.

It's generally accepted that neck/jaw tinnitus has a cochlear origin, and the brain is simply receiving more auditorial input from other areas due to hyperactivity in the dorsal cochlear nucleus.

 

[FGG]

Perhaps Progenitor Cell Activation has some effect of reversing, to some extent, damage/scarring? I believe it was in the Q&A at the JPM conference, one of the members at Frequency mentioned testing PCA formulations on "a thousand" donated cochlea. I find it hard to believe that after the broad spectrum of cochlea collected, this wouldn't have surfaced in the lab, and contributed to the first 321 formulations of FX-322. Perhaps during the progenitor activation process, a new hair cell is created adjacent to scarred tissue? Maybe I don't know what I'm talking about; I can only speculate that so much of what is discussed here has been scrutinized heavily over the last 5 years of substantial R&D at Frequency in order to release a viable, profitable product.

I agree with your other points, but drug numbers are not named because of the number of formulations (it's not like WD-40 famously was). They are given numbers during the IND stage when testing centers are contracted so that no two tested drugs at the same center will have the same number. It's an extra safe guard for keeping records straight.

I looked this up when another member had a conspiracy theory about "322" being an ivy league cross and bones virtue signaling reference.

 

[FGG]

Very clear and useful explanation.

What about tinnitus caused by something else such as...TMJ/Neck Injuries etc?

How about Damaged Supporting Cells?

This drug won't help tinnitus not caused by cochlear injury (e.g. TMJ or neck/brain stem injury), unfortunately.

 

[Ben S]

Perhaps Progenitor Cell Activation has some effect of reversing, to some extent, damage/scarring? I believe it was in the Q&A at the JPM conference, one of the members at Frequency mentioned testing PCA formulations on "a thousand" donated cochlea. I find it hard to believe that after the broad spectrum of cochlea collected, this wouldn't have surfaced in the lab, and contributed to the first 321 formulations of FX-322. Perhaps during the progenitor activation process, a new hair cell is created adjacent to scarred tissue? Maybe I don't know what I'm talking about; I can only speculate that so much of what is discussed here has been scrutinized heavily over the last 5 years of substantial R&D at Frequency in order to release a viable, profitable product.

Right, I am sure that the men and women at Frequency Therapeutics who have worked 5 years on the formulation and have extensive backgrounds and knowledge about the cochlea have taken these matters into account. I'm pretty sure they have been able to overcome these issues with the current version of FX-322. Hence why Phase 1 has revealed some subjects as having more than 100% improvement in hearing capabilities. If epithelial scarring was a problem, there is no way that there would be these astonishing results... As smart and informed as many of you are, I am certain that these folks know WAY more. (I mean no offense!).