Frequency Therapeutics — Hearing Loss Regeneration
- Thread starter RB2014
- Start date
Memberhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572385/
Some takeaways:
The good:
Some takeaways:
The good:
- Support cells (SC) aid in the apoptosis pathway to determine whether HCs live or die; can trigger this process for even in-tact HCs—this would suggest that "damaged not dead" stereocilia etc. would more likely be killed than spared, and thus would be targets for hair cell regen.
- I still think the epithelial scar may be an obstacle to overcome before the restored HC's become viable. Am I the only one with this fear? This happens at sites in the mammalian cochlea that undergo apoptosis but at one point I remember @FGG talking me down off the ledge with this once.
- SGN and peripheral auditory fibers' survival may depend on SC survival.
- Depletion of SC in the event of ototoxic damage was not well-examined; depleted SC regions were sites of migration for "SC-like" cells which secrete similar growth factors in completely decimated HC/SC regions
- If SC's are sufficiently damaged, their ability to remove the dead HC could be hampered which could result in dead HC's staying in place. This article does not touch on this or make this outcome clear but it would appear to be a hurdle in the event of widespread concomitant HC & SC depletion.
brokensoul
Member
- Dec 31, 2019
- 223
- Tinnitus Since
- 02/05/2019
- Cause of Tinnitus
- unknown:medication,cannabis,stress,sleep deprivation
Very interesting publication on ototoxic damage to the inner ear which touches on intercellular connectivity, communication, collaboration, dependency, et cetera. Several worrying statements though like SGNs depending on neurotrophic factors of supporting cells to survive and so on.
Good find. Lots of info to digest. Will reread again later.
Horrorpopz
Member
So FX-322 won't be good for those whose problems are caused by ototoxicity 
I love being myself.
I love being myself.
Venture a guess as to how problematic epithelial scarring would be to hair cell regrowth?
It certainly reads that way, particularly for us neomycin suffers. I guess I'll have to wait a decade to possibly get some relief. I need to get an expanded audiogram. It appears this is only test that can possibly determine the extent of damage to ear. I hope this will assist with pinpointing which treatment protocol(s) will be best for me.So FX-322 won't be good for those whose problems are caused by ototoxicity
I love being myself.
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.
This one paper isn't the end-all, be-all. Like the paper shows, even in areas of complete decimation, SC-like cells migrate to take their place, which possibly keeps SGN's in tact in addition to presenting themselves as a target for multiplication from FX-322.
I think there's a huge limitation of research papers, in general: It's hard to know what to correlate clinically. I wish there were more dual researchers/clinicians--the only one I can think of is Kopke at Hough--because clinical experience is very valuable when interpreting these results.
Example: Kopke answered the question about tinnitus being in the brain and whether or not regeneration would help by saying *clinically* he has seen the majority of his hearing aid users improve tinnitus. This correlates with CI studies showing the same thing. His clinical experience (in addition to his research) helped him decide that treating the cochlea will treat tinnitus. So, even if we see brain changes, we can very reasonably conclude with clinical data that those will changes improve with the cochlea.
Same with papers on support cells, the stria vascularis etc. In the case of SV, if it was hugely influential in music, what populations should experience music distortion? And do we see that?
Same with support cells. Is there a gradient for hair cell death as evident on audiogram? Shouldn't the SC be more damaged in areas of more HC damage since they are adjacent and receive the same blood supply? I get that ion channels preferentially insert an ototoxin into some cell types more than others, but I have yet to see histology in sections where HCs are minorly affected but support cells are decimated. I think we would expect *clinically* more progressive hearing loss in areas of widespread support cell decimation.
I'm all for discussing theories but comparing papers without any clinically (especially using human data) meaningful comparison seems to be missing the most important means of interpreting the data.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202415/pdf/10162_2002_Article_28.pdf
Mixed news for acoustic trauma/NIHL folks...
"Noise exposure in mouse, as in other mammalian models of acoustic injury, can lead to histopathology in virtually all structures of the cochlear duct, including hair cells and supporting cells of the organ of Corti, neuronal terminals and somata, fibrocytes in the spiral ligament and limbus, as well as cells of the stria vascularis... a common pattern of hair cell damage was selective loss of outer hair cells OHCs) with general preservation of supporting cell structure"
"Collapse of several types of supporting cells was common at both acute and chronic survivals. At all exposure levels there was acute collapse of the Hensen cells and the outer space of Nuel, which they enclose Fig. 3A,B). At moderate sound levels there was buckling of pillar cells Fig. 2C). At the highest exposure levels the reticular lamina was often acutely ruptured, with hair cell and other cellular debris ̄oating in scala media Fig. 4). These ruptures, which always occurred between outer pillar head and ®rst-row OHCs, were patent as late as 1 week post exposure. At longer survivals, these disrupted regions resolved to a state in which the organ of Corti was replaced with a largely undifferentiated epithelium, although remnants of pillar cells were sometimes identifiable."
Mixed news for acoustic trauma/NIHL folks...
"Noise exposure in mouse, as in other mammalian models of acoustic injury, can lead to histopathology in virtually all structures of the cochlear duct, including hair cells and supporting cells of the organ of Corti, neuronal terminals and somata, fibrocytes in the spiral ligament and limbus, as well as cells of the stria vascularis... a common pattern of hair cell damage was selective loss of outer hair cells OHCs) with general preservation of supporting cell structure"
"Collapse of several types of supporting cells was common at both acute and chronic survivals. At all exposure levels there was acute collapse of the Hensen cells and the outer space of Nuel, which they enclose Fig. 3A,B). At moderate sound levels there was buckling of pillar cells Fig. 2C). At the highest exposure levels the reticular lamina was often acutely ruptured, with hair cell and other cellular debris ̄oating in scala media Fig. 4). These ruptures, which always occurred between outer pillar head and ®rst-row OHCs, were patent as late as 1 week post exposure. At longer survivals, these disrupted regions resolved to a state in which the organ of Corti was replaced with a largely undifferentiated epithelium, although remnants of pillar cells were sometimes identifiable."
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.
SC does not mean widespread loss. That's why I'm pushing for all of us to think about this clinically. If SC were widely lost, esp in NIHL, FX-322 wouldn't work and you wouldn't get dramatically improved word scores.
I'm sure I'm biased as someone who used to be a clinician but research paper wanking without clinical correlates has got to go. Because you can find papers to suggests nothing will work and yet it does.
Right, but here the question would be: do hearing aids depend on SC's utility in ion signaling or do they improve hearing/tinnitus entirely independent of them?
This is precisely what I've been worried about. Wouldn't there have to be corresponding losses of highly related HC-SC's? If this were the case, this solution would be essentially worthless, because the depleted HC population would be depending on a similarly depleted SC population.
I am reminded that the population that benefitted in phase 1 had significantly more damage than me, which abates my fears somewhat... but this issue is still extremely troubling.
Exactly. That's what I am trying to say. Think about this clinically. People with up to 60 dB losses, still responded and responded very well which means there is enough SC to respond.
HootOwl
Member
Hensen cells are not part of the LGR5+ population of supporting cells and therefore are not targeted by FX-323 in any way.
Pillar cells could refer to either inner or outer (Inner is LGR5+, Outer is not). However the paper later shows that all ruptures occurred between the outer pillar cells and the first OHC row meaning those Inner pillar cells were not affected either.
If anything this paper shows the opposite. Noise induced cochlear damage does not affect the LGR5+ population of supporting cells in any meaningful way.
And FGG is right, clinically it would make zero sense if it did.
Edit: I just want to add that in the event those inner pillar cells were damaged (which I still don't think they are), the inner border cell can transdifferentiate into the IHC if needed. Outer dieter cells are being used for the OHC.
Look, I'm super happy to hear all of this. Really. But I'm just trying to acknowledge the fact that objectively we have very little actual data to go off of—I don't want to find out things that are scary, believe me. I wouldn't characterize this as research wanking by any means. I don't want this shit. I don't want to wake up every morning terrified of my therapeutic window and outcomes, feeling like I'm light years away from every rejoining some modicum of a normal life. The reason I relay things here is because 1) they are relevant, and 2) someone, like yourself, might have a better informed opinion when analyzing such papers.
HootOwl
Member
Uh, I think I might have been quoted by mistake my dude >.>
I was just trying to reassure you that the LGR5+ population is well intact (for acoustic damage at least) and agreeing with FGG that clinically this would have to be the case.
Papers can be scary - I've freaked out over papers many times over only to have other forum members tell me I'm reading them completely wrong. Believe me I feel you, I'm scared everyday, but I think the paper you found in this case shows the exact opposite of what you feared.
HootOwl
Member
I just wanted to add that I've done my fair share of research wanking lol but it's always important to step back and say "but why are we seeing the opposite clinically". It's really fucking hard to do because we're all scared and suffering, but it helps prevent misunderstandings.
@mrbrightside614, I was the one who said "research wanking", not Hootowl and I meant it more playfully than it sounded.
I would just like to see any research paper brought up analyzed through the lens of what we see clinically because otherwise we literally have no idea how relevant it is.
I would just like to see any research paper brought up analyzed through the lens of what we see clinically because otherwise we literally have no idea how relevant it is.
I didn't want to double quote or throw an @ lol but yeah I know you didn't say such. Either way I'm happy I posted it because dwelling on it in isolation with my misunderstanding would've made me feel worse.
I guess that's a good point. Worth posting things in isolation if you need talking down for your mental state.
I think there would be way less fear in general, though, if people would weigh the clinical picture higher than random papers. That's all I was really trying to say.
Don't let buzzwords freak you out.
I know how easy this is to do. I did the same thing. I got turned around by stria damage being the reason for my severe distortions but then I realized clinically I haven't had any audiogram progression which happens with enough strial damage and people with age-related hearing loss generally have a lot of strial atrophy to the point of losing endocochlear potential and can usually hear music fine with hearing aids.
Stepping back and looking at the clinical picture is what allowed me not to give too much weight to esoteric worries. And my post was coming to this realization for myself and hoping it will help others, too.
I do pray there is something that will help those affected by ototoxins. I know these research papers are based on animal studies thus leaving considerable room to postulate but I must admit the findings can be rather frightening. However, thank you all for encouraging me to research the ear anatomy in greater detail.
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.
- Feb 14, 2020
- 1,630
- Tinnitus Since
- 1-2019
- Cause of Tinnitus
- 20+ Years of Live Music, Motorcycles, and Power Tools
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.
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