Inner Ear Hair Cell Regeneration — Maybe We Can Know More

Don't forget about Acousia. Starting phase 1 soon.

 

Thanks, Aaron. Could you please provide a link to Audion's latest mixed results? Would that mean Frequency's approach might not work either?

 

Mixed results aren't necessarily bad. Even if it helps only 50% of the people, that would still be amazing. I think because you have so many different ways in which someone can get tinnitus, I do not think they will find a one cure for all, but rather targeted cures for targeted patient populations. Once they finally come to the realization that that is how its going to be, it will be much easier.

This is why i am always so frustrated when they put patients together in trials who had different causes for their tinnitus. Because this way you can never get sound results.

 

Sorry, my post wasn't clear. Will try again.

First, I'm not sure Audion has released any results much less mixed results.

Second, Audion's approach was founded based at least in part on a paper out of Albert Edge's lab (http://www.cell.com/neuron/fulltext/S0896-6273(12)00953-1?_returnURL=http://linkinghub.elsevier.com/retrieve/pii/S0896627312009531?showall=true). That paper used a γ-secretase inhibitor which inhibits Notch signalling. Inhibiting Notch was found to transdifferentiate supporting cells into hair cells - i.e., directly transform supporting cells into hair cells. More recently, a paper by Heller and Groves (and co-authors) found that this only worked on young animals (http://journal.frontiersin.org/article/10.3389/fncel.2015.00110/full). (It's very, very important to pay attention to the age of animals in studies. Does the drug/whatever work on adults or only newborns?) My point was that there are mixed results using using γ-secretase inhibitors to inhibit Notch which is the approach taken by Audion - not that Audion had itself published mixed results.

How does this affect Frequency? A second line of work has looked at changing both Wnt and Notch signalling (e.g., https://www.nature.com/articles/srep29418). This work finds that the results are much better when both pathways are manipulated as compared to only 1, and it is increasingly apparent that significant gains are only going to result from the manipulation of multiple signalling pathways.

As far as we know, Frequency's approach (http://www.cell.com/cell-reports/abstract/S2211-1247(17)30136-5) manipulates both Notch and Wnt signalling (among other things) so it is not subject to the same concern as Audion's approach.

Thus, while I am happy that Audion is starting a trial, I am less confident in their approach than I am in Frequency's.

Hopefully this is clearer.

 

@Aaron123 Thank you for your clarification. So from what you know, will manipulating Notch and Wnt signalling improve the chances for the therapy to work on us older animals?

 

I resemble that remark....

Results for adults are much harder to come by. When they exist they tend to be weaker. In the context of Frequency, I wrote the following post after their paper came out in February. In it I try to break down what they found in the different experiments and what, for what it is worth, I am looking/hoping for in the next paper.

https://www.tinnitustalk.com/thread...g-loss-regeneration.18889/page-13#post-249079

Bottom line is that I think it is possible though it may involve more than just Notch and Wnt and the results may never be quite as good for adults as for newborns. I think Frequency would argue that it is definitely possible because other tissue like our intestines regenerates throughout adulthood.

 

@Aaron123 Interesting, thank you. However, Audion includes people up to 80 years old in their inclusion criteria, I dont see why they would do this if they did not have animal data where their therapy works on adults as well?

 

Wanted to chime in here and mention that Prof. Hudspeth primarily studies sound transduction and hair bundle mechanics in species that do not have inner hair cells versus outer hair cells. His work has focused on reptiles and amphibians which have much shorter, uncoiled basilar membranes. In reptiles and amphibians (and birds as well) "active mechanisms" in the hair bundle itself can explain all of the non-linear processing in the cochlea. Mammals are probably different. Our basilar membrane is longer and coiled. We have one row of inner hair cells and three rows of outer hair cells. In mammals, it is clear that outer hair cells do a lot of the "frequency focusing" and non-linear amplification that can be achieved purely through bundle mechanics in lower verterbrate animals. Hope that clears some things up. Hudspeth is one of the most highly accomplished scientists in our field and perhaps the best scientific communicator I have ever seen. When he speaks, it is as if listening to a living textbook. I'm sure his video is quite compelling!

 

uhhh, yeah! Believe it or not, your BRAIN actually contributes a lot to the perception of sound (to be more accurate, it creates your perception of sound entirely). For a group of people with a disorder that arises from the brain, you all sure are obsessed with the ear!

 

The original work included "adult" animals but that doesn't mean that they used an animal model for the inner ear of an 80 year old human. Cellular degeneration in the ear is so widespread that no single mechanism of therapy is going to do that much good. Consider that if their drug does everything it is hyped to do (haha) it still would not help the degeneration of non-sensory cells that are losing their tight junctions, thereby disrupting ion homeostasis and the endocochlear potential. Nor would it help with the loss of synaptic contacts onto inner hair cells. ...and the list goes on.

I think some of these companies hype themselves up just to get bought by bigger companies. At this point in the game, the only reasonable approach to inner ear drug therapies that could deliver in the near term are drugs of protection. Nobody has the technology to rebuild an inner ear that has been ravaged by chronic, widespread damage or aging. Yes, some drugs can begin to address individual facets of degeneration but how useful is it to repair the cylinder head of your car's engine when oil pump, radiator and ignition are still broken? I think the smart money is looking at drugs of protection, not regeneration.

 

You sound like you work for one of those companies. Frequency Therapeutics has shown very promising results in the lab for regenerating hair cells and increasing supporting cells. A lot of money is being invested in both Decibel and Frequency who are looking at hearing regeneration by big players like Google . I doubt that $20-$50 Million Dollars is being invested in those companies just so that a "bigger company" will buy them. Smh.

 

Really? I think it's the opposite. There's no money in protection because literally no one is interested in protection. At least not in this day and age. People don't care about tinnitus, hyperacusis and hearing loss until they get it themselves.

 

I agree. For $150 you have molded earplugs, still 95% at festival walk around without protection.

 

Protection would be very helpful for individuals who need platinum based chemotherapy drugs and aminoglycoside antibiotics so there are definitely people who are interested in this - and people who are working on it.

 

I wasn't referring to that kind of protection (though that is good too). I was talking about promising drugs that act on the inner ear to provide protection against noise exposure and ototoxins. Oricula, for example (http://www.oricularx.com/our-team). I know this thread is about regeneration so I won't wander too far off topic.

 

No, I'm an academic who runs a NIH-funded research lab with no ties to any company. I sit through ~100 lectures on these topics per year at conferences and seminars and I know several of the founders of these companies pretty well. Was just offering an opinion to the TT community.

 

Ah, I see. Maybe the army would be interested in it too, but I was thinking more of average Joes.

 

How is that gonna help us now?

 

You already came across very knowledgeable, so that explains. In your view, given your references, why would Decibel change their strategy and go for "protection" drugs, instead of "restoration" drugs?

The way I read from several companies publication, like FX, Bohringer/Kyoto collaboration, are really focusing on restoration of hearing with stem cells, drug, etc. Based on your knowledge, with regards to inner ear/hair cell restoration, do you expect this to be possible in the near future or do you foresee too many unaddressed issues?

 

What makes you think Decibel has changed their strategy? Maybe you all have info that I do not, but I don't think they ever announced a lead compound. You might assume they were gunning for regeneration based on the founders but Decibel isn't being run by the founders, it is being run by an experienced, successful team of biotech veterans. My point is not that Decibel is pursuing protection drugs (though I think it's a good idea), rather that I'm not sure how serious they were about putting regeneration drugs front and center to begin with. Regeneration can help raise money and excitement for early rounds of funding but now they have to get into the business of taking a drug to market. Just my opinion. I have no first-hand knowledge of what they are doing.

 

My unvarnished opinion is that focusing on inner ear regeneration drugs as a treatment for chronic, subjective tinnitus any time soon is a complete and total waste of time.

 

It isn't.

 

But, as I have stated on other threads, I'm enthusiastic about many other approaches to understand and treat tinnitus. This myopic obsession with inner ear regeneration as near-term treatment for tinnitus has always had me totally baffled. I think y'all are barking up the wrong tree!

 

@HomeoHebbian - If, in your opinion, functional inner ear regeneration is an unrealistic proposition at this point in time, is there any kind of treatment modality that you believe may offer some measure of hope of tinnitus reduction in the coming years? No doubt, it's a question you would be asked often.

 

@HomeoHebbian Do you know much about the work Frequency Therapeutics is doing? They're supposed to go into clinical trials next year.

 

Oh, looks who's back. Looks like today's his monthly shitstorm day. I almost forget about you.

It always amazes me that a random, unknown guy from the Internet claims to know more than a half dozen companies which raised like 100 million dollars in the last few months.

 

I have been following some of the discussion on Frequency and don't know anything beyond what is being discussed. I agree that they really do seem to be focused on regeneration through Wnt signaling but I don't know a whole lot about this.

 

But still you sound a bit pessimistic
I would suggest you dig a little further in Fx, as a neuroscientist it would be really interesting...i bet

 

Aren't we all just random people from the internet?
(https://en.wikipedia.org/wiki/Unicorn_bubble)

 

I remain to be optimistic. Though my own definition for an optimist usually is "uninformed pessimist"..