Inner Ear Hair Cell Regeneration — Maybe We Can Know More

[jeff W]

That there is only a couple of millions being invested each year,

You draw that inference from? How do you calculate only a couple of million?

 

[Ambassador]

According to the World Health Organization, there are still no effective treatments available for around three quarters of the 30,000 diseases known today worldwide.

 

[acufenero]

The best option for a "new trobalt" is 1OP-2198 right ?

I believe Profesor Tzounopoulos at the University of Pittsburgh is working on some kind of potassium channel opener drug like Trobalt, too, backed by a big pharma, though it's almost been a year since last news. Maybe someone can email him?

By the way, 1OP-2198 is now called XEN1101. Phase 1 is expected to start later this year with a phase 2 rolling out in mid 2018. Since Trobalt works/worked for many of us, me included, I'd definitely keep track of this new version.

 

[Marlino]

Xen1101 is interesting, but not much on the website. I will try to get in touch with xenon pharma ir and let you know if I can get some more infos.

 

[Michael Larsen]

Yes but it's being developed for epilepsy, more potent with fewer side effects (hopefully won't turn you blue and give you milky man tits).

If it's going to be for T it would be off label use.

I would not care about all side effects, Just that would not have an effect on my eyes

 

[VRZ78]

https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372587

This is great they are actually on time with the recruitment dates. First patient was enrolled on 30/05.

Hopefully everything will go well

 

[Paulmanlike]

This is great they are actually on time with the recruitment dates. First patient was enrolled on 30/05.

Hopefully everything will go well

The assessment of tinnitus outcome is in their second objective to see if it makes it better or worse. Time will soon tell.

 

[Paulmanlike]

I may have asked this question before, but a theory of tinnitus persistence is that the signal are boosted in the dorsal cochlear nucleous (something like that) during a hearing threshold shift. When the hearing returns back to normal, tinnitus (or the DCN boosting its signals) remains a memory.

How would hearing cell regeneration fix that memory to alleviate tinnitus? This may explain why tinnitus does not always accompany hearing loss?

 

[VRZ78]

The assessment of tinnitus outcome is in their second objective to see if it makes it better or worse. Time will soon tell.

It's not likely to tell much IMO as the time between the injection and the surgery can go from 0 h to 24 h. It's likely the effect of the drug won't even seen in that little amount of time.
It's really more a trial to measure the quantity of drug that goes in the cochlea and in the bloodstream. Other things are just bonus

 

[GregCA]

Yes but it's being developed for epilepsy, more potent with fewer side effects (hopefully won't turn you blue and give you milky man tits).

Seems like an acceptable trade-off

 

[HomeoHebbian]

I may have asked this question before, but a theory of tinnitus persistence is that the signal are boosted in the dorsal cochlear nucleous (something like that) during a hearing threshold shift. When the hearing returns back to normal, tinnitus (or the DCN boosting its signals) remains a memory.

How would hearing cell regeneration fix that memory to alleviate tinnitus? This may explain why tinnitus does not always accompany hearing loss?

The idea is that the loss of input from the ear triggers a compensatory response on the dorsal cochlear nucleus that, in effect, increases the amplification on all remaining inputs. The pathologically over-powered amplification disrupts that patterning of electrical activity transmitted up the pathway. So, it's not a 'memory' in the strict sense of the word but you are right that it is a persistent physiological trace of earlier trauma. The idea is that the gain can be turned down once a more normative input from the cochlea is restored. Damage to cochlear hair cells (inner or outer) profoundly attenuates the strength of the signal going from the ear to the brain so many have argued that they are a reasonable target for cellular therapies for turning down the over-charged gain in the DCN (and elsewhere) and eliminating tinnitus. That is the theory, in a nutshell.

 

[HomeoHebbian]

I believe Profesor Tzounopoulos at the University of Pittsburgh is working on some kind of potassium channel opener drug like Trobalt, too, backed by a big pharma, though it's almost been a year since last news. Maybe someone can email him?

By the way, 1OP-2198 is now called XEN1101. Phase 1 is expected to start later this year with a phase 2 rolling out in mid 2018. Since Trobalt works/worked for many of us, me included, I'd definitely keep track of this new version.

He is working with physical chemists and industry partners to develop a targeted, better tolerated compound that will act on the KCNQ2/3 variant of the voltage-gated potassium channel. The preliminary data I have seen in animal models look promising.

 

[Fabrikat]

The preliminary data I have seen in animal models look promising.

As they're testing for epilepsy, what makes you think it looks promising for tinnitus?

 

[HomeoHebbian]

As they're testing for epilepsy, what makes you think it looks promising for tinnitus?

They are looking at this compound very closely for tinnitus as well. After all, tinnitus and epilepsy have a lot in common. The data I saw showed changes in the intrinsic electrical excitability of neurons in the mouse central auditory pathway. Like AUT00063, this drug shifts the voltage-dependent conductance of the channel to more negative potentials. Unlike AUT00063, the KCNQ2/3 channel is active at more hyper polarized membrane potentials, closer to the cell's resting membrane potential. This makes it harder for weak, poorly organized inputs onto central auditory neurons to drive cells over the threshold to fire an action potential. The implication is that strong, well-organized inputs that convey information related to the auditory environment can be processed normally but weak, poorly organized excitatory inputs generated by spontaneous activity are no longer translated into the "digital" spiking output of the cell. In their 2015 paper, they showed a variant of the compound SF0034 reduced behavioral changes consistent with tinnitus (see below).

If it comes from the Tzounopoulos lab, it is very high quality work and you can be sure they are thinking about possible applications to tinnitus. As this topic has nothing to do with hair cell regeneration, this might not be the best thread for this discussion. But I think these variants of KCNQ2/3 activators are an interesting therapeutic option that, in theory, could find its way into trials in the near future.

J Neurosci. 2015 Jun 10;35(23):8829-42. doi: 10.1523/JNEUROSCI.5176-14.2015.
Potent KCNQ2/3-specific channel activator suppresses in vivo epileptic activity and prevents the development of tinnitus.
Kalappa BI1, Soh H2, Duignan KM2, Furuya T3, Edwards S3, Tzingounis AV4, Tzounopoulos T5.

 

[acufenero]

He is working with physical chemists and industry partners to develop a targeted, better tolerated compound that will act on the KCNQ2/3 variant of the voltage-gated potassium channel. The preliminary data I have seen in animal models look promising.

You mean prof. Tzounopoulos' work, don't you?

If it comes from the Tzounopoulos lab, it is very high quality work and you can be sure they are thinking about possible applications to tinnitus.

I thought tinnitus was their main (and only) target. At least that was what we were told in their last press release. Have they changed their focus?

 

[HomeoHebbian]

You mean prof. Tzounopoulos' work, don't you?


I thought tinnitus was their main (and only) target. At least that was what we were told in their last press release. Have they changed their focus?

Yes, I was referring to preliminary data I saw from Tzounopoulos. Yes, tinnitus has been (and will remain) a major focus for his group. Someone mentioned that the drug was being tested for epilepsy and asked why I thought it would be applicable to tinnitus (or at least that was my understanding of their question).

 

[Fabrikat]

Thanks @HomeoHebbian for your detailed response. Drugs usually take a very long time to come market, if they are successful. Are we in fact looking at a seven to ten year time frame for something like this to become available to the general public?

 

[HomeoHebbian]

Thanks @HomeoHebbian for your detailed response. Drugs usually take a very long time to come market, if they are successful. Are we in fact looking at a seven to ten year time frame for something like this to become available to the general public?

Yes, you are absolutely right about that. My recollection from seeing a talk a few months ago was that the pre-clinical data were strong enough to warrant a healthy dose of funding from a big Pharma partner for Phase 1. I'll ask around and if I learn anything useful will report back...

 

[Roger_S]

This seems like the most interesting thread about curing tinnitus.

Is there any thread as hopeful as this one?
Can someone start a new thread #2 with the same topic summarizing what has been going on so far? I'm reading about starting a Phase I on page 2-5. I still get tired quickly and I think I'm not the only one.

I also don't know how inner ear hair cell regeneration is done. Is it anything like 3D printing?

[rant]
When I got my T, I was already down, because of the last time I visited a hospital in 1998 for a broken toe wasn't exactly how advanced I pictured hospital technology would be, being accustomed to the progress of computergames in my life, going from black-and-white when I was a toddler to full-color vast 3D world of Mario 64.
"Let's wait and see what's gonna happen.. surgery? I wonder how that would take place.. Oh hi doctor!.. ... ...Oh, I'm not going to get surgery. Okay, well that's sad, but come to think of it, it's probably because it's too expensive to do so for just a toe. Oh well, show me the graphics, I want to see it.... Wait.. what!? A plastic sheet on an old backlight!? Now I know schools use those, but that's because they can use them on projectors for the whole class to see as current computer monitors aren't flat screens, but this looks straight out of the 1960's or 1970's at most. This is 1998! This is terrible! It's not even in high-resolution. I can't see a thing on this! And they just send me home!? I can't believe this! These people are decades behind!
[/rant]

So I knew what to expect when IT tech, which is what I consider 3D printing to be, has only recently just replaced the prosthetics department these last few years, with prices going down from tens of thousands of dollars to just a couple of bucks, but the real stuff has yet to happen, 3D printing body parts.
So that's why I'm curious to how inner ear hair cell regeneration relates to if at all.
See this story of patient #1 that will be the first human to recieve an outer ear: http://silentgrapevine.com/2016/04/...ent-to-receive-functional-3d-printed-ear.html

 

[GregCA]

I also don't know how inner ear hair cell regeneration is done. Is it anything like 3D printing?

No, it's nothing like 3D printing.

 

[acufenero]

Yes, you are absolutely right about that. My recollection from seeing a talk a few months ago was that the pre-clinical data were strong enough to warrant a healthy dose of funding from a big Pharma partner for Phase 1. I'll ask around and if I learn anything useful will report back...

Isn't Allergan backing the research as stated in the pr?

By the way, do you think that these kind of approaches can "cure" tinnitus (that is, shut the ringing down) after taking the drug for some time? Or are they more likely to be taken on a daily basis?

 

[Rubenslash]

Isn't there a separate thread to discuss the potassium channel openers?

 

[Flamingo1]

This seems like the most interesting thread about curing tinnitus.

Is there any thread as hopeful as this one?
Can someone start a new thread #2 with the same topic summarizing what has been going on so far? I'm reading about starting a Phase I on page 2-5. I still get tired quickly and I think I'm not the only one.

@Roger_S This thread is shorter and should answer some of your questions. https://www.tinnitustalk.com/threads/frequency-therapeutics-—-hearing-loss-regeneration.18889/

 

[EatMoTacos]

Found this article to be interesting, it appeared on my news feed:

https://www.umaryland.edu/news/arch...s/breakthrough-discovery-in-hearing-loss-.php

Breakthrough Discovery In Hearing Loss
August 4, 2017

Researchers at the University of Maryland School of Medicine (UMSOM) have announced a breakthrough discovery that could eventually help scientists repair hearing problems or protect those at risk for hearing loss – a condition that affects some 40 million Americans.

 

[Champ]

Maybe. But I am concerned that there is no way the newly formed connections will be the same or perform the same as the original ones and that it may not stop the tinnitus.

Even if they aren't, I think you and I would be happy to have it 90% back to the way it was.

 

[Marlino]

You draw that inference from? How do you calculate only a couple of million

Its obviously far less than a billion $ each year. I guess here on this forum we know about 90% of all projects. Even the most expensive ones, like am101 costs just a medium 2digit M$ amount even during their costly trial phase.

So in poker it would be called a blind what is invested right now.

Just compare the numbers, consider the VW diesel scandal and how much money is paid for this health issue. Ridicilous!

 

[DoNotGoGentle]

 

[jeff W]

Its obviously far less than a billion $ each year. I guess here on this forum we know about 90% of all projects. Even the most expensive ones, like am101 costs just a medium 2digit M$ amount even during their costly trial phase.

So in poker it would be called a blind what is invested right now.

Just compare the numbers, consider the VW diesel scandal and how much money is paid for this health issue. Ridicilous!

So a couple of million was an incorrect summary of the monies involved?

 

[rsmcfar]

http://newsok.com/article/5560970

This article came across my news feed. Don't see it posted yet, although the trial has been discussed below.

 

[Fabrikat]

http://newsok.com/article/5560970

Gotta love a 'serendipitous discovery'!