Can Blocking HCN2 Ion Channels Silence Tinnitus? RNID Funds Prof. McNaughton's Team to Find Out

[Nick47]

I did not attend.

This was 2023, @StoneInFocus.

 

[StoneInFocus]

This was 2023, @StoneInFocus.

You are right, my mistake.

 

[BB23]

It is going to take at least a decade for this drug too.

I wonder if they are in the discovery phase for anything at all or just going to cop out like Prof. Tzounopoulos did. I mean his job is so simple at the moment. If your drug is messed up and is neurotoxic, get XEN1101 and test it on a small group of people. That's it...

We can't regenerate what we lost. We don't even know what is lost inside, and it would be different from individual to individual. We can only mess around with the signals associated with tinnitus, but we don't have any drugs available for us.

Great time to be alive. Science is so advanced, you guys.

 

[Nick47]

It is going to take at least a decade for this drug too.

Well, all I can conclude is that they (Kings College London) are partnered with Merck, who will put the compound through clinical trials. The RNID have extended funding for the project.

In November I got in touch with the RNID who said they had identified several more promising compounds. So yes, discovery. The main focus is on chronic neuropathic pain, of which Professor Peter McNaughton hypothesized is tinnitus.

As it's a new angle, and he is willing, it would be a good idea to get him on a podcast. Is this on the radar, @Markku?

It would stop emails to him from here. It would update us on where he is.

 

[Markku]

Well, all I can conclude is that they (Kings College London) are partnered with Merck, who will put the compound through clinical trials. The RNID have extended funding for the project.

In November I got in touch with the RNID who said they had identified several more promising compounds. So yes, discovery. The main focus is on chronic neuropathic pain, of which Professor Peter McNaughton hypothesized is tinnitus.

As it's a new angle, and he is willing, it would be a good idea to get him on a podcast. Is this on the radar, @Markku?

It would stop emails to him from here. It would update us on where he is.

We have reached out to him.

 

[Nick47]

We have reached out to him.

Legend!

 

[BB23]

During the interview, please ask them how the Kv7 channels are connected to HCN2 channels and whether modulating Kv7 channels helps HCN2 channels, as Tzounopoulos suggested.

 

[HighleyTall]

I don't know if this has been discussed yet, but this is a paper from Prof. McNaughton, too.

Hyperpolarization-activated cyclic nucleotide–gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy

PDN is a typical 'die-back' neuropathy, in which unmyelinated C-fibers and thinly myelinated Aδ nociceptive fibers retreat first, and in which spontaneous firing develops in small fibers. The work reported here provides further support for the idea of spontaneous firing in small nociceptive nerve fibers.

Where do we find these unmyelinated C-fibers? What if they cause spontaneous firing in small nociceptive fibers? Why do my ears burn?

Again, it's all about the OHCs, that's why an audiogram is irrelevant. Or, the hidden hearing loss was always hidden. Hyperacusis/noxacusis is also all about OHCs, but probably due to discordance with IHCs.

Why did Dr. Jack L. Pulec have great success cutting the auditory nerve?

I'm sure there is "brain tinnitus," too. I experience it as well. A steady tonal tinnitus, not reactive, located in the brain.

Prof. McNaughton is the man to watch!

 

[BB23]

Again, it's all about the OHCs

My DPOAEs are fine, which means OHCs are healthy; I have tinnitus, hyperacusis, and TTTS.

 

[Nick47]

Again, it's all about the OHCs, that's why an audiogram is irrelevant.

Outer hair cells amplify sound. That's why audiograms are relevant.

 

[HighleyTall]

My DPOAEs are fine, which means OHCs are healthy; I have tinnitus, hyperacusis, and TTTS.

Maybe because your symptoms are not noise / trauma induced?

Distortion Product Otoacoustic Emissions (DPOAEs) In Tinnitus Patients

Outer hair cells amplify sound. That's why audiograms are relevant.

Audiograms are irrelevant for tinnitus diagnosis.

This electrical snakepit painnitus is not in my brain, I can feel the nerves burning. Tinnitus (just the sound) is nothing (I've been there).

Those who complain of tinnitus sound only are pussies.

 

[Stayinghopeful]

Those who complain of tinnitus sound only are pussies.

I don't know about that.

 

[dan]

Those who complain of tinnitus sound only are pussies.

Really? Wow...

 

[Jonno02]

Those who complain of tinnitus sound only are pussies.

Perhaps it's best you find yourself another online community that aligns with your view.

Tinnitus Talk is a support forum, not a place for you to subjectively legitimise your own suffering and discard others.

What an ignorant person you are.

 

[HighleyTall]

Don't take me too seriously and don't take it personal.

Maybe ask Prof. McNaughton if he is actually targetting spontaneous firing in small nociceptive nerve fibers at the cochlea. After all, he claims Dr. Shore discovered "abnormal activity in the auditory nerve".

 

[StoneInFocus]

Those who complain of tinnitus sound only are pussies.

You're an idiot, humble yourself.

 

[HighleyTall]

You're an idiot, humble yourself.

Keep trying.

 

[Nick47]

If @Markku gets him on, I will become a Tinnitus Talk Podcast Patron.

 

[Nick47]

'A Link With Pain'

Peter McNaughton, professor of pharmacology at King's College London, has suggested that tinnitus could be treated with new drugs for preventing chronic pain due to similarities with phantom limb pain, where amputees feel as if pain is coming from a limb that has been amputated.

McNaughton's group has identified a type of ion channel in nerve cell membranes, called HCN2, that is responsible for driving neuropathic pain. Using drugs to block these ion channels proved to be effective at reducing chronic pain in mice. HCN2 channels also occur in the nerve fibres of the auditory system, which can be damaged by the noise exposure that can lead to tinnitus. To clarify the role of ion channels in tinnitus, the King's College London team produced genetically engineered mice in which the HCN2 channel is no longer expressed in the auditory nerve.

Now, hearing science researcher Mark Wallace and colleagues at Nottingham University are working with these mice and with normal mice to further explore the causes of tinnitus and if it can be silenced by HCN2 blocking drugs.

"The results so far are certainly promising," Wallace told Medscape News UK, while emphasising that the journey from early animal trials to clinical trials and bringing any drugs to market will be long, and the transition from animals to humans can often disappoint.'

→ Medscape UK: Is There Hope for People With Tinnitus?

 

[Utdmad89]

This is years away. It will help those in the future who gets tinnitus. Lucky them.

 

[Markku]

If @Markku gets him on, I will become a Tinnitus Talk Podcast Patron.

Hi @Nick47!

Prof. McNaughton agreed to an interview, but our technical set up is maybe a little challenging for him. We always like to record in high quality, knowing how our audience can be hearing sensitive, and that creates a few extra steps rather than just having a quick phone call.

@mrpetrov will be seeing Prof. McNaughton face to face mid-April; he would be willing to ask him questions. Please add yours below.

We are hoping to have Prof. McNaughton officially on the podcast soon as well, but we are very grateful to @mrpetrov for wanting to facilitate this.

Thanks guys!

 

[Nick47]

Hi @Markku, good work. It's a good lead into what else is happening in tinnitus research, too, as Prof. McNaughton is involved with the hearing and tinnitus research group at Nottingham University, led by Alan Palmer.

Thanks @mrpetrov, too!

As for the recording, I can see the concerns, although maybe I could help with a transcript or something?

In terms of questions, I think the first step after his introduction and hypothesis is to find out where he is. The original compounds worked in Gerbils, however could not progress to a human trial, due to toxicity issues. When I contacted the RNID (part funders), they said they had identified several promising additional compounds since June 2023. As such, they have extended funding for this project. I suppose we could ask if animal trials are ongoing or taken place with these?

Aside from the current status, what are his thoughts on chronicity of both neuropathic pain and tinnitus being success factors?

He may also be able to share other information or enquiries from the lab, although I'm not sure.

 

[dd314]

There's another HCN modulator called Guanfacine, which is an a2-adreno agonist like Clonidine used for ADHD. I tried making a survey here about its effect on tinnitus, but the sample size is too small:

Can Guanfacine Make Tinnitus Worse?

 

[mrpetrov]

There's another HCN modulator called Guanfacine, which is an a2-adreno agonist like Clonidine used for ADHD. I tried making a survey here about its effect on tinnitus, but the sample size is too small:

Can Guanfacine Make Tinnitus Worse?

That's interesting - my son is actually on Guanfacine for ADHD... I can certainly ask my doctor if it's worth a try.

 

[mrpetrov]

Just a quick update on the Guanfacine. I'm on day 3 so far (2 mg), so it's far too early to make any bold claims. That said, my Morse code reactive tinnitus appears to be (significantly) reduced, and it coincided with the first day of taking the Guanfacine. It may well be a placebo or just a random chance, but I'll update in due course.

 

[Hazel]

Update:

We are interviewing Prof. McNaughton this coming Tuesday. We already have an episode lined up for publishing in May (arguably one of our most exciting ones to date), but Prof. McNaughton's episode will come right after that.

Please submit your questions below!

 

[BB23]

1. How are Kv7 channels connected to hcn2 channels? Can Kv7 modulators help modulate HCN2 like Prof. Tzounopoulos suggested?
2. What do you think of Arnaud Noreña's new paper claiming KCC2 are responsible for tinnitus?
3. When can we expect HCN2 drugs to be out?

 

[Nick47]

1) Have you got a lead candidate compound?

If yes;

2) What is the next stage (petri dish, animal testing etc.) and when are you looking to do this?

3) If it is effective in animals again, when would you pencil in for a first human pilot trial?

4) Have you discussed acute vs. chronic tinnitus possibilities? Were animals only with acute tinnitus tested? Do you hypothesize this affects the outcome?

5) How has the new guidance on clinical trial approval and speed affected timelines for bringing new products to market?​

In response to the COVID-19 vaccines, the government MHRA revised guidelines in the UK, making it one of the most attractive countries to run trials: MHRA to streamline clinical trial approvals in biggest overhaul of trial regulation in 20 years

Just a quick update on the Guanfacine. I'm on day 3 so far (2 mg), so it's far too early to make any bold claims. That said, my Morse code reactive tinnitus appears to be (significantly) reduced, and it coincided with the first day of taking the Guanfacine. It may well be a placebo or just a random chance, but I'll update in due course.

Who knows. This is how Retigabine was discovered on Tinnitus Talk! Good luck, fella.

Just a general note on Professor McNaughton. He is not a tinnitus specialist. His expertise is in pharmacology and chronic neuropathic pain. So he is well placed to answer questions on those like @BB23 has asked. He may have insights into other research on tinnitus through associating with Alan Palmer's group in Nottingham. However, he has not researched tinnitus himself. He just had a hypothesis, which he tested on animals, and proved it so far correct. The key is the development of a safe molecule that's effective in humans with chronic tinnitus.

I believe the biggest challenge will be overcoming preclinical tests that are free of toxicity but still produce efficacy in animals. Only then 'MAY' the fun begin.

 

[Josh59]

In addition to discussing Prof. McNaughton's own research, what is his opinion on somatosensory tinnitus, which can worsen?

Does he share the view of other researchers that tinnitus is located in the cochlear nuclei and the brain stem, which is why some people experience an increase in symptoms via non-auditory stimuli?

 

[Nick47]

In addition to discussing Prof. McNaughton's own research, what is his opinion on somatosensory tinnitus, which can worsen?

Prof. McNaughton is not a tinnitus expert.