Hough Ear Institute's Hair Cell Regeneration Project

I've come to the conclusion that there is always collateral damage... it doesn't matter what we do! I myself am collateral damage of the medical industry.

 

Oh yeah? Like a pill to treat the skin? Skin... largest organ in the body... cochlea... not so much.

Go ahead and argue, the blood flow is not there, the medicine won’t make it to the ear...

 

If a pill couldn't penetrate the cochlea, then ototoxicity wouldn't be a thing except with IV drugs and that clearly isn't the case.

 

Reading comprehension - 5 pts. Argumentative...lol.

WHERE did I say a “pill” couldn’t penetrate the cochlea? A pill doesn’t travel intact through the bloodstream does it? Lol

You have ototoxicity because some medicine does get to the ear... but most of it goes elsewhere.

The CONTEXT was someone saying treating the inner ear is basically the same as treating ANY part of the body, which it isn’t. It is more difficult... that is why it is even more tragic that people lose their hearing and get tinnitus from a medicine to treat something else, and was collateral damage.

Please get the context correct. But it was true, I was using hyperbole when discussing the lack of blood flow and the efficacy of medicine getting to the ear. This is why many take niacin, to increase blood flow after a trauma. Some don’t realize hyperbole from a literal meaning, c'est la vie.

Reading is fundamental.

 

I think you missed my point because you thought I was saying an intact pill goes through the bloodstream. I probably wasn't super clear so i will try again:

Aminoglycosides (for instance) penetrate the cochlea (after being normally metabolized of course) *far* less than other organs that have more blood flow (e.g.. Kidneys) obviously but they still have enough penetrance to greatly effect the cochlea.

My point is you don't need much of a substance to have a great negative effect (ototoxicity) so it seems illogical (to me) that you couldn't have enough volume of distribution to have a positive effect with an oral medication.

 

Ok enough with my saltiness, my apologies. I just got in from S. Korea and I’m cranky.

This is what I was getting at....

@FGG, from another thread, “Either way, I got an email confirmation that Pipeline's drug reaches the entire cochlea to the apex after IT injection and both Otonomy and Pipeline use poloxamer 407 in their vehicle. Hopefully, Frequency will do something similar eventually.”

Thanks

 

Nah. No worries. Even though I disagree with you at times (esp politically ), I like you. You seem completely who you are without any pretense at all. Cheers.

 

Yawn.

 

Burp... lol.

Good chat, thanks for your thoughts.

How’s your cold?

 

I think I'm on the tail end. Thanks.

I have faith we'll get there, friend. I am not a biologist or drug developer. There are plenty of pills out there that target specific areas. High BP, cholesterol, Viagra, migraines, schizophrenia, acid reflux, etc etc. We will get there. Pill or not.

 

Sorry to tag you @Hazel but I reaaaally hope De Moss knows about this resource.

 

Hope the interview went well today.

 

I have faith too, I just hope it’s soon.

 

One question, how is this benefiting tinnitus?

Asking because my colleague had sudden hearing loss (not gradual) in one ear several years ago, is deaf in that ear and has no tinnitus...

Please educate me...do we think this will help us?

 

It repairs synapses and regenerates the A1 nerve fibers connecting to them. Synaptopathy has long been suspected to be one cause of tinnitus and Hough has claimed they have seen good results in their animal data with regard to alleviating/eliminating tinnitus after administering the compound found in the pill.

Myself and others have doubts for if this will work for chronic cases due to the compound being an antioxidant and not a growth factor but I hope our fears are unfounded. Their patent data shows that administering the pill 4 weeks after acoustic damage still showed neurite outgrowth which is promising.

 

I pulled some of their figure data that I think is most important:

FIG. 23 shows HPN-07 and NAC reversed noise-induced excitotoxic loss of IHC ribbon synapses in vivo. A one-time noise (8-16 kHz for 2 hours at 110 dB) caused 30%-40% loss of synapses at higher frequencies in Sprague Dawley rats. HPN-07/NAC treatment reversed the damage. Comparisons were made between Noise alone group and Noise+HPN-07/NAC group. ** and *** represent p<0.01 and 0.001, respectively. Twenty-four hours post injury ribbon synapse loss is permanent so recovery must be regenerative.

FIG. 28 shows NHPN-1010 treatment (HPN-07 plus NAC) restored hearing function in a pilot study of established hearing loss. Permanent threshold shift was established by open field blast insult. Treatment was initiated at 4 weeks post-injury, with HPN-07 plus NAC dosed at 300 mg/kg twice daily for 14 days. ABR threshold improvements were shown 14 weeks post-injury (8 weeks post-treatment) versus pre-treatment.

FIG. 29 shows NHPN-1010 treatment (HPN-07 plus NAC) restored IHC ribbon synapse numbers in established, chronic hearing loss model. NHPN-1010 treatment was initiated 4 weeks after injury and dosed daily for 14 days. Ribbon synapse counts were significantly restored 8 weeks post-injury.

FIG. 30 shows NHPN-1010 treatment (HPN-07 plus NAC) resulted in recovery of ABR Wave I amplitudes in established chronic hearing loss model. The amplitudes in response to the 4 kHz and 8 kHz stimulus at both 80 and 70 dB SPL in the placebo group were reduced by blast exposure and continued to decrease as time progresses. Reduction in the amplitude responding to the 8 kHz stimulus at 80 dB SPL recovered completely to the pre-treatment level at 8 weeks post-NHPN-1010 treatment.

FIG. 33 shows HPN-07 and NAC reversed noise-induced synapse loss in vivo. In this experiment, five doses of HPN-07/NAC treatment appeared to be more effective than two doses in reversing the noise-induced synapse loss. Comparisons were made between Noise alone group and Noise+HPN-07/NAC group (5 doses). ** represents p<0.01.

 

That's unfortunate. I appreciate your efforts regardless.

 

Hinting at some good news?

 

I'm just so grateful for your persistence and enterprise. Thank you so much.

 

I've got a question.

To the best of my knowledge, there are four main components in our auditory pathway that carry the sound to our brain. They basically are:
1) outer hair cells;
2) inner hair cells;
3) ribbon synapses;
4) spiral ganglion neurons (that is auditory nerve endings).

We know that FX-322 and Audion will take care of 1) and 2). Moreover, they may even have a virtuous effect on 3).
Then we have OTO-413, PIPE-505 and the Hough pill, all of which will help us fix 3).

My question is: are there any treatments currently tested which address 4)?
Is the Hough pill a potential treatment for damaged spiral ganglion neurons?

 

Quick answer:

FX-322 will mainly regenerate OHC I believe and to some extent also IHC. Their current solution however does not reach the apex of the cochlea, but hopefully they can invent a better hydrogel that does extend all the way down to the apex. It’s only a matter of time until they do. We also don’t know for sure if it is capable of regenerating the maximum possible hair cells in the regions the compound reaches. Current trial results look very promising however.

Frequency Therapeutics clarified that the regenerated hair cells will also have ribbon synapses. Otherwise the hair cells would obviously not be able to generate an action potential towards the synapses and send a signal to the ganglion cells in the auditory nerve. However it is not a solution that will resolve cochlear synaptopathy, meaning that functional hair cells with a decreased number of synapses will not have more synapses after FX-322.

In order to really solve cochlear synaptopathy, what is often described as one of the potential main causes of tinnitus, we will need a working solution like Pipeline Therapeutics is trying to create. My knowledge is limited on PIPE-505 and I don’t know exactly how far they are and to what extent their solution is really going to solve this problem.

A combination of FX-322 and a working PIPE-505 will however, in my opinion, largely restore basic cochlear damage to a large extent. This should have a very significant impact on tinnitus for people who have tinnitus induced by these two particular types of cochlear damage.

I am currently not aware however of anyone working on restoring ganglion cells and I also don’t know how probable it is that this type of potential damage is likely to happen and/or is involved in the generation of tinnitus. I have never seen it mentioned.

Hough Ear Institute however claim their compound of NAC+HPN-07 (anti-oxidant) restores auditory nerve function iirc. I haven’t seen them mention anything about ganglion cells however, but they are part of the auditory nerve.

Maybe others can complete my understanding.

 

Possibly Rinri - you can email and ask if you want. And with the DNA reprogramming Chen is doing it would be likely you would see restorative measures there as well.

If it makes you feel better cochlear implant recipients need mostly intact SGNs for the implant to operate so even profoundly deaf people have them working more or less.

 

It DOES make me feel better! You totally read my mind and understood what my concern was!

 

@brokensoul @HootOwl really like your explanations on these topics. Has helped me a lot to understand more about the possible treatments and the working of our ears in generals. Thanks a lot!

 

It looks like in *humans* you can be very old and deaf most of your life and still not lose very many spiral ganglions per this study.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753358/

Humans have unmyelinated SGNs which makes any scary rodent studies hard to equate to us. I really don't think Spiral Ganglion are going to be a problem for most of us with the possible exception of rare ototoxins (hopefully not macrolides in my case) -- I think there is a kind of snake venom that can do this.

Additionally, per the article, in the rare case you are down to 10% of your SGN, you can still score excellent in word scores after CI implantation. It seems there is a lot of redundancy built into SGNs in humans in that case.

 

Woah. If anyone is worried (@Caveman) about SGNs please please skim through the case studies in this paper. There are people in there who are basically deaf above 1khz and their SPN count is like only 100-1000 less than a normal hearing person. Thank you for finding that paper FGG, it’s a massive relief!

It looks like us humans got really lucky by having unmylinated SGNs.

 

For anyone curious PIPE-505 is a gamma secretase inhibitor that is entering Phase 1/2 in the upcoming months. Their drug penetrates the entire cochlea (down to the apex) in all of their preclinical testings. They use the same poloaxmer as OTO-413 (which is BDNF) which also shows complete penetrance.

Through email correspondence with their CSO Dan we have also discovered that they generate OHC as a secondary measure and that they all align properly and display OHC characteristics and morphology. They do deplete supporting cells but Dan believes only in a small amount.

Edit: just wanted to add that they don’t generate very many OHC. It was never the main goal so they didn’t focus on it much.

If you look at their Chicago conference presentation their data is extremely promising. Their method has more therapeutic benefit than NT3 which Liberman has shown to get you to almost naive levels of regenerative benefit (if the dose is high enough). Their data shows something very similar - you can take a look at the synaptic count and the ABR wave 1 graph specifically.

They also include tinnitus treatment in their patent.

And again, OTO-413 can also be used in conjunction with PIPE-505 to maybe clean up any loose ends that PIPE-505 might miss.

(Actually as an aside, Hough’s patent data shows that a combination of BDNF and HPN-07 had great synergistic effects for regeneration. I would most likely do both the pill and OTO-413 at the same time if possible.)

 

Speaking of nerve repair/regeneration, so we know that there are two different kinds of nerve fibers in the ear - Type 1 1 which are connected to IHCs and Type 2 connected to the OHCs with different properties. Are they aiming to target both and restore both kinds to their proper functionality? Apologies if this has already been clarified - I feel like my grasp of inner ear biology is v tenuous!

 

No prob, the inner ear is a complicated place! No synaptopthy drug thus far regenerates A2 OHC fibers. This is because A2 fibers are extremely resilient to sound and ototoxic damage and don’t degrade readily or easily. They also only comprise 5% of the nerve fiber total and don’t influence “typical” hearing function so companies don’t see much point in trying to regenerate something that is:
1. Likely not damaged in the first place
and
2. Won’t improve audiogram or word scores

For those with noxacusis the problem isn’t that the A2 nerve fibers are damaged but that they are consistently being stimulated by ATP leakage, generating pain. The current theory is that this can be addressed by restoring OHC to prevent ATP leakage or by using a kv7 channel modulator such as what Dr. Thanos is working on for tinnitus.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664349/#idm139719422741808title

However if you do have missing A2 nerve fibers Chen has stated in an email to me that they regenerated both using his method of DNA reprogramming. But this is because they were working with an entirely flat epithelium. Most of us are no where near that point.