Inner Ear Hair Cell Regeneration — Maybe We Can Know More

Sorry. Wow awesome I am a lot more enthusiastic!!!

 

I believe so.

My understanding is that they drill a hole in the cochlea and inject directly into the scala tympani. This may vary by paper, but from http://www.nature.com/articles/srep46058

"Using the dark stria vascularis as a landmark, scala media was opened by cochleostomies in the second turn and third turn. Experimental substances where introduced through the second turn cochleostomy and excessive fluid was allowed to escape from the third turn. First, 2 μl of stem cell media (TeSR-E8 supplemented with 10 μM Y-27632, see stem cell procedures) or media with 10 mmol/l sodium caprate (Sodium decanoate, Sigma-Aldrich Co., St. Lois. MO) were injected into scala media. As noted above, some animals received only these fluids to assess their effects on native tissues, in others, these fluids were followed by 2 μl of human stem cells (~20 million/ml)."

 

I believe they drill a hole it it. This is the procedure for the Genvec/Novartis trial.

This seems plausible.

I've seen no evidence that Anc80 is designed with potassium in mind. It's not mentioned in the methods paper (http://www.nature.com/nbt/journal/v35/n3/full/nbt.3781.html). It's also not necessary as the injection is through the RWM into the perilymph (see methods section of the paper). In fact, in the paper, they speculate "The reason for lack of rescue in 6 of 25 mice was not clear, but may have been due to failed injections, clogged injection pipettes or injections that missed the targeted perilymphatic space." So Anc80 is not injected into a high potassium environment.

Again, this seems plausible though I don't think I have seem specific discussion of why it is that Anc80 is more effective across the full range of IHCs.

 

For those with a good sense of history outside of GenVec how many hearing restoration human clinic trials have there been? Kinda seems like a good sign that more than 5 are gearing up.

 

For someone with access to the RWN article above do you know how it would compare with the staple approach in terms of the percent of OHC and IHC it reaches. Either way with all the testing that has occurred I think ANC80 with the coating is ready for human testing.

 

What papers do you have in mind?

No.

Doesn't matter. They diffuse through the RWM into the perilymph.

No.

 

They do. How else is the prosthesis going to act as a piston and move freely in the hole?
There's only a sleeve that is inserted between the piston and the hole, which is made from a graft. For me they took a vein from my hand.
The piston has to be able to transmit the mechanical vibrations from the ossicular chain into fluid waves in the cochlea.

That's actually one of the risks with the procedure. For people who have endolymphatic hydrops, there can be extra pressure from the fluid in the cochlea which results in a "gusher" when they finally poke through. It's not good when that happens.

 

Reading all the posts and some documents (very basic understanding) lately I am starting to think Gen-therapy will be suited better for inner ear regeneration than stem cell therapies. At this moment in time that is. Perhaps in future that will change?
I used to think that stem cell therapies would be first.

 

I had a stapedotomy. They removed the arch but kept the footplate in place (they drilled through it).

Stapedotomy. Pretty much everyone does stapedotomies now.

They need some tissue from the patient to wrap the piston into before it goes into the inner ear. It has to be solid enough that it won't break (in years of friction), but flexible enough that the piston can move with it around it. It turns out that our veins are made of a tissue that is pretty good for that, so they opened my hand, cut a piece of vein, sliced it (the tube/pipe) such that they end up with a somewhat square piece, which is then used to wrap the prosthesis.

My understanding is that it goes all the way through (hence the risk of gusher). I don't think they can just try to shake the footplate, because that's the very part that is ankylosed from the bone remodeling focus.
I think the graft acts as a new membrane to propagate the sound into the inner ear.
Watch this. It's actually described by the surgeon who did my surgery. It also shows the vein graft process.

Otosclerosis - Laser Stapedotomy

 

If you guys want to have an in-depth discussion about stapedectomy/stapedotomy, it would make sense to start a new thread (unless there is an existing one).

 

What made you come to this decision? The paper describing the toxicity of the potassium channel? I wonder if the gel used in these viral injection would help with the survival of injected stem cells.

 

Yes, the mods should feel free to move the last couple of messages to their own "Stapedotomy details" thread.

Actually no, it got infected. It almost never happens, but hey, almost never is not never. Topical antibiotic helped healing. That's nothing, it's just superficial. I'd happily trade my T for hundreds of these over my body. Now it's just a scar on my hand.

I had mixed loss going in (conductive + sensorineural). The surgery pretty much closed the air-bone gap completely, so I did regain significant hearing in the low frequencies. However, my high frequencies got worse (which is a known risk). That's the only negative thing out of the surgery: I didn't get much dizziness, didn't lose taste or get any facial problems (they didn't have to touch the chorda tympani), etc.
The recovery is a bit difficult because of the packing in the ear: you can't hear anything for a while, and the T becomes really overwhelming.

I'm now left with sensorineural losses: it's all downhill from 1 kHz up.

It can, unfortunately (hence the sensorineural part of the losses). In some cases the bone remodeling process releases cytokines into the inner ear fluid, and they are harmful to the hair cells (see, we stay on topic here!). So if your otosclerosis starts attacking the inner ear, you can get SNHL. Look up "cochlear otosclerosis".

So the T can be a combination of individual Ts coming from various sources. The T that comes from the middle ear stiffness is generally low frequency. There is a paper that explains the fluid dynamics equations behind it - I read it about a year ago. You may be able to find it on pubmed (I think that's where I found it first).
The T that comes from the inner ear damage is more on the high frequency side, probably because the bone focus is close to the base of the cochlea, which is where the HF cells are (that's only my guess - nobody really knows).

I went into surgery with a 50/50 chance of getting rid of T. That was one of my main motivators. It didn't work for me. The T morphed into something different, with less of a pulsatile component. It's still horrible, but it's different.
The good news is that my severe hyperacusis got reduced to almost nothing after surgery. So that's a big win for me.

 

Agreed. I think I gave all the info I had to @Samir in my last message. I don't expect a lot of follow up on that, but if there is we should definitely do that somewhere else.

 

@Aaron123 Can you discuss how the paper describing injected stem cell death within the ear matches some of the prior success Dr. Rivolta has had with neuron stem cells? Would neuronal stem cell for nerve repair and synaptic regrowth have to travel through the high K environment? Did he just lose a lot of stem cells and make up for that in terms of quantity?

https://www.tinnitustalk.com/thread...m-cells-into-the-inner-ear.17306/#post-201751

 

Can anyone speculate on the effects of multiple viral injections of the AAV or ANC-80? Would the immune system react to a second injection? Has this been tried in animals? I think multiple viral introductions may be useful for companies with the goal of increased synaptic connections using growth factors.

 

Since the target was spiral ganglion neurons, the cells were not injected into the inner ear so potassium was not an issue.

Nonetheless, I am far more skeptical about this paper than many people here.

We could all speculate, but it would not, as far as I know, be based on any published research and so there would be little or no point.

 

What makes you say that? I dont think your wrong because stem tech has been around long enough that more of these questions should have been answered. I know the US has stifled research. Still if you have lost or damaged beyond repair some SGNs would there be another to replace them? If gene or drug therapy is as successful as we hope there still may be utility in a success stem treatment.

 

Actually they went another way with this see article below. So we will still have Phase 2 and Phase 3 before market release

http://www.npr.org/sections/health-...gottlieb-to-head-food-and-drug-administration

 

Apparently it is difficult if not impossible at this moment in time to get stem cells to survive in the inner ear.
Also the first attempt (GenVec) is a gen therapy. The one Frequency Therapeutics is discussing is also gen therapy.

 

Do they have to get to the inner ear to be effect for neuron regrowth? Could/do the majority of stem cells injected into the middle ear make it to the SGN? If they do how much type 1 and type 2 neuronal regrow results? If at this time stem cell injected into the middle ear are not useful for hair cell regrowth but do create type 1/2 nerve fibers then for tinnitus that is the whole ball game and we should be happy that there is a different treatment option. If not than I agree stem cell are a long way off from being useful for hearing restoration.

@Samir I know. But in the US I kinda feel like DC is tying the hands of these research facilities.