Frequency Therapeutics — Hearing Loss Regeneration

I was somewhat surprised that GenVec makes a little hole in the cochlea with a laser to get the drug in.
Do you have a source that confirms this? I have seen people mention this, but not an actual article describing it. Where in the cochlea do they make the hole?

What will this laser damage in the inner ear?
I guess it depends where they make the hole. My first fear wold be leaking perilymph. With that said, it's not the first time that holes have been made in the cochlea.

Some types of ear surgery (now generally abandoned) used to leave the round window open to the outside world and covered over the oval window. Sound pressure therefore hit the round window but was shielded from the oval window. It therefore traveled "backwards" around the cochlea but still gave useful hearing as the hair cells were still deflected in the same way.

Source: https://en.wikipedia.org/wiki/Round_window#Clinical_significance

I always figured that a slow releasing gel on the round window was an effective way of getting drugs in the inner ear. Perhaps not (yet?).
I guess it depends on what you mean by drugs. GenVec and Frequency use fundamentally different therapies. Small molecules may be able to pass through the round window membrane, but maybe not whole cells or viruses.
 
I also read that the Novartis procedure is like a stapedectomy. I don't know much about it, but that may answer your questions. Supposedly its a standard procedure that only takes 30 minutes and it is done all the time by ENTs.

http://www.hearinglossjournal.com/cgf166-latest-news/
http://www.kansascity.com/news/business/health-care/article47551535.html
It was mentioned in these articles.

Good point, Samir, on the small molecules. That is probably why there is the difference between the two therapies.

I was originally interested in the Novartis gene therapy trial, but after reading some patient accounts Its hit and miss right now. It is too risky for me. I see this as a more promising therapy, plus it is not as invasive as putting a hole in the cochlea.
 
Apparently, there is more to "intra-tympanic" (or transtympanic) injections than you might think. There are actually 2 different versions of this delivery method. One is where you puncture the tympanic membrane with the needle. The second one is where incision is made in the tympanic membrane and the hole is wide enough to allow you to stick an endoscope through it.

1: Tympanopunction
This one is probably more common. It relies on an anatomical structure in the middle ear cavity called the round window niche. It also relies on tilting your head just the right amount, which is about 45 degrees contralateral to the unaffected ear, so that the round window is at the lowest point of the middle ear cavity. It's also vital that the amount of medication is just enough to fill up the cavity and cover the round window, and not drain down the eustachian tube.

Image courtesy of Auris Medical:

NoiseHealth_2013_15_63_83_110285_f2.jpg


2: Myringotomy

In this version, a small incision is made in the tympanic membrane. This has two advantages. It prevents pressure from building up in the middle air cavity by allowing air to escape through the incision. The eustachian tube may not always open for air displacement. It also allows to check the patency (openness) of the round window membrane by using an endoscope. This also allows for a controlled injection by seeing the fluid level rising around the round window membrane. This approach may be more relevant for patients who had otitis media, eustachian tube dysfunction, etc.

Image courtesy of Auris Medical:

NoiseHealth_2013_15_63_83_110285_f3.jpg
 
I also read that the Novartis procedure is like a stapedectomy.
That would mean removing the stapes bone and replacing it with a prosthetic? This seems wasteful to me if the stapes is mobile and functioning normally. It might be an option in case of mixed hearing loss (CHL and SNHL).

Supposedly its a standard procedure that only takes 30 minutes and it is done all the time by ENTs.
All these procedures are done by ENT surgeons. But the time it takes is of no significance. Using round window membrane access takes about the same time.

The procedure involves going down the ear canal and detaching the tympanic membrane (ear drum) to reach the cochlea. A laser is used to create a hole in the cochlea to deliver the CGF166. Remarkably, it only takes 30 minutes and the patient is sent home the same day.

http://www.hearinglossjournal.com/cgf166-latest-news/
Hole in the cochlea! But where?

To get this therapy into a patient's inner ear, Staecker makes an incision to open the eardrum and then uses a laser to drill a tiny hole into a bone that presses against the inner ear. Through that opening, he injects a tiny droplet, less than two-thousandths of an ounce, into the inner ear.

http://www.kansascity.com/news/business/health-care/article47551535.html
What bone? The bony labyrinth?

I see this as a more promising therapy, plus it is not as invasive as putting a hole in the cochlea.
Making a hole in the cochlea is called cochleostomy. We know from cochlear implant surgeries that cochleostomy and round window enlargements causes most damage to the cochlea and it can cause endolymphatic hydrops which is quite serious (source). Round window membrane diffusion seems to be the most viable option. But it may not work for all types of therapies.
 
@Samir pardon my ignorance but these hair cell regeneration will this be useful for someone who has nerve damage death? I think that is a common experience for those with hidden hearing loss. How would nerves attach these new hair cells. Would it matter if there are less nerves that exist? While I'm on the topic are there any nerve regeneration research groups?
 
@Jim51042 The problem is two fold! It involves regenerating sensory cells, and regenerating nerve synapses. The main focus has been on sensory cells, i.e. inner and outer hair cells. These are most likely to be damaged in most people with hearing loss. But recent studies show that people can have nerve damage without sensory cell damage. The two can also coincide.

The so called hidden hearing loss is characterized by normal hearing thresholds and difficulty understanding conversation in noisy environment. This has been attributed to nerve damage. Two causes for this have been identified actually. One is synaptopathy, which was discovered by M. Charles Liberman, who also coined the term hidden hearing loss. The second cause is due to disruption of the heminode, which was discovered only recently by Gabriel Corfas.

I don't know the exact mechanics of synaptogenesis, but I am sure it involves nerve growth factors. In fact, I think it was Corfas and Liberman who showed that neurotrophin 3 can regenerate nerve synapses. I would expect nerve regeneration to be of huge interest to the scientific community, because it has the potential to cure so many different diseases of the peripheral and central nervous system. I have not been looking at the wide picture of nerve regeneration per se, but when the inner ear is concerned I have just given you the names of two of the most prominent researchers in the field. Like I said, restoring hearing is a two fold problem. You not only need sensory cells, but also functional nerve synapses. You can't have one without the other and have a good hearing.

Thankfully, nerve degeneration is a slow process. It happens at different stages. Most importantly, nerve cell bodies show a long term survival. So there is a good chance that nerve axons and synapses can be regrown and reattached to the survived or regrown sensory cells.
 
http://www.huffingtonpost.co.uk/ent...erse-hearing-loss_uk_58ad5e99e4b0d0a6ef4657da
"While the team had to artificially nudge the cells into becoming hair cells this wouldn't actually be necessary inside a live ear.

"We only need to promote the proliferation of these supporting cells, and then the natural signalling cascade that exists in the body will drive a portion of those cells to become hair cells," says Jeffrey Karp, an associate professor of medicine at Brigham and Women's Hospital and also a senior author on the paper."

I think that, if indeed you can make use of this natural signalling cascade that exists in the body, possibility to succeed is greater. After all, this "natural signalling cascade" is the product of many, many years of evolution and is stored in DNA.
Or do I misunderstand?

I like "We only need..." (-;
 
http://www.huffingtonpost.co.uk/ent...erse-hearing-loss_uk_58ad5e99e4b0d0a6ef4657da
"While the team had to artificially nudge the cells into becoming hair cells this wouldn't actually be necessary inside a live ear.

"We only need to promote the proliferation of these supporting cells, and then the natural signalling cascade that exists in the body will drive a portion of those cells to become hair cells," says Jeffrey Karp, an associate professor of medicine at Brigham and Women's Hospital and also a senior author on the paper."

I think that, if indeed you can make use of this natural signalling cascade that exists in the body, possibility to succeed is greater. After all, this "natural signalling cascade" is the product of many, many years of evolution and is stored in DNA.
Or do I misunderstand?

I like "We only need..." (-;
For me that also mean that they can't decide which type of hair cell to create and they don't have to care about that since hopefully the body handles that on its own after the proliferation of supportive cells. That makes things a lot easier IMO, and hopefully it will work.

Is thete different types of supporting cells for high and low frequencies for example like for hair cell ? Hopefully not...
 
Is thete different types of supporting cells for high and low frequencies for example like for hair cell ? Hopefully not...
I have wondered about that myself.
For inner hair-cells that is the case.
hopefully the body handles that on its own after the proliferation of supportive cells. That makes things a lot easier IMO,
I wonder if at the moment it is still too complex for scientists to do this.
 
@ Samir Still trying to get my head around this whole thing. But I do recall reading something from Stefan Heller where he said after promoting new hair cell growth the nerves have a tendency or appear to attempt to reattach.
 
@dmorg Don't push yourself too hard! I think it's safe to assume that "this whole thing" is well beyond our level of understanding, myself included. That's why we have biologists and chemists who understand this at a much deeper level than any of us. Then even they are puzzled about it and need more time and research done to expand their knowledge or to "get their head around it". (y)

I can only understand the basic ideas, and I am happy to follow their work. But what an amazing work they are doing! :) I don't just say that because they are doing something that will help me in the end, and others like me. It's by reading about tinnitus research and hearing restoration that I have come to realize just how much work they put into this and how complicated this is. The more I read about it the more I realize the difficulty of the task and the more I appreciate their effort.

I do recall reading something from Stefan Heller where he said after promoting new hair cell growth the nerves have a tendency or appear to attempt to reattach
Do you happen to have a link to the article? I seem to remember reading something along those lines in a Wikipedia article on synaptopathy or neurodegeneration but I am unable to find that exact line.

This also reminds me a bit of the statement that Jeff Karp made in Huffington Post (see the link above).

We only need to promote the proliferation of these supporting cells, and then the natural signalling cascade that exists in the body will drive a portion of those cells to become hair cells

The same may be true for synapses.
 
If this is true how well would these new hair cells actual have to "work" to get a reduction in T. Lets say they were only mildly effective in sensing sound (summing them together say a response level of 25dBA at X frequency) and relaying that to the brain. Would the brain then stop sending signal back to the ear or would it simply send less signal back to the ear (aka milder T)?
 
Currently I have no need of hearing improvement (and am at least grateful for that). If this theory were true it would be a roundabout method for me and many other people to reduce their T. By this I mean gaining hearing sensitivity when more hearing sensitivity was not the original goal.
 
If this is true
If what is true? Are you having doubts about hearing restoration in general or something in specific? You doubt that hearing restoration can reduce tinnitus?

how well would these new hair cells actual have to "work" to get a reduction in T.
A little? Less efficient hair cells giving less reduction, more efficient hair cells giving more reduction? No one really knows for sure. We don't even have an objective way to measure tinnitus. It's all based on your perception, and so is the standard hearing test.

Lets say they were only mildly effective in sensing sound (summing them together say a response level of 25dBA at X frequency) and relaying that to the brain.
This statement doesn't make a lot of sense. We are talking about hearing level. A hearing level of 25 dB on average is a subjective perception of sound that takes place in the brain. Decibels are not objects that need to be stored or relayed by the ears to the brain. If anything, it's something that your brain relays somatically (you press a button) or verbally (you say a word) to the audiologist administering the test. It's about using physics to measure hearing sensitivity. But ears and brains don't understand what Decibel is. They operate on the basis of chemistry.

This brings us to people who appear to have perfect hearing when you look at their audiograms. You would think that a person that has a hearing level of 10 dB on average across all frequencies has perfect hearing. Yet they complain about not hearing conversation well in noisy environment, and some of them even have tinnitus. That's because they likely have hidden hearing loss. The damage inside their ears cannot be measured with a standard hearing test. Synaptic loss is largely attributed to this condition. Once you have that kind of hearing loss, measuring Decibels won't help you to assess the damage. Likewise, once you have had a hearing restoration therapy, using an audiometer to measure the improvement in hearing is not ideal. Which points to the lack of diagnostic tools in this medical practice.

I should not have to tell you that people who have noise induced hearing loss also have tinnitus. When you look at their audiograms right after the damage has been done, they will display maybe mild to moderate drops in hearing level. When they take the same test a few months later, they may display an improvement in hearing level. But they may also develop tinnitus. You would think that these people don't need hearing aids or hearing restoration therapy because their hearing levels measured by an audiologist are within the "normal" 0 - 20 dB range. But if you can find a way to do it, look inside their cochleas and you will discover they have sensory and synaptic damage. How much of that post-damage boost in hearing level is to thank recovered hair cells for and how much is to blame on central gain increase in the brain, no one really knows.

Would the brain then stop sending signal back to the ear or would it simply send less signal back to the ear (aka milder T)?
Assuming that tinnitus is a side effect of or maladaptation to sensory cell loss or synaptic loss, then restoring these cells and synapses may reverse this process and either significantly lower the tinnitus or completely eliminate it. No one knows for sure until we have thoroughly tested this in people. Hopefully this will happen in not too far off future.

I don't think it's the signal from the brain to the cochlea that's causing tinnitus. I think it begins with the lack of input from the cochlea to the brain. It's a two way street. Sound input to the brain comes mainly from inner hair cells, but outer hair cells help in sound perception by amplifying the sound and they receive input from the brain to do so. That's my very simplistic version of how it works. The outer hair cells actually vibrate on their own without any external sound stimulation, and this is what's causing the so called otoacoustic emissions. I think it's safe to say that the discovery of these emissions is one of the biggest discoveries in otology in the last 100 years. The inner hair cells also receive some input from the brain, but I don't understand yet what the function of that is.

To get back to your question, you should not expect the brain to stop sending signals to the cochlea. That's just not normal function. You won't be able to hear! Remember what I said about outer hair cells and how they amplify sounds. You don't want to lose that function. But this signaling to amplify the sound may be reduced if the normal function of inner hair cells is restored.

Basically what you want to do is reduce signaling in both directions, to the brain and back to cochlea. The best way to do that is to have any damaged inner and outer hair cells repaired or missing ones regenerated. Likewise, you want to have those connective nerves restored.

No one really knows at what stage of hearing process tinnitus occurs. The hypothesis presented by Liberman is that it's the loss of afferent nerve fibre density of inner hair cells that stages tinnitus. But no one has been really able pinpoint exact location along the auditory pathway where tinnitus is generated. Given it's subjective nature, it's difficult to link it to physiology.

But it's hard to ignore the fact that tinnitus is evident in so many people with hearing damage, measurable or not (hidden hearing loss). With that in mind, perhaps the best way to go forward is by experimentally proving this in human subjects, by providing a first-ever therapeutic treatment for hearing restoration. That's what everyone is busy working on now, and what patients with tinnitus as well as people with hearing loss are waiting for. Hearing restoration research is so much in focus now that tinnitus research has taken the back seat, awaiting results from these hearing restoration attempts. Restoring hearing therapeutically should put some of these old and new tinnitus hypotheses to rest once and for all.
 
New article about Frequency
Let me quote the parts I found interesting.

Researchers have used cells in regenerative medicine for decades – in 1931, the father of cell therapy, Paul Niehans, treated a patient with material from calf embryos.
Interesting! I did not know that.

When scientists first derived stem cells in 1981 – a decade after Niehans's death – many heralded the innovation as a new chapter in regenerative medicine.
Interesting!

Langer and Karp discovered that the epithelium in the human GI tract is filled with hyper-active progenitor cells that drive the epithelium in the GI tract to regenerate itself every five days.
This answers one of my own questions that I have had.

"When people began 'Progenitor Medicine 1.0,' they would take cells out of the body, manipulate them and try to put them back in the right place and get them to integrate and do the right job. That's really complicated, particularly from a cell delivery and integration perspective," Loose explained.
I think this helps answer one of the question that @Reinier had in the hair cell regeneration thread. Right Reinier? :)

Instead, Frequency Therapeutics developed a proprietary combination of small molecule drugs that's injected into the ear to activate the progenitor cells.
(...)
"We think we're leading the revolution for 'Regenerative Medicine 2.0,'" said Frequency Therapeutics co-founder and COO Chris Loose. "As we look back, we think maybe this is the way that regenerative medicine should have been done in the first place."
Go Frequency, go! Tell it to them... :rockingbanana:

The company plans to use a clinically-established injection into the middle ear of a slow-release gel, in a 3-minute office procedure that's been used for years to administer drugs to treat ear infections.
Wow! That's fast! But I don't think so. It really takes about 20 to 30 minutes for the molecules to diffuse through the round window membrane.

Loose said working with Frequency Therapeutics and its progenitor cell activation technology reminds him of Langer's advice when Loose was a graduate student at the Massachusetts Institute of Technology: "It takes the same amount of work to solve a really important problem as it does an unimportant problem, so work on something that's really important." "
I'll drink to that! :beeranimation:
 
The procedure, aka the injection, lasts three minutes [sic].
Ah so! That sounds more like it, with the anesthesia and all that. When they said "office procedure" I thought they were referring to the therapeutic procedure as a whole. Only 3 minutes! That would be like getting coffee at the local café. :) I would not mind if t takes 60 minutes!

Either way, I think the intratympanic delivery through the round window membrane is the best way to go. The cell transplant modality is much more complicated. So I think Frequency has a winning concept here.
 
Not to be a downer about all this, but my worry is that what if once the hearing is corrected, the T remains?
You are not alone with this thought. This is on everyone's mind.

Don't cross the bridge until you come to it!
 
Not to be a downer about all this, but my worry is that what if once the hearing is corrected, the T remains?
Seems to me we should be able to test this now with hearing aids. Shouldn't using hearing aids to boost the frequencies you cannot hear simulate getting your hearing back well enough that if it makes your T go away then you know restoring your hearing will make your T go away and if it doesn't then you'd be out of luck.

Has anyone out there used hearing aids (without maskers) to achieve T reduction? I haven't heard of anyone who has....
 
Not to be a downer about all this, but my worry is that what if once the hearing is corrected, the T remains?
I'd take this as a win personally. I'd be super happy to have my near perfect hearing back. Assymetrical hearing loss, even only 5dB at multiple frequencies to trained ears like mine, has felt like it has destroyed what i've worked nearly half my life towards.
 
Seems to me we should be able to test this now with hearing aids. Shouldn't using hearing aids to boost the frequencies you cannot hear simulate getting your hearing back well enough that if it makes your T go away then you know restoring your hearing will make your T go away and if it doesn't then you'd be out of luck.

Has anyone out there used hearing aids (without maskers) to achieve T reduction? I haven't heard of anyone who has....

There's lots of discussions on this throughout TT. Some have had success, and some not so much. I have a friend/employee, who has his T go away completely when wearing his hearing aids. His hearing loss was noise induced.
 
Has anyone out there used hearing aids (without maskers) to achieve T reduction?
Yes, there were a few posts about it a little bit earlier in this thread. Some people seem to be able to reduce their T with hearing aids significantly, and in some cases they can even make the T go away.

But I don't want to be the one to bring back the discussion on hearing aids. It's not popular to discuss hearing aids in a thread about Frequency Therapeutics. There are several threads you can check out.

So yeah, this is a strong indication that hearing restoration may reduce or completely cure T. The only problem is that we don't have a hearing restoration therapy readily available yet to put the theory into practice. But we'll get there soon enough! Like everyone else, I would rather see it happen sooner than later. But we can't will the treatment to be available tomorrow.
 
Not to be a downer about all this, but my worry is that what if once the hearing is corrected, the T remains?
I am inclined to think that even though hearing is restored that tinnitus will remain, at least in some cases.
The reason I say this is that there are for me personally so many other symptoms to T.
Brain buzz and insane laser sounds when waking up that I simply do not believe are related to hearing loss.
Its something else, something chemical ... Maybe started with hearing loss but something happens in the brain.
 
Well we have seen some cases of improved hearing reducing T (stem cell therapy, LLLT). But I am weary of accepting this as a solution. @RaZaH I now have the electrical head buzzing as well and it does not seems like normal T. Here's my best guess in trying to have a positive approach: we know that hearing loss causes the nerves to become overactive, I think this causes a chain reaction to other surrounding nerves (some which can feel like they're buzzing) perhaps if the root of the overactivity (the hearing loss) were addressed, it would stop the chain reaction.

I am leaning toward the brain as well at least for cases like mine. My hope lies with DBS. I don't mind being half robot.
 
For noise induced hearing loss I would think that restoration of the signals would reduce/eliminate T. You can look at examples where an injury has occurred T develops but over time the injury is repaired and T is eliminated. The brain is constantly interacting with your ears so if there is a change to your ears either negatively (more damage) or positively (restoration of damage) the brain should follow suit. I get that time is factor here but really I think that the brain will update to changes.

Now if brain damage is the major cause of someones T then fixing the ears may not play a role.
 
Agree @RaZaH and @Cal18 - this thing is in the head now, the switch has been triggered and over excitement taking place - this is where I see a solution for my type of t (have no obvious hearing loss), DNS or something that addresses the neuron's response...

Still studying the whole thing, very complicated...
 

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