Inner Ear Hair Cell Regeneration — Maybe We Can Know More

This only mentions inner hair cell regeneration?

Why is outer hair cell regeneration not important, when it's centric to painful hyperacusis.

Outer hair cells only make up 5% of the hair cell population and have to do with amplification and pain reception of the inner ear.

Damage to outer hair cells (OHC) and their respected nerve fibres is what causes painful hyperacusis because the nerve fiber of the outer hair cell responds to damage by dropping the pain threshold tolerance level.
https://jhu.pure.elsevier.com/en/pu...pe-ii-afferent-neurons-report-cochlear-damage
 
This only mentions inner hair cell regeneration?

Why is outer hair cell regeneration not important, when it's centric to painful hyperacusis.

Outer hair cells only make up 5% of the hair cell population and have to do with amplification and pain reception of the inner ear.

Damage to outer hair cells (OHC) and their respected nerve fibres is what causes painful hyperacusis because the nerve fiber of the outer hair cell responds to damage by dropping the pain threshold tolerance level.
https://jhu.pure.elsevier.com/en/pu...pe-ii-afferent-neurons-report-cochlear-damage

Where did you hear out hair cells are only 5% of the population. Everything I've seen suggests 3 outer hair cells to 1 inner hair cell. Look at the cross section of a cochlea.

https://ars.els-cdn.com/content/image/1-s2.0-S037859551630260X-gr1.jpg

http://www.cochlea.eu/en/hair-cells
 
Where did you hear out hair cells are only 5% of the population. Everything I've seen suggests 3 outer hair cells to 1 inner hair cell. Look at the cross section of a cochlea.

https://ars.els-cdn.com/content/image/1-s2.0-S037859551630260X-gr1.jpg

http://www.cochlea.eu/en/hair-cells
I stand corrected, I misunderstood the information. 95% of the nerve fibers associated with the cochlear hair cells are inner hair cell nerve fibres and 5% our outer hair cell nerve fibres. I assume that meant that outer hair cells only made up 5% of the population.

upload_2018-5-23_12-59-29.png
 
Would this also include regenerating the hair cells in the vestibular system? Because ever since I had sudden hearing loss overnight, I have been extremely dizzy, to the point of falling down.
Yes, some believe math1 has a better chance of application for vestibular hc loss. Note: this would not apply for neuropathy disorders of scarpas ganglion. Just for hair cell loss. Let's hope it effects both.
 
OTOSTEM — Result In Brief
https://cordis.europa.eu/result/rcn/221335_en.html

OTOSTEM tested two therapeutic approaches to treat hearing loss: A cell-based treatment introducing stem/otic progenitor cells into the cochlea, and a drug-based treatment to protect or regenerate sensory hair cells.

Researchers utilised various stem cell sources to obtain otic progenitor cells (OPCs). These included native stem cells from foetal and adult human otic tissues, and embryonic or induced pluripotent stem cells. The generated OPCs had to fulfil certain criteria such as in vitro expansion and differentiation into sensory hair cells, supporting cells or otic neuronal cell types.

OTOSTEM developed protocols with morphogens or small molecule compounds that induce and determine otic cell fate. OPCs were tested for biological function and absence of tumorigenicity in various ex vivo and in vivo assays. Through comparison of OPC phenotype and gene expression, OTOSTEM partners identified native human stem cells as the stem cell source with the highest otic differentiation potential.

Functionality of the generated otic or neuronal cell types was validated in in vitro experiments. Electrophysiological monitoring demonstrated that transplanted cells resembled those of mouse cochlear hair cells. Human otic neuronal progenitors were tested in preclinical animal models of auditory neuropathy. Hearing restoration was achieved and preserved for more than 30 weeks after transplantation with no adverse effects.

Currently, there is no quantitative cell-based assay for testing drugs specifically toxic to the ear (ototoxicity) in humans, thus even approved drugs bear the risk of causing hearing loss. To address this, and facilitate drug safety studies, the OTOSTEM consortium designed drug screening assays. This 'hearing loss in a dish model' employed otic progenitor cell-like cells derived from human induced pluripotent stem cells. The human assay was used for medium-throughput testing of more than 2 000 pharmacological active compounds including FDA-approved drugs. Surprisingly, several of these drugs were identified to be ototoxic.

The OTOSTEM consortium has developed novel compounds with otoprotective and otoregenerative activity. Otoprotective compounds prevent death of human ear hair cells. Otoregenerative drugs induce replacement of lost sensory cells. The OTOSTEM findings are of outmost commercial significance to the largely unexplored but growing market of otoprotective and regenerative drugs.

Given the association of hearing impairment with neurodevelopment in young, and dementia in older people, there is an imminent unmet need for clinically validated therapies. Industrial partners envisage that the OTOSTEM models can be incorporated into the drug discovery pipeline to enable the identification of new and better drugs to treat hearing loss. As Dr Avci outlines, "With the support of the Seventh Framework Programme, we significantly advanced the development of novel therapies against hearing loss and we are eager to continue our success within the H2020 programme.
 
This is about the wrong kind of hair cells, but interesting nonetheless. It is science after all. It's about unexpected discoveries not too unlike those of Penicillin.

Turning hair into a biomedical nanomaterial
https://www.nanowerk.com/spotlight/spotid=50317.php
A key challenge in developing materials for biomedical engineering is their biocompatibility. Of course, it would be ideal if high-performance biomaterials could directly be obtained from patients themselves.

This is exactly what a team of scientists in China has now demonstrated. They discovered that the hierarchical micro- and nanostructures of human hair can be turned into hierarchical micro- and nanoparticles with a simple top-down procedure and be used as a novel type of biomaterial for medical applications.

This strategy of preparing biomaterials from abundant human hair might provide a potent tool for producing autogenous materials from patients themselves to overcome the drawbacks of synthetic materials.

"Our study began with a very interesting coincidence," Zhang recounts. "When we were preparing a sample for electron microscopy scanning, a piece of hair dropped on the object stage. Coincidentally, we observed the beautiful hierarchical structure in this piece of hair. Our major research interest is discovering new materials for solving biomedical problems, and materials obtained from the human body might be very suitable to address these challenges. Looking back at the whole research process, I think curiosity has motivated us to conduct this work."

From a chemical perspective, hair is mainly composed of melanins and keratins – two polymers that are ideal materials for biomedical applications. Keratin-based biomaterials display superior performances in bone regeneration, hemostasis, and cell protection. Pigments of melanin, a kind of functional polymer existing in most life forms, have versatile functions in regulating redox equilibrium, photothermal conversion, and dynamic coloration.

In their experiments the team found that, compared with commercialized carriers, such as liposomes or albumin nanoparticles, the hair particles exhibited negligeable immunogenicity and intrinsic blood compatibility.

"Due to the satisfactory photothermal conversion of melanin, both hair micro- and nanoparticles showed high and continuable photothermal conversion ability, and this feature made them ideal materials to achieve photothermal therapy," says Zhang. "Furthermore, these biomaterials displayed attentional abilities on light absorption and free radical scavenging. We also found that, when made into sunscreen, they could prevent skin from UV-induced damage. The aqueous dispersion of these particles could also relieve symptoms of cataracts, rescue mice from vein thrombosis, and suppress tumor growth."

In their next research stage, the team will further investigate the bio-safety and durability of these materials. In the present study, all hair samples were used immediately after collection. However, translating an eventual hair-based hierarchical biomaterial from conceptional work into clinical applications, exploring and optimizing the standard conditions of hair collection, transportation and storage would be an inevitable step.

"Advances in medicine in the areas of genomics, proteomics, tissue engineering, and regenerative medicine are occurring at a rate that was previously unthinkable," Zhang concludes. "The purpose of our research is to discover high-performance biomaterials through interdisciplinary methods and help facilitate their successful introduction into clinical applications."
 
I wrote about professor Hudspeth earlier. He was in the news today, so I thought I would post a small note here. He has been awarded with the Kavli Prize, a gold medal and 1 million dollars in cash prize. I would say that's well deserved, for his 50 years of foundational work in the field of auditory science.

A. James Hudspeth to receive Kavli Prize in Neuroscience
https://www.rockefeller.edu/news/22736-james-hudspeth-receive-kavli-prize-neuroscience/

When Hudspeth began his studies in the late 1960s, very little was known about hearing beyond basic anatomy and physiology. Hudspeth revealed the role of the receptor cells of the inner ear, as well as the role and development of hair cells, which translate sound-induced mechanical actions into electrical signals for transmission to the brain. He also showed how sound is amplified by thousands of these hair cells covering the cochlea, a conch-shell-shaped cavity in the inner ear. Recently, Hudspeth has begun exploring the possibility of using hair cell regeneration as treatment for hearing loss. His studies of the neural mechanisms of hearing are facilitated by a specially designed microscope that can record a million measurements a second, with subnanometer resolution.
 
I wrote about professor Hudspeth earlier. He was in the news today, so I thought I would post a small note here. He has been awarded with the Kavli Prize, a gold medal and 1 million dollars in cash prize. I would say that's well deserved, for his 50 years of foundational work in the field of auditory science.

A. James Hudspeth to receive Kavli Prize in Neuroscience
https://www.rockefeller.edu/news/22736-james-hudspeth-receive-kavli-prize-neuroscience/

When Hudspeth began his studies in the late 1960s, very little was known about hearing beyond basic anatomy and physiology. Hudspeth revealed the role of the receptor cells of the inner ear, as well as the role and development of hair cells, which translate sound-induced mechanical actions into electrical signals for transmission to the brain. He also showed how sound is amplified by thousands of these hair cells covering the cochlea, a conch-shell-shaped cavity in the inner ear. Recently, Hudspeth has begun exploring the possibility of using hair cell regeneration as treatment for hearing loss. His studies of the neural mechanisms of hearing are facilitated by a specially designed microscope that can record a million measurements a second, with subnanometer resolution.
I enjoyed the lecture series you posted, very informative.
 
neuro.jpg


The dream team? It turns out Hudspeth will be sharing the prize with Robert Fettiplace, university of Wisconsin-Madison, and Christine Petit who is on the scientific advisory board of Sensorion. (y)

Here is a short summary of their work.

"James Hudspeth has provided the major framework for our understanding of the process that transduces sound into neural signals. Extending from each hair cell is a bundle of fine processes that act as sensors. Hudspeth used ingenious methods to reveal how sound-induced vibrations, which set the hair bundle in motion, evoke an electrical response in the hair cells through a direct mechanical connection between the hair bundle and ion channels. He also revealed how sound signals, which can be extremely small, are amplified within the inner ear."

(This so called cochlear amplifier is technically named electromotility and I was reading up on it just the other day. Fascinating stuff! Only the outer hair cells exhibit this motile property. No other cell type in the human body has this property. Not even the muscle cells, because the method by which you excite them is different. Hair cells are sensory cells, and sensory cells don't normally have motile properties.)

"Robert Fettiplace has made fundamental contributions to our understanding of sound transduction and demonstrated that each hair cell in the cochlea of the inner ear is sensitive to a specific range of sound frequencies. His experiments revealed that hair cells are organized along the cochlea in a pattern that reflects their frequency selectivity. Using sensitive physiological measurements and theoretical modeling, he discovered that this selectivity reflects an intrinsic electrical property of the cell, set by the density and kinetics of its ion channels that induce a resonance at a particular frequency."

"Christine Petit has explored the genetics of hereditary deafness in humans and identified more than twenty genes that are required for hearing and inner ear development. She elucidated the mechanisms through which these mutations cause hearing deficits, thus illuminating the unique biology of hair cells and informing deafness diagnosis and counseling. Several of the genes she identified form major components of the hair cell mechanotransduction machinery."


"Collectively the breakthroughs made by this year's Kavli Prize laureates have unveiled the molecular and cellular mechanisms that underlie hearing and deafness."

"The work of the 2018 prizewinners may even have a practical application in future through gene therapy, or regeneration of hair cells in the inner ear to replace those that become damaged over time.

Medical applications aside, the Kavli Neuroscience Prize of 2018 honours curiosity-driven basic research that advances our understanding of hearing."

Full story here:
http://kavliprize.org/prizes-and-laureates/prizes/2018-kavli-prize-neuroscience

The Kavli Prize is presented every two years. Who knows who will be honored with the Kavli Prize and what for in the year 2020...
 
It is SO Good to see that after all the years of attention and subsequent progress that they have made with the eyes, that hearing is finally starting to get the attention it deserves.
 
Hi everyone, what about the CGF166 gene therapy trials? Do you know if they are still ongoing? The latest articles I found are from one year ago so I was wondering if you knew anything on them...Thanks!
 
if gene therapy beats Frequency-tx to the market only the super rich will be able to afford it and it will be 10 times less effective.
 
Hi everyone, what about the CGF166 gene therapy trials? Do you know if they are still ongoing? The latest articles I found are from one year ago so I was wondering if you knew anything on them...Thanks!
Nothing more has come out on the CGF166 trials than what has already been posted.
 
They were over the moment their CEO said they were going to focus on otoprotective treatments. Sure fire dead end.

What is otoprotective treatments?


I'm guessing drugs that prevent hearing loss during chemotherapy.
 
Decibel should be working on something to hidden hearing loss and synaptic connections, while frequency focuses on hair cell regeneration.
 
Hello, I am a long time lurker and have followed the discussions here with great interest and knowledge gain, albeit I of course have not read every single thread and started following rather recently - so I beg your pardon in case I ask dumb questions. Something that keeps bugging me for quite some time now and which makes me post this as a question in this forum: I read somewhere that Frequency Therapeutic's approach likely won't work for genetic hearing loss. I have two questions:

1) What qualifies as genetic hearing loss? In my case, we have a line of hard-of-hearing running through the family with the hearing loss setting off from age 15 onwards so I guess there is a case for genes playing a role here. However, none of the cases known to me has resulted in complete deafness.

2) What is the reason Frequency Therapeutics' approach likely won't work for genetic hearing loss? Are there any alternatives in the game?
 
1) What qualifies as genetic hearing loss? In my case, we have a line of hard-of-hearing running through the family with the hearing loss setting off from age 15 onwards so I guess there is a case for genes playing a role here. However, none of the cases known to me has resulted in complete deafness.

2) What is the reason Frequency Therapeutics' approach likely won't work for genetic hearing loss? Are there any alternatives in the game?

I'm not sure what qualifies for a genetic hearing loss, but there are over 400 different genetic hearing loss disorders, and the only way to know for sure is to do broad testing. Your question got my attention because I also have the same history of hearing problems as you and your family. My loss was discovered when I was 18 and I got my hearing aids at 28, now at 38 I can't live without them.

My guess for the Frequency approach is that in many cases, a genetic hearing loss is caused by a defect in a specific protein in cochlea. I recon without this protein, the procedure just wont work as well as to those with e.g. noise induced hearing loss. Unfortunately for us. But then again, everything on this stage is pure guessing. The inner ear is so delicate and I really hope I'm wrong about it not working.. after all, some of my hearing loss is noise induced.
 
Hello, I am a long time lurker and have followed the discussions here with great interest and knowledge gain, albeit I of course have not read every single thread and started following rather recently - so I beg your pardon in case I ask dumb questions. Something that keeps bugging me for quite some time now and which makes me post this as a question in this forum: I read somewhere that Frequency Therapeutic's approach likely won't work for genetic hearing loss. I have two questions:

1) What qualifies as genetic hearing loss? In my case, we have a line of hard-of-hearing running through the family with the hearing loss setting off from age 15 onwards so I guess there is a case for genes playing a role here. However, none of the cases known to me has resulted in complete deafness.

2) What is the reason Frequency Therapeutics' approach likely won't work for genetic hearing loss? Are there any alternatives in the game?

I am also in the same boat. Hearing aides at 22 and noticeable loss at 15. Usually from what I have found in the articles when they mention genetic hearing loss it is a problem at birth. In our cases we are born with fully functioning ears and then as time goes on due to a defective gene we lose our hearing faster than normal. As mentioned there are people that lose their hearing faster than others and I'm not sure all of the reasons are understood as to why. We are speculating, but I would guess that the approach would work as long as you can catch it in time which is why they say this will work for people with moderate hearing loss, but not for profound. We will have to see what they come up with on the tests.

When they did the Genvec trial there, they were looking for people with noise induced hearing loss, but there were people on there that lost their hearing faster than normal and it was mentioned that it ran in their family so that would mean a genetic defect as well.
 
I am also in the same boat. Hearing aides at 22 and noticeable loss at 15. Usually from what I have found in the articles when they mention genetic hearing loss it is a problem at birth. In our cases we are born with fully functioning ears and then as time goes on due to a defective gene we lose our hearing faster than normal. As mentioned there are people that lose their hearing faster than others and I'm not sure all of the reasons are understood as to why. We are speculating, but I would guess that the approach would work as long as you can catch it in time which is why they say this will work for people with moderate hearing loss, but not for profound. We will have to see what they come up with on the tests.

When they did the Genvec trial there, they were looking for people with noise induced hearing loss, but there were people on there that lost their hearing faster than normal and it was mentioned that it ran in their family so that would mean a genetic defect as well.

I really hope your are right on this as it's my only hope for recovering my hearing. By now I have about 60db loss on both ears, but I have a cookie-bite loss, meaning my hearing is better in the bass and treble area of the audiogram.
I wonder, what if only certain parts of the hearing is profound but other parts are lets say moderate/severe, how would the drug work? To me, any gain of hearing would be welcome, regardless of the frequency.
 
What does Secretase Inhibitor have to do with the hearing loss market?
Not a scientist, but in essence a protein which can be triggered to signal Notch. And with Notch they theoretically they could initiate creation of hair cells. E.g. what Audion is doing with LY 3056480.
 
Birds may be mediocre at cochlear hair cell regeneration or just too many progeintor cells were dead in this experiment.

https://www.ncbi.nlm.nih.gov/pubmed/10516389
In a nutshell this 1999 study is saying that the birds they deafened successfully regenerate their low frequency hair cells but only partially regenerate high frequency hair cells. High freq hair cells regenerate without any or little synaptic connections making them less efficient.

This seems concerning because most hearing loss is high frequency related not low.
This might be a problem that bio tech like Frequency Therapeutics might encounter with clinical trials in humans.

However the good news maybe the fact that this might be easily explained by the fact that these birds had intentionally suffered a severe degree of hearing loss due to being intentionally deafened by ototoxic drugs and loud noise that completely killed the high frequency progenitor cells. The cells necessary for regenerating hearing hair cells which Frequency Therapeutics is making use of to regenerate human hearing. Frequency Therapeutics has also openly stated incases of progenitor cell death (severe hearing loss) they may not be able to repair hearing.

So hopefully the case is that mild to moderate hearing loss allows high frequency hair cells to reform correctly and that this poor bird was just to far damage to be rehabilitated.

Don't panic but we won't know until http://frequencytx.com/ begins stage 2 clinical trials.
 

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