Inner Ear Hair Cell Regeneration — Maybe We Can Know More
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The biggest issue I see is not so much does the hair cell attach to nerves but rather the immune response of the patient. If the patient has an immune response to the adenovirus, then that could inactivate the vector that transfers the gene. And that would render the treatment ineffective. Ex-vivo human tests probably would not have that kind of issue as a live patient. And mice do not have a response to the virus. Perhaps they have to suppress the immune system. But this has implications for any gene treatment using this kind of vector.
Could be a problem but it does not strike me as a big deal since they came up with an altered virus it means it works or it will work with modifications. The real big deal is how this gene therapy works IF it works in living human beings, and if hair cells regenerate satisfactory, function correctly and last in time.
Just a question… What if supporting cells have also a essential role in hearing mechanisms (frequencies discrimination) ? If there's only a transdifferentiation (and no mitosis), the resulting lack of supporting cells could be a problem… you could hear a noise but not understand it because your brain would be unable to recognize the frequency...
Well it is an issue raised by the scientist in the video (if you watch it) and it is an issue to watch. Yes, they may change the adenovirus but let's hope it is not necessary. Yes, there is always a big "IF". But so far, the trials look promising. They did show that it lasted 4 months out. So I don't think that lasting is an issue. It would be either the virus does not infect the supporting cells or the nerves do not reattach. But I am hopeful that the research so far proves those are non issues.
I also disagree with tomytl and others that this will be 10+ years out. If it works (yes IF) then it could be much sooner. There are a lot of US vets and the US government trying to get this to thousands of US war vets with hearing loss. It is costing them billions on hearing care. This alone is one of the major pushes. The US government funded most of not all of this research and that was one of the major grants. War veterans are in the early 20s with major issues. So this is a rather urgent push. I am very optimistic this will move fast (IF) it works with no major readjustments.
hmmm ...good point. Thanks for the paper. We really do need better testing of hearing loss in general. Like a better OCT, etc. What if the patient has plenty of hair cells but no nerves attached. So it is pretty much a guessing game with the lame technology we have now. It is pretty primitive to say the least.
People are trying to use ABR testing to do just that. In tinnitus patients with normal audiograms, they record reduced brain wave amplitudes. This indicates that less electrical signals are being carried to the brain.
But I'm not sure an ABR will help if you have hearing loss (and show a loss on an audiogram) and you want to determine if the nerves at the base of the hair cells are damaged or the damage is more upstream in the brain. I think that was the purpose of the OCT mentioned in the paper that was linked.
But you are right, there will have to be an arsenal of testing criteria to better resolve the cause to focus the treatment (like the ABR). I still think we are a ways from that with the lame technology we have today.
Is is assumed that once the hair cell dies, so does the attached neuron. I've also read somewhere (can't recall right now at work) that these neurons may take a long time to completely die off.
But I do not see any good way to check for nerve damage if there is no way to stimulate said nerve.
Yes, I think I read that somewhere too. Nerves may not die right away. But that might be ok if new hair cells can grow, then very likely (according to research in rats) they will find and reattach (even new neurogenesis in the area). However, how long the nerves have been dead and how atrophied the dendrites, axons, etc are, may be a problem to reconnect. I think they might be able to detect atrophied nerves somehow without innervating them (it might leave a dark area on imaging). Or maybe sending a sound wave to stimulate adjacent nerves to help give contrast. It seems it could be possible to get a better resolution of damage. Maybe someone can point to another research paper. I'm at work too so I can't go digging at the moment.
This is an unmet need for this kind of stuff. Audiometry is just too rudimentary for diagnosing hearing disorders. A tool capable of assessing proper inner ear functionality would be most welcome.
"Two-photon laser scanning fluorescence microscopy was first described by Denk and coworkers [27]. It is a light microscopy technique that allows in vivo imaging up to a depth of one millimeter from the surface of a specimen in some tissues [28–30], providing subcellular resolution and good light penetration as well as low phototoxicity [31, 32]."
cool
They worked in imaging the blood vessels of the cochlea. Still very far from being able to observe inner hair cells at work in-vivo.
I'm not really worrying about auditory nerve : http://medicine.umich.edu/dept/khri...rch-projects/auditory-nerve-survival-regrowth
… or even ribbon synapses : http://elifesciences.org/content/early/2014/10/17/eLife.03564
I'm more concerned about lack of mitosis in supporting cells…
… or even ribbon synapses : http://elifesciences.org/content/early/2014/10/17/eLife.03564
I'm more concerned about lack of mitosis in supporting cells…
I'm not really worrying about auditory nerve : http://medicine.umich.edu/dept/khri...rch-projects/auditory-nerve-survival-regrowth
… or even ribbon synapses : http://elifesciences.org/content/early/2014/10/17/eLife.03564
I'm more concerned about lack of mitosis in supporting cells…
Also interesting is that if you transdifferentiate a supporting cell to a hair cell you use them up. And according to the paper you linked to: "We also show that supporting cells in these epithelia are the key endogenous source of the neurotrophins....Moreover, supporting cell-derived Ntf3, but not Bbnf, promoted recovery of cochlear function and ribbon synapse regeneration after acoustic trauma" So these supporting cells do have an important function to protect and regenerate some nerve damage due to acoustic trauma. If we lose those supporting cells, we may lose further protection. hmmmm.
Interesting... Also interesting is the fact that the therapy may not work and you end up using all your reserved (supporting) cells to no avail. The atoh1 therapy currently give about 50% success in converting supporting cells to functioning hair cells. They may perfect it in the fairly distant future...
Also, there is the possibility that the supporting cells are not enough, damaged or dead due to the extend of acoustic trauma, so therapy may not work at all.
Add all this to the fact that this is intended for hearing impaired people, no mentioning of tinnitus, and the possibility of chronic T being transferred in the brain and that it may remain there even after fixing the cochlea (not making any sense to me, just mentioning it here since there are so many fans of this...).
All these are just suppositions though. I keep searching for a happy note to all of this, just to lighten the spirit. I cannot find any.
I guess I have a little more *faith* since it did work in the lab (on rats and human tissue ex-vivo). I do think if you grow new hair cells, the electrical signal will start getting to the brain and the brain will start to function again ... and the T will go down or away over time. A functioning nervous system would help the brain recover.
.....
On the other hand, if it does not work, then you have destroyed your supporting cells and any hope of further therapy
Also, those 3 patients that got the injections to test safety probably destroyed their supporting cells with little benefit and can't get any more treatment.
On the other hand, if it does not work, then you have destroyed your supporting cells and any hope of further therapy
This is only the first generation of such treatments though. If there's a way to trans-differentiate supporting cells then there probably is away to induce mitosis in supporting cells.
This would be the best! If this ever happens, it will mean complete gene transformation, one could get deaf time and again and then get well every time!
I wonder: Do birds do that too? Regenerate supporting cells along with hair cells I mean...
I am a big believer that if hair cells can be regrown then T will go away if your T is due to hearing loss. Lately I start my day with T in the morning. I put on my hearing aides and off to work I got. As I talk to more people and concentrate on work the T goes down to almost zero. The more I listen to people talk and the more I talk the quieter it gets. When I come home and take off my HAs T starts to come back slowly. Stimulating the hair cells with the frequencies I am missing take my T from a 5 to a 1 or less everyday. It doesnt take weeks, or months, it takes minutes to hours for the T to go away.
Dont get me wrong there are a lot of other factors involved. Lack of sleep, stress, anxiety etc all play a role in the loudness of my T, but I can always get it lower by just wearing my hearing aides and concentrating on what people are saying to me. I can also sometimes get it lower by meditating or trying one of I who love musics tricks.
T really is all over the brain as we are now discovering. There are so many things that can affect it. I really think we are getting closer to understanding how it works. Just the fact that I can have a 1 one day and an 8 the next gives me hope that we can replicate with medicine the circumstances that give me a 1. Even if we can get it down to 2 or 3, the more we get it out of our heads the more we can ignore it.
I have read just about everything on the net and I dont know how many times chickens can regenerate their hearing. It would be interesting to see what the answer to this is. If they can keep regenerating their hearing then that is really good news.
Dont get me wrong there are a lot of other factors involved. Lack of sleep, stress, anxiety etc all play a role in the loudness of my T, but I can always get it lower by just wearing my hearing aides and concentrating on what people are saying to me. I can also sometimes get it lower by meditating or trying one of I who love musics tricks.
T really is all over the brain as we are now discovering. There are so many things that can affect it. I really think we are getting closer to understanding how it works. Just the fact that I can have a 1 one day and an 8 the next gives me hope that we can replicate with medicine the circumstances that give me a 1. Even if we can get it down to 2 or 3, the more we get it out of our heads the more we can ignore it.
I have read just about everything on the net and I dont know how many times chickens can regenerate their hearing. It would be interesting to see what the answer to this is. If they can keep regenerating their hearing then that is really good news.
Well if this CGF166 trial even has a small percent of hope and does not cause any harm from the genes, then this will open up more novel treatments. The thing is the drug companies usually run from "novel" treatments because they are high risk and hence low returns on profit. But if the CGF166 delivery works, it may motivate more competition and more treatments. Maybe a treatment in the adenovirus to create mitosis and transdifferentiation at the same time. If this CGF166 causes harm or fails miserably, then companies will run for the exits and probably only our grandchildren will get a cure
I wish more countries with less Big Pharma would get into this...such as India, Japan or China. Their governments do more to get research into testing much quicker and way cheaper. For example, Japan has already started stem cell trails for retinal problems in eyes. The Japanese invented iPSC. India also has done some clinical trials with stem cells for corneas. So many countries are going faster when they don't have to wait for a rich company to find a profit in our suffering. So perhaps if Novartis runs for the exit...maybe Japan or India will put resources on it.
I wish more countries with less Big Pharma would get into this...such as India, Japan or China. Their governments do more to get research into testing much quicker and way cheaper. For example, Japan has already started stem cell trails for retinal problems in eyes. The Japanese invented iPSC. India also has done some clinical trials with stem cells for corneas. So many countries are going faster when they don't have to wait for a rich company to find a profit in our suffering. So perhaps if Novartis runs for the exit...maybe Japan or India will put resources on it.
Well if this CGF166 trial even has a small percent of hope and does not cause any harm from the genes, then this will open up more novel treatments. The thing is the drug companies usually run from "novel" treatments because they are high risk and hence low returns on profit. But if the CGF166 delivery works, it may motivate more competition and more treatments. Maybe a treatment in the adenovirus to create mitosis and transdifferentiation at the same time. If this CGF166 causes harm or fails miserably, then companies will run for the exits and probably only our grandchildren will get a cure
I wish more countries with less Big Pharma would get into this...such as India, Japan or China. Their governments do more to get research into testing much quicker and way cheaper. For example, Japan has already started stem cell trails for retinal problems in eyes. The Japanese invented iPSC. India also has done some clinical trials with stem cells for corneas. So many countries are going faster when they don't have to wait for a rich company to find a profit in our suffering. So perhaps if Novartis runs for the exit...maybe Japan or India will put resources on it.
The Genvec Trial is still a proof of concept trial and it's not likely to enter any clinical application in its form.
If they coud reach the aims:
-save delivery to inner ear
-regeneration and enhancement in vestibular
-regeneration and enhancement in hearing
it's something nobody did before.
If it's possible, they need to perfect any aspect of this therapy to really help people and
to get the ok of FDA, because the therapy must be better than what's on the market, andprobably
CI does help people more at least.
It's all speculation, but I think if researchers learn and know how reactivate the regeneration cycle, they will
optimize the outcomes and the procedure to apply the drug.
Dr. Hinrich Staecker does a pioneer thing, many of very good reseachers don't believe in a real success
in this kind of therapy, because nobody was able to replicate this trial in other labs.
So maybe they optimized it already and disclosed the abstracts or the strategy is something different.
I guess there must be a substance, without Novartis wouldn't give their name for.
But exciting times are coming, I put many hopes in the LGR5 (Audion Therapeutics) approach.
I guess you are talking about Notch inhibition:
http://hsci.harvard.edu/news/harvard-researchers-regenerate-sound-sensing-cells-mice-hearing-damage
But seems to do the same thing...transdifferentiation of the supporting cells. No mitosis either.
http://hsci.harvard.edu/news/harvard-researchers-regenerate-sound-sensing-cells-mice-hearing-damage
But seems to do the same thing...transdifferentiation of the supporting cells. No mitosis either.
Supporting cells can divide... only in newborn mouse so far it from what I could gather.
http://www.sciencedirect.com/science/article/pii/S104474310900205X
http://www.sciencedirect.com/science/article/pii/S104474310900205X
New updates from Stanford on hearing loss
https://hearinglosscure.stanford.edu/
We need more people like this. My contributions have been small compared to this but every bit helps.
http://www.latimes.com/local/education/la-me-ln-caruso-usc-20150603-story.html
https://hearinglosscure.stanford.edu/
We need more people like this. My contributions have been small compared to this but every bit helps.
http://www.latimes.com/local/education/la-me-ln-caruso-usc-20150603-story.html
One more lab doing research on inner ear regeneration. Dr. Sen is involved in some leading projects like nanoCI and Otostem.
http://www.ear-research.ch/
http://www.ear-research.ch/
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