Inner Ear Hair Cell Regeneration — Maybe We Can Know More

Discussion in 'Research News' started by Hopeful, Sep 6, 2013.

    1. Reinier
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      I understand that researchers suggested neurotrophin-3 for SGN and nerve fibre reconnecting. Not stem cells.
      Perhaps we will have nerve fibre reconnecting long before regenerating hair cells.
       
    2. Samir
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      Isn't that molecular/drug therapy?

      Then go out there and march for science!

      https://www.marchforscience.com/
       
    3. Reinier
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      I think you are correct. I stand corrected (-;
      But this molecule that targets a pathway in progenitor cells is inside a virus, which could make it better suited to reach the "target" than stem cells are able to do. I wonder, is this targeting of a pathway in the progenitor cell not gene therapy? Are you not changing the DNA?
      I don't know.
       
    4. Samir
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      That's not my understanding of it at all.

      First of all the molecules are not put inside a virus. That's only done with gene therapy, as far as I know.

      The molecules do target progenitor cells. Pathway is short for cell signaling pathway. Think of it as a military chain of command. In mammals, the pathway for regenerating hair cells is put out of operation following initial development. It's as if the chief in command has fallen asleep. Once he has fallen asleep, everyone below his rank has also fallen asleep.

      What Frequency is trying to do is wake these suckers up! Either by waking up the general or one of his minions, who will then wake up everyone else in the chain, and have them do the same work once more, the same work they once did during development.

      It's like a domino effect!

      domino_effect.jpg

      But it would hopefully look more like a cochlea, like this:

      19a9jz97rsvsvpng.png

      I don't know why these molecules can reach the target better than the stem cells. They are more resilient somehow, I guess. Either way, we know they work. So I think molecular therapy will be the first, followed by gene therapy, then maybe stem cell therapy. We may not even need stem cell therapy by the time we have developed molecular and gene therapy. It may work well for other organs and tissues, but right now, it looks like stem cell therapy will have to wait. Or scientists will have to come up with new tricks to allow the cells to survive better, like changing the endolymph temporarily, as we have seen in the paper that Aaron posted.

      Not to my knowledge, no. It's not gene therapy unless you add, remove or replace genes. You can easily recognize gene therapy by the use of viruses.

      These images are very informative, from SICHL project page.

      Gene therapy:


      genetherapy1.jpg

      genetherapy2.jpg

      Molecular therapy:

      moleculartherapy1-400x240.jpg
       
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    5. Jim51042

      Jim51042 Member

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      How easy is it to put a molecule inside a virus? I ask because this would necessary to accomplish synaptic regrowth by inserting NT-3 and BNDF into a ANC80 virus. However we haven't received word that Decibel has been able to do this yet. After they do I'm assuming they'd need more time to test within mice/monkeys before clinical trials. That so a Frequency trial might occur years before a Decibel trial :( Its a good method I just wish it would be available soon.

      I
       
    6. Jim51042

      Jim51042 Member

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      Still the good news is that because Frequency and Decibel are working on different things the success of one hopefully won't stop work for the other. For Frequency's newly created hair cells a genetic infection with synaptic growth factors would enhance their functionality. I could the standard procedure becoming a Frequency injection with a follow up Decibel injections 1.5 months later.
       
    7. Jim51042

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    8. Reinier
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      @Samir
      I think what you posted is correct. I read what Frequency Therapeutics is doing :cell.com/cell-reports/fulltext/S2211-1247(17)30136-5
      I read so many documents I start to mix them up.:dunno:
      Is that a fact? They only did research in cochlear Explant tissue if I read correct.
       
    9. jeff W

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      You are right to be. I was on the phone to a German prof (who works on a common project) when I asked him why others in the field found it strange that key preparatory elements of the es line were missing from the paper, he became absolutely "furious" I mean he lost his sh1t completely. 5 years later and nobody has repeated it.


      But I like to keep an open mind, you know maybe, just maybe Dr Riv0lta has access to a time machine with which he can bring back alien technology from the year 2069 to produce such an extraordinary paper!


      upload_2017-4-11_12-15-35.png
       
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    10. Aaron123

      Aaron123 Member

      That's very interesting. I wasn't aware of the missing discussion of preparation. Do you have any more information about this?

      Some of my concerns, discussed below, may relate to this.

      While I appreciate that other people chose to answer on my behalf, no one has explained my relative skepticism.

      1) Most people here seem to be excited about Rivolta's work as a result of a PRESS RELEASE by action on hearing loss. AOHL has funded his work in the past and is currently funding his work. They also want people to contribute money. Thus, their press release is not an unbiased evaluation of the work. I generally don't get excited about press releases as they often overstate the actual results.

      2) It's a single paper on a mouse model of auditory neuropathy which doesn't speak to how well it will do in other contexts.

      3) Embryonic stem cells are challenging to work work with due to the possibility of tumors.

      4) It isn't clear that the "worm gel" solves the problems. There are a few papers describing it, but none that show it can do what is needed here. Maybe it can, but I am skeptical until there is proof it works - first in some application and then in the inner ear. That proof may be forthcoming, but it doesn't exist yet so I am skeptical.

      5) He hasn't followed up on this work in the 5 years since its publication. One would expect additional papers showing it works in a different species or refining the procedure in some way so that it is more effective. As far as I can tell, his subsequent published work hasn't built on this paper.

      6) In looking at the papers that cite the 2012 paper, it doesn't appear that anyone else has replicated or improved upon it. (I didn't look carefully at every paper so I might have missed something.) Moreover, a paper on the prospects for replacing auditory neurons with stem cells (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594553/) written by Albert Edge and a co-author in 2013 does not reference this paper. One would think it would be the leading example.

      My fifth and sixth points are consistent with what @jeff W has shared.

      Thus, I am more skeptical than many people here - including you:
      Having said all of this, I would be very happy if he published a paper tomorrow that answers all of these concerns, but these are the reasons for my skepticism.
       
    11. Jim51042

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      Haha. Let me clarify by effective treatment I think that with enough injected ES stem cells a patient would see improvement in their auditory function. That doesn't mean they wouldn't end up with tumors down the line and possibly it would result in their death.

      Are there any other labs also working on auditory neuron stem cell research/treatment? Has anyone referenced the Edge paper in their work on stem cells?

      @Aaron123 at this point do you view auditory stem cell treatment as not efficacious (doesn't increase synaptic connections) or just too dangerous (tumor development).
       
    12. Samir
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      Does it not already consist of a molecule?

      A basic virus consists of a nucleic acid (DNA or RNA) - itself a molecule, nucleocapsid (a protective shell made of protein) - itself a molecule. Molecules are basically everywhere.

      3D reconstruction of ANC80 capsid:

      adeno%20viral%20capsid.jpg

      So you would replace the DNA/RNA with NT-3/BNDF?

      And this would then cause the infected nerve cells to grow?

      Interesting idea! But I'm not sure it's possible...

      It may not be necessary if the synaptic components of regenerated hair cells naturally release NT-3 or BNDF.

      On the other hand, even if you can make the nerve fibers grow this way, you may not be able to connect them to the hair cells whose synaptic components are damaged.

      Which makes me question if hair cells with damaged synapses can survive for a very long time. It also makes me question the fundamental efficacy of hair cell regrowth - if the old damaged hair cells stay in the way, they might prevent new hair cells from regrowing in these places where you have live hair cells with damaged synaptic components. We would have to kill them off or wait for them to die off naturally and for the body to absorb them, so they don't stay in the way of any new hair cells. Or we could try to come up with ways to repair these synaptic components, assuming this is the only thing that's damaged in the cell.

      What's this method? Using NT-3/BDNF in place of DNA/RNA in viruses? Who says that Decibel is working on this?

      Where did you read about "genetic infection with synaptic growth factors"?

      You mean because stem cell technology has been around for a long time, there should already be ways of controlling and stopping differentiation?

      I'm not qualified to answer that. But one thing I noticed in the linked text is that they discuss use of gels for effective stem cell delivery, not viruses. The same might be done with NT-3 and BDNF.

      That's alright! :huganimation:
      (y)

      I have not read a comparative study between the two approaches. I don't think there is one. This is my own impression based on what I have read so far.
       
    13. jeff W

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      There is not one single point you have made that I disagree with.
      I do not understand the politics of peer review so I will refrain from using names, it would be most irresponsible of me to do so. But several labs (not just 1 or 2) that I spoke to all mentioned their concern about key elements of the es line being questionable. I mentioned this criticism to one of the most famous within otology and I was quickly put in my place by "This is a natural part of the peer review process". I presume by reading your posts that you read a hell of a lot of papers, probably much more than I do. Its the control data and objective measurements is where I get lost in the sand. The difference with undergrads and profs at the bench is that they work with cell lines all the time and can pull the raw data apart very quickly as being abnormal or suspicious, people in the stem cell field watch "everything" stem cell, not just their own area. One researcher scolded me with "extraordinary claims require extraordinary evidence". Another described it as "dubious claims" I remember where I was when Rivolta's voice came from the telly and I walked in to hear the news story, after hearing "nerve viii and its branches cannot spontaneously repair after injury" here was this "genius" telling us otherwise. I would be extremely pleased to be wrong in my suspicion (just as you would) and would gladly look the fool for disbelieving, but I remember someone pointing out the claims it made in the amount of hearing recovery, like virtually zero measured cap to nearly 80 percent after the administration of the cells. It just sounded too good to be true. I think we should crowdfund and get this repeated ourselves, there is enough of us. I think action on hearing loss costed it around 150k sterling. That's doable through a crowd fund, although I am not sure how many countries allow es cell testing, I believe intervention by the patient body is the next logical step..................that is if they continue to yield nothing with the standard peer review process. Also, have you ever wondered why Rivolta isn't part of the HHF symposium?
       
    14. Jim51042

      Jim51042 Member

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      Yea I did read about the size issue later on. Just brainstorming.

      This is exactly why I'd prefer to use a neural regrowth treatment now regrow to the synapses that aren't dead and then maybe later try hair regrowth using frequency. This is a fantasy cause I don't believe any neural regrowth treatments are less than 2 years from clinical trials (please correct me if I'm wrong).

      Well put do we know how Decibel will achieve their goals? Did anyone from their company claim they'd have a clinic trial in 18months back in Jan 2017? Maybe a trial might be a long longer off if they are still working on a technique

      I think it might be useful for Frequency to test a subset of the trial candidates with an injection of theses neural growth factors (NT-3 and BDNF). The newly created hair cells will need a lot of functional neural connections and aside from just injecting as of 4/11/17 I don't know of any better delivery mechanism for these growth factors.
       
    15. Samir
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      But there would not be a need to regrow any nerve fibers had there not been any synaptic damage. Synaptic damage does not happen only on the nerve side or hair cell side. The nerve fibers retract following synaptic damage. See the video below.

      Tinnitus and traumatic sound: R Pujol, S Blatrix


      See this image:
      moleculartherapy1-400x240b.jpg

      My understanding is that they will be working with gene therapy.

      They have been very quite lately. I can only hope that it's a good sign, i.e. that they are busy working in the lab rather than blabbing about it in the press. My understanding is that they continue to do basic research to gain more knowledge. So yes, it may be true that their first clinical trial will have to wait longer, but it may be more effective. Who knows?

      I don't know if they can design a trial this way. If they can do it, that's great! I would also like to see the outcome of this. But before they do it in humans they will have to do it in animals first. Have they done it in animals yet? Not that I know of.

      Yes, but these newly created hair cells may be able to secrete NT-3 or BDNF on their own. In which case they may not need our help, our intervention, by assisting them with NT-3/BDNF injections.
       
    16. Jim51042

      Jim51042 Member

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      So synapses cannot be regrown with growth factors? Maybe if the ear was flooded (inducing hair and synapses) with the ANC80 virus that promoted this growth factor the synaptic point would be regrown... Has this already been shown to be possible?
       
    17. TikTok

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    18. Samir
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      My understanding is that NGF can help prevent noise damage, grow and attract nerve fibers, maintain and grow neurons. But I'm not so sure about synapse formation. If the synapse has been lost once, the damage may be on both ends of the synaptic gap.

      Let me illustrate:

      synapse.jpeg

      Both A and B side may be damaged. If you use NGF and you manage to bring in the nerve fiber to the hair cell, it may not have anything to connect to if that other side is damaged. It's like having a half of a bridge. You need that other half to cross the river. This is something that NGF may not help you with.

      Here is an overview of an IHC and its synapses:

      nrneurol.2016.10-f3.jpg

      The key to restoring the synapses here may be the preservation of the synaptic ribbon, and this is the synaptic component of hair cells that I mentioned earlier. You can see it up-close in the image to the right above.

      Can you regrow synaptic ribbons in hair cells? I don't know! That would be fantastic! It would mean we can repair the hair cells rather than having to regrow them. Of course you can't repair a completely dead cell. So that would depend on the severity of the damage.

      Here you see the ribbon synapse under a microscope:

      ribon synapse electron microscope.jpg

      Here you see how NT-3 can help prevent noise damage:

      nejmcibr1413201_f1.gif

      The image to the left shows normal, functioning hair cell. In the middle you see a hair cell after noise damage. To the right you see a hair cell that has survived noise damage, thanks to NT-3 "overexpression" in its supporting cells. The hair cell is colored in blue, the green and yellow represents supporting cells.

      I don't know. It may be possible, maybe not. The article from where I took that last image may provide some answers or clues to that. They don't allow me to read the full article. But you can see from the image above that NT-3 can help protect against noise damage. We also know that NT-3 has even more important roles to play for nerve cell survival and axonal sprouting.

      The full article can be found here:
      http://www.nejm.org/doi/full/10.1056/NEJMcibr1413201
       
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    19. Jim51042

      Jim51042 Member

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      @Aaron123 Is it crazy to think that stem cells can provide some help reestablishing neural connections? See Harvard link for another source https://hsci.harvard.edu/hearing-loss-0. I'm just curious if this truly a dead non-efficacious pathway (meaning we should rely solely on gene therapy) or just one that needs more work done by more labs?
       
    20. Samir
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    21. Jim51042

      Jim51042 Member

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      Humm. I would love the to see the full article. Even thought multiple sources have said neuron regrow is simpler I am gaining a new perspective on why this is difficult. But who knows maybe this has been solved by Wan and you simply need that high expression of NT-3 in the hair cells for this synaptic re-connection to occur (and this can occurs years after noise damage).
       
    22. Jim51042

      Jim51042 Member

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      @Samir I think I'm realizing how complicated this all is. I was briefly looking at the papers referenced by Decibel and it seems they may have addressed some of the questions we were discussing. They may even contained some solutions for synaptic regrowth.
       
    23. jeff W

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      http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30390-X
       
    24. Aaron123

      Aaron123 Member

      Will have to look more closely. Quick impression is that 1) a better understanding of the molecular underpinnings and signalling pathways is good, and 2) they apparently had success in adult mice which is encouraging.

      At the same time, this is another reason to be skeptical that cgf166 will work: "Attention has focused on ectopic ATOH1 as a potential gene therapy for HC regeneration; however, studies from our lab and others suggest that ATOH1 is inefficient in converting SCs to HCs in adult cochleae." (from the actual paper, not the press release)
       
    25. Aaron123

      Aaron123 Member

      No.
      This is essentially a press release and is thus useless for understanding what is going on.
      Of course more work needs to be done.
       
    26. Jim51042

      Jim51042 Member

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      @jeff W I think that paper is about hair cells not neurons
       
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    27. Samir
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      You may be able to read it for free if you visit a university library. They usually pay to have full access to these journals. I don't care about it that much to take a trip downtown and visit the local university campus. I will leave that to the professional researchers.

      You could also pay 20 USD and access it.
       
    28. Jim51042

      Jim51042 Member

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      https://www.tinnitustalk.com/thread...ute-university-of-sheffield-cell-lines.20748/

      With Sheffield's ES stem cell lines now available for distribution couldn't the questions/doubt over the results be settled by another lab?

      Yes because of this toxicity I would say molecular and gene approaches are more likely to develop hair cells. However when it comes to repairing/regrowing SGNs you would not need to have the injected stem cells go through the endolymph. So I think that stem cell research should rightly focus more on improving SGNs and synapses.

      Do you mean human testing?
       
    29. jeff W

      jeff W Member

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      Can you link me to the paper behind the paywall? I thought it was this one you could not access.
       
    30. jeff W

      jeff W Member

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      1) As Aaron123 already pointed out, I was wondering the exact same thing, why have we not seen anything from someone else? If you ask the lab or aohl they say "We believe that Dr Rivolta's work is at a more advanced stage than any other research team"

      2) No, I mean rodent models and then primates. We must consider the possibility that nothing will result from the current research arm within the next 10 years (although I hope that I am wrong). Why not a put our own dog in the race instead? Imagine having our own lab? These patients did not want to wait http://realbusiness.co.uk/funding/2...raises-world-record-for-biotech-crowdfunding/
       

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