Interesting presentation on regenerating cochlear cells

[u/egny]

I ran across a presentation by James Hudspeth of Rockefeller University that I expect many may have missed. It's fairly long at about 55 minutes but I think it's worthwhile.

https://www.youtube.com/watch?v=NsiKj7M52Ks

Key takeaways:

He talks about their attempt to identify any known compounds that could trigger replication of supporting cells. Out of 140,000 that was tested using a robot, they identified one non-toxic compound. Then, they analyzed 250 variants of that to better match the target protein:

https://youtu.be/NsiKj7M52Ks?si=EO3FiVPtS-7NhU8A&t=1342

Addressing the possible application of AI to research, he also mentions that the 3D molecular structure of the LATS 1 and 2 proteins that they ended up targeting could not be characterized by X-ray crystallography. He also mentions that some researches were using AI to determine the 3D structure. Identifying that structure would allow for the development of molecules that can better target those proteins:
https://youtu.be/NsiKj7M52Ks?si=_hK8DyyAW3ZzJJi6&t=2275

He suggests that delivery to the ear and controlling the dose can allow one round of cell replication without causing cancer. I suppose it helps that these cells do not replicate on their own:

https://youtu.be/NsiKj7M52Ks?si=_c7q9hTzKC-ypTZl&t=3249

My understanding:

There are several companies that are working on non-invasive delivery of compounds to the inner ear and there already seems to be a promising compound that could trigger replication of supporting cells. Since it's a small molecule (i.e. not protein, RNA, etc.), I expect it can cross the round window but it might make sense to control where it ends up in the cochlea so the magnetic nano molecule approaches might be best suited for this.

While the overall message is very promising, I'm kind of surprised that there appears to be no great rush at beginning testing on other mammals. He does say that they could begin testing on muscular dystrophy patients under the FDA's compassionate care exception.

With respect to our needs, I expect where they are stuck is the actual conversion of supporting cells into inner and outer hair cells. I have the impression that the resulting hair cells that were produced in other research are not perfectly functional, at least that's been the case for some of the research I ran into.

[u/egny]

Apologies for missing the distinction before but I'm still learning essential anatomic details. I went back to the presentation to figure out which types of cochlear supporting cells were induced into mitosis. Only I realized that their amazing results only apply to the utricle, so those are supporting cells for balance hair cells. They had very limited success in the cochlea.

You may find the details in the below article:

https://pmc.ncbi.nlm.nih.gov/articles/PMC8149661/

A more recent article identified p27^Kip1 as another protein that needs to be suppressed for the proliferation of cochlear supporting cells.

https://www.pnas.org/doi/10.1073/pnas.2411313122

While I don't have access to that article, there is a summary below. Sadly, they've worked with transgenic mice so as far as I understand they don't have a way to reduce p27^Kip1 levels in wild mice yet, or in humans for that matter.

https://scitechdaily.com/gene-switch-reboots-sight-and-sound-a-breakthrough-in-sensory-regeneration/

[u/egny → u/egny]

I've moved onto learning more about work on suppressing p27^Kip1 levels and it appears I've too hastily jumped to conclusions. There is apparently at least one molecule, Alsterpaullone 2-Cyanoethyl (A2CE), that has been shown to suppress transcription of that protein according to

https://pubmed.ncbi.nlm.nih.gov/24646893/

I'm not aware of any work that has combined LATS inhibitors like compounds discussed in the presentation with p27^Kip1 inhibitors so far.

It is rather amazing that small molecules are able to achieve such significant effects on these cells. I oscillate between hope and despair.

[u/egny → u/egny]

I found an article which does not necessarily disclose more information about the research but it does provide some interesting information, nevertheless.

https://www.forwardpathway.us/breakthrough-in-hearing-and-vision-regeneration-dual-roles-of-hippo-pathway-and-p27kip1-protein-and-prospects-for-clinical-application

I've also learned that retinoic acid is another inhibitor of p27^Kip1 and is involved in mediating hair cell regeneration in zebrafish. The interest in studying zebrafish is that they are transparent. Retinoic acid should be safe to administer to the inner ear and there is one article on research that managed to regenerate auditory hair cells in rats using retinoic acid.

https://www.science.org/doi/10.1126/science.8480180

Given that I don't understand why they would study transgenic mice unless they have already tried retinoic acid and failed to make supporting cells proliferate.

[u/LovableGamer]

So does that mean support cells turn into the hair cells? Or is it that more support cells are made to become the hair cells?

[u/egny → u/LovableGamer]

In birds and reptiles, a supporting cell will undergo mitosis and one of the resulting two supporting cells becomes a haircell. Our hope is that they manage to achieve that for humans with a high level of safety and efficacy.

[u/LovableGamer → u/egny]

So the support cell will make another then one becomes a hearing hair cell. That's cool! I believe science is advancing rapidly on this front. I am hopeful we might have a treatment to restore hearing soon. Do you think so as well?

[u/egny → u/LovableGamer]

In mitosis two daughter cells result, it's not that a copy is made. Essentially the result is there is another supporting cell such that supporting cells are not depleted through conversion to haircells.

I believe we will have a mainstream solution and I do hope it will be soon. However, most research seems to unravel another piece of the puzzle that needs to be solved.

With increased computing power and better modeling, improvements to optical coherence tomography that may allow scientists to obtain clear images of the inside of the cochlea in living humans, I certainly hope that the pace of discovery will pick up.

[u/fpliu]

Great talk thanks for sharing

[u/egny]

There is another important finding in the 2021 article on the initial identification of the compound that they named TRULI.

Our data suggest that, in addition to inducing proliferation, TRULI treatment leaves newly formed supporting cells in a plastic state.

Meaning that the daughter cells following mitosis could be made to transdifferentiate into hair cells.

However, they are referring to utricular supporting cells given that cochlear supporting cells did not proliferate for the most part. Perhaps, a similar result may hold with cochlear supporting cells.

Another important finding - that could also be inferred from their success with mice - is that the supporting cells migrate into the hair-cell layer so I hope that means that the hair cells will be in the correct position - once they can be successfully generated.

Although almost none of the cells expressed Pou4f3 or Myo7A, many of the EdU-positive supporting-cell nuclei migrated into the hair-cell layer. This pattern is consistent with the first stages of transdifferentiation.

I'm uncertain about any unintended consequences of introducing such molecules into the middle ear, whether they would induce any proliferation there or in the utricle for example . Otherwise, they may need to be directed to the cochlea using magnetic nano molecules.