Developing a Safe and Efficient Way to Transport Stem Cells Into the Inner Ear

[Aaron123]

So neuropathic deafness does not include hair cells? It is the neurons (ganglion neurons) that are lost?

Auditory neuropathy does not itself involve hair cells.

The improved ABR threshold shift they mention is because of synaptic reconnecting and Ganglion neurons regeneration?

Yes.

They do mention hair cell-like cells, which are not actual hair cells. I assume this is important because hair cell-like cells could become functioning hair cells.

People seem to use "hair cell like cells" to mean different things so it is important to look at the papers to see what characteristics they do and do not possess. However, it is not the case that they then have the potential to become hair cells. They are the end result of the attempt to regenerate hair cells.

 

[Reinier]

@Aaron123 Thanks to take time to answer my questions. Much appreciated.

 

[Nick Pyzik]

There's nothing novel about this. Hair cell loss is the primary cause of observed (as opposed to "hidden") hearing loss. (That said, I don't think Rivolta and colleagues are particularly focused on hair cell death. To the best of my knowledge they have not been successful in generating functional hair cells.)



The noise level and duration were chosen so as to cause temporary but not permanent threshold shifts: "We adjusted the sound level and duration of an octave-band noise exposure to produce a moderate, but reversible, threshold elevation" (pg 14079; Kujawa and Liberman 2009).

Rivolta's work being referenced is primarily Chen et al (2012) in Nature. They looked at an animal model of auditory neuropathy. Like Kujawa and Liberman, their approach preserved the hair cells but unlike Kujawa and Liberman, they killed about 95% of the SGNs : "Application of ouabain directly to the round window selectively damages the type I SGNs, preserving the hair cells and the organ of Corti 26 (Supplementary Fig. 10). After ouabain application, only a small number of SGNs survived (6.4%; see Supplementary Table 11)" (pg 279; Chen et al. 2012). In contrast, Kujawa and Liberman report a worst case survival rate of about 50% of synapses at high frequencies (pg 14082).

So it is a difference between about 6% of SGNs being functional vs. about 50%. Even the 50% loss in Kujawa and Liberman does not result in noticable threshold shifts because of other compensation: "Thus, diffuse loss of half the cochlear nerve and the resultant 50% decrease in response amplitude, can be compensated either by doubling the discharge rates in remaining neurons or doubling the number of neurons responding. Either of these compensatory increases is accomplished with only a few dB increase in stimulus level..." (pg 14082). Thus, it takes a tremendous loss of SGNs (or the ribbon synapses) to cause a significant across the board increase in hearing thresholds as seen in Chen et al. (2012). The damage must be so extensive that it is not possible to increase the discharge rate or other functioning neurons by enough to compensate.

So the purposes of the papers and thus the set-ups are completely different. Kujawa and Liberman (2009) show that noise levels below which hair cell death occurs have consequences for hearing - though not for thresholds. Chen et al (2012) are able to use human embryonic stem cells to restore SGN function in an animal model of auditory neuropathy (drug rather than sound induced). Neither paper involved hair cell loss, and neither finding contradicts the other.

Aaron,

I appreciate the informational response!

Would you say you have a pretty reasonable understanding of how the spiral ganglion neurons work within the inner ear? I have a question or two on the spiral ganglion that I was wondering if I could ask you?

 

[Jim51042]

This means that they could travel beyond the site of damage in the inner ear, and more worryingly, divide uncontrollably and form tumours

This was from the article. How often do stem cell treatment lead to tumours?

 

[Twitch]

Given that most IV stem cells get stuck in your lungs (Google pulmonary first pass), I would imagine it's rare for tumours to form from them

 

[Jim51042]

@Twitch I think this approach actually is injecting the cell into the ear. A gel delivery mechanism is being tested. I was just wondering how likely stem cells without being in a medium would turn to cancer.

 

[Jim51042]

Thus, it takes a tremendous loss of SGNs (or the ribbon synapses) to cause a significant across the board increase in hearing thresholds

I been thinking about this and presuming one still has enough intact haircells a recovery of say only 10% of your original SGNs should have large impact on hearing thresholds and presumably tinnitus. If Rivolta's the stem cell gel injections adds maybe 2% of you SGNs following a 10 month growth period and you go for 5-10 injections (likely there would be diminishing SGNs returns with each injection) why wouldn't this be a cure today. I get the worry about the long term viability of those neurons but long period of nerve growth for the gerbils implies that those nerves will not revert. It almost seem like the only thing holding this back right now is the risk of cancer and the economic model. That is why I'm curious how likely with the type of cell Rivolta is using that cancer grow can occur.

The other big brake would be the economics and logistics behind the stem cell treatments. With a method available there would be overwhelming demand. Fortunately Rivolta is using the UK Stem Cell Bank to distribute to other research facility were treatments could be applied. Seem like instead of wondering if there is going to be a cure we rather we should be asking is there going to be a cancer free cure because it seem like Rivolta is on the cusp of an effective treatment for T.