Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

Will McLean said on Reddit that a significant loss of OHCs means you need hearing aids, but a significant loss of IHCs means you need a cochlear implant. The participants in their trial were in hearing aid territory at the worst.

Someone at Pipeline clarified this for me. *Normally* to get bad inner hair cell damage you would have decimated your OHC first because almost everything preferably destroys OHC first. This is not because losing your IHC themselves makes you an cochlear implant candidate but rather because by the time they are significantly damaged (usually) your OHC are in the severe to profound range.

There are a few things, though, (like Cisplatin and high dose Azithromycin) that prefer to destroy IHC first though (edit: and it's hell from personal experience).

 

[FGG]

Is Dr. Chen's treatment administered via oral or intratympanic route?

There is no treatment yet. Just molecules tested on rats.

 

[FGG]

Yeeea this cuts pretty deep. Would "prescribing" this therapy just result in referral to Frequency Therapeutics to apply the method themselves, or do you think they'll disseminate the products to ENT practices for them to administer? Little worried about the technical know-how of everyone in this field and would much rather pay more to better ensure proper delivery. I really don't understand how our healthcare system works (U.S.).

Edit: I imagine this decision is made after it passes all FDA stage criteria before deciding how the product is to be used.

Frequency Therapeutics is not a clinic. You don't go to a drug company for treatment.

 

[HootOwl]

Yeeea this cuts pretty deep. Would "prescribing" this therapy just result in referral to Frequency Therapeutics to apply the method themselves, or do you think they'll disseminate the products to ENT practices for them to administer? Little worried about the technical know-how of everyone in this field and would much rather pay more to better ensure proper delivery. I really don't understand how our healthcare system works (U.S.).

Edit: I imagine this decision is made after it passes all FDA stage criteria before deciding how the product is to be used.

It was always meant to be administered via intratympanic injection by a local ENT. That was kind of their whole elevator pitch. You walk into your ENTs office and boom, one shot later you have increased hearing thresholds.

The risk lies in who you trust to administer the shot. You would probably want a very experienced ENT who is well versed in doing injections to be your go to (but that's always been true for intratympanic injections since it was approved as a delivery method).

But also remember that Otomagnetics might release their nanoparticle delivery method around the same time if all goes well with their clinical trials. Might not even need to get the shot.

 

[HootOwl]

Someone at Pipeline clarified this for me. *Normally* to get bad inner hair cell damage you would have decimated your OHC first because almost everything preferably destroys OHC first. This is not because losing your IHC themselves makes you an cochlear implant candidate but rather because by the time they are significantly damaged (usually) your OHC are in the severe to profound range.

There are a few things, though, (like Cisplatin and high dose Azithromycin) that prefer to destroy IHC first though (edit: and it's hell from personal experience).

Just wanted to tack this on. Here is a study in Chinchillas which perfectly demonstrates this phenomenon. They used Carboplatin, a less severe analog to Cisplatin.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241314/

The schematic audiogram and schematic cochleogram illustrate the results obtained when carboplatin induced a moderate IHC lesion, but no OHC damage.

In these cases, thresholds in quiet were surprisingly unaffected, increasing very little despite the fact that 40–60% of the IHC were missing (Lobarinas et al., 2013). To understand the relationship between hearing loss and IHC loss, the threshold shifts post-carboplatin were plotted as a function of percent IHC loss as schematized in Figure Figure3C. Hearing thresholds were largely unaffected by small IHC lesions (<35%). Threshold shifts gradually increased with moderate IHC lesions (40–75%), but then increased substantially once the IHC lesions exceeded 80%.

One interpretation of these results is that the pure tone audiogram is very poor at detecting small to moderate sized IHC lesions and that thresholds in quiet only begin to rise after the vast majority of IHC have been destroyed. Apparently, only a few IHC and type I neurons are needed to detect a tone in a quiet environment.

The important implication of the above results is that DPOAE and pure tone audiograms, two of the most commonly used techniques for assessing hearing, are insensitive to profound IHC/type I neuron damage.

 

[mrbrightside614]

It was always meant to be administered via intratympanic injection by a local ENT. That was kind of their whole elevator pitch. You walk into your ENTs office and boom, one shot later you have increased hearing thresholds.

The risk lies in who you trust to administer the shot. You would probably want a very experienced ENT who is well versed in doing injections to be your go to (but that's always been true for intratympanic injections since it was approved as a delivery method).

But also remember that Otomagnetics might release their nanoparticle delivery method around the same time if all goes well with their clinical trials. Might not even need to get the shot.

Damn, I haven't read up on Otomagnetics at all. That's awesome. Crazy how most reasonably hopeful treatment seems to be landing within the next 1-5 years. If only my ear could've held out that long. This is like the AIDS of otology.

 

[Caveman]

It was always meant to be administered via intratympanic injection by a local ENT. That was kind of their whole elevator pitch. You walk into your ENTs office and boom, one shot later you have increased hearing thresholds.

The risk lies in who you trust to administer the shot. You would probably want a very experienced ENT who is well versed in doing injections to be your go to (but that's always been true for intratympanic injections since it was approved as a delivery method).

But also remember that Otomagnetics might release their nanoparticle delivery method around the same time if all goes well with their clinical trials. Might not even need to get the shot.

And there's also this on the horizon: https://www.cuimc.columbia.edu/news/3d-printed-microneedles-open-ears-new-treatments

 

[d'Wooluf]

But also remember that Otomagnetics might release their nanoparticle delivery method around the same time if all goes well with their clinical trials. Might not even need to get the shot.

You get the shot, then you get the magnet. I'd like to think that Otomagnetics are the real deal, but all we've seen thus far is a lot of talk and not much else.

 

[JohnAdams]

You get the shot, then you get the magnet. I'd like to think that Otomagnetics are the real deal, but all we've seen thus far is a lot of talk and not much else.

It would almost make more sense to block the eustachian tube with a plug and then apply a positive pressure to the middle ear. I'm not sold on the magnet thing at all.

 

[tarmaced]

It would almost make more sense to block the eustachian tube with a plug and then apply a positive pressure to the middle ear. I'm not sold on the magnet thing at all.

Would this work, or just compress the gas in the inner parts of the inner ear, advancing the drug down the tube only incrementally?

 

[JohnAdams]

Would this work, or just compress the gas in the inner parts of the inner ear, advancing the drug down the tube only incrementally?

If the plug stayed in place then I think it would work.

 

[Reinier]

Source?

I read it from different sources, but a source is https://en.wikipedia.org/wiki/Hair_cell
quote: " Outer hair cells extend the hearing range to about 200 kHz in some marine mammals.[12] They have also improved frequency selectivity (frequency discrimination), which is of particular benefit for humans, because it enabled sophisticated speech and music."
I think the frequency selectivity in particular helps us to "tune in" on sounds. I also understand that it actually is possible to strain your ears if you want to hear something better. perhaps this also is done by outer hair-cells. It is not just an expression.

Thought that was the synapses.

I understand that if you lose synapses, the ones for the higher sound levels on a hair cell are the first to go. In my case I do not have the resolution anymore I used to have. So that could be because of the synapses for the higher sound levels.

I just hope there is something available before we need a solution for presbycusis.

 

[Coleoptere]

@Reinier: thanks for the response. I knew you would come back after the Q of @FGG. Hope to shake hands with you (and many others) once something injectable is available.

 

[FGG]

I read it from different sources, but a source is https://en.wikipedia.org/wiki/Hair_cell
quote: " Outer hair cells extend the hearing range to about 200 kHz in some marine mammals.[12] They have also improved frequency selectivity (frequency discrimination), which is of particular benefit for humans, because it enabled sophisticated speech and music."
I think the frequency selectivity in particular helps us to "tune in" on sounds. I also understand that it actually is possible to strain your ears if you want to hear something better. perhaps this also is done by outer hair-cells. It is not just an expression.

I understand that if you lose synapses, the ones for the higher sound levels on a hair cell are the first to go. In my case I do not have the resolution anymore I used to have. So that could be because of the synapses for the higher sound levels.

I just hope there is something available before we need a solution for presbycusis.

Can you explain what you mean by "higher sound levels"?

 

[RingingBrother]

Anyone know of any updates with phase 2a yet?

 

[FGG]

Anyone know of any updates with phase 2a yet?

They are still recruiting participants for this trial.

 

[JohnAdams]

Anyone know of any updates with phase 2a yet?

They haven't said anything.

 

[Reinier]

Can you explain what you mean by "higher sound levels"?

Difficult to give dB values. A conversation in a group of people is more difficult when people talk loudly.

If it is because of more reverb in a room or loudness I am not certain. I think it is both. Certainly also the sound level. Not only more complex sound because of reverb. Is this 70 dB or even sometimes 80 dB? I can not be sure.

 

[Chinmoku]

Tinnitus is not an exclusion factor. Tinnitus as a primary concern was.

This is not good, though. It means people with distressing, severe tinnitus will not be tested on FX-322, and those are the tinnitus people who would need the medication most.

 

[ChrisBoyMonkey]

This is not good, though. It means people with distressing, severe tinnitus will not be tested on FX-322, and those are the tinnitus people who would need the medication most.

That was for the first trial. This ongoing trial is actually officially looking at how it may effect tinnitus.

 

[Chinmoku]

That was for the first trial. This ongoing trial is actually officially looking at how it may effect tinnitus.

Thank you, I had misunderstood, but for clarity: does that mean that in this second trial they allow for patients with severe tinnitus as well, and patients with hearing loss but whose primary concern is tinnitus?

 

[John Queen]

Will McLean said on Reddit that a significant loss of OHCs means you need hearing aids, but a significant loss of IHCs means you need a cochlear implant. The participants in their trial were in hearing aid territory at the worst.

That guy on Reddit (Leviathan or whatever his username was) is not Will McLean, it's a postdoc researcher who worked in Frequency's team.

 

[John Queen]

And there's also this on the horizon: https://www.cuimc.columbia.edu/news/3d-printed-microneedles-open-ears-new-treatments

Awesome invention, looks like we're on the right track... that would mean they will be able to inject the drugs directly in the cochlea, like in an intralabyrinthine injection procedure, which currently is a very hard procedure to do. And oh, the perforation completely heals in one week, that's also awesome!

 

[JohnAdams]

That guy on Reddit (Leviathan or whatever his username was) is not Will McLean, it's a postdoc researcher who worked in Frequency's team.

You don't know that.

 

[John Queen]

You don't know that.

Woops, you're right. I've got some wrong info. It might be that he's actually McLean.

 

[ChrisBoyMonkey]

Thank you, I had misunderstood, but for clarity: does that mean that in this second trial they allow for patients with severe tinnitus as well, and patients with hearing loss but whose primary concern is tinnitus?

They actually don't specify, but their primary concern is still hearing loss. Some people on here tried but were denied for not having the hearing loss they were looking for.

 

[d'Wooluf]

Awesome invention, looks like we're on the right track... that would mean they will be able to inject the drugs directly in the cochlea, like in an intralabyrinthine injection procedure, which currently is a very hard procedure to do

3D-printed means each needle is customised for the patient? Which means that each patient's ear is scanned and measured. The manufacturing process has to be to medical grade with incredibly fine tolerances. And then you need to find an ENT with very good skills. Sounds like a much more difficult thing to do than an intra-tympanic injection. I'm just wondering whether this is something that can ever be made available to the hearing-impaired masses. I hope so.

 

[FGG]

3D-printed means each needle is customised for the patient? Which means that each patient's ear is scanned and measured. The manufacturing process has to be to medical grade with incredibly fine tolerances. And then you need to find an ENT with very good skills. Sounds like a much more difficult thing to do than an intra-tympanic injection. I'm just wondering whether this is something that can ever be made available to the hearing-impaired masses. I hope so.

They can print 3D models of bone from CT scans to help surgeons plan Orthopedic surgery for really complicated repairs. The technology exists already. At least in animals. I'm not sure if human orthos ever do this or not. Either way, it's not as much of a barrier as it sounds.

 

[JohnAdams]

3D-printed means each needle is customised for the patient? Which means that each patient's ear is scanned and measured. The manufacturing process has to be to medical grade with incredibly fine tolerances. And then you need to find an ENT with very good skills. Sounds like a much more difficult thing to do than an intra-tympanic injection. I'm just wondering whether this is something that can ever be made available to the hearing-impaired masses. I hope so.

I too was wondering about the logistics behind this. It's not like the RWM is just waiting behind the eardrum, it's like up and around the corner and everyone has a different shape to their inner ear like their faces. I think this would likely involve removing the eardrum first and then reattaching it. Sign me up!

 

[d'Wooluf]

They can print 3D models of bone from CT scans

What they're printing here is a working tool. It can't break or splinter. And it has to be really, really small. Hopefully it's easier than it sounds, but it really doesn't sound very easy.

"The microneedle shaft has the thickness of a human hair, and the microneedle tip has a radius less than 1% of a human hair's thickness."

Is there a direct unimpeded line from the eardrum to the round window membrane? I guess there must be. How else would they do it?