Inner Ear Hair Cell Regeneration — Maybe We Can Know More

http://www.isrctn.com/ISRCTN59733689
I think Audion is already in clinical trial with their LY 3056480.

 

Participant exclusion criteria
1. Presenting with a primary complaint of tinnitus

So it's not for us. And I wonder why with such a large population at these forums we never find anyone who participates in any medical trials or is willing to stay long enough on the forums to tell.

We have seen some AM-101 trial patients here but that's basically it. While there have been much more trials.

 

Part 1:
1. Occurrence and severity of procedure related local and systemic AEs are measured using clinical examinations, laboratory tests and patient interviews at visit one, two and three
2. Occurrence of systemic AEs as measured by potentially clinically significant changes by ECG, vital signs, physical examinations and laboratory tests at visit one, two and three
3. Occurrence of surgical and injection sites reactions in and around the treated ear as assessed by otomicroscopy at visit one, two and three
4. Safety of the treatment is assessed using changes in hearing, facial nerve function and balance at visit one, two and three

Can anyone help me here, does this mean that it also helps people who have congenital hearing loss?

 

Secondary outcome measures
1. Change in hearing is measured using Pure Tone Audiometry (PTA) (dBHL) at baseline and week 12
2. Balance is measured using several balance tests at visit one, two, and three
3. Tinnitus measured using a questionnaire at visit one, two and three

So they can suffer from tinnitus, but it can be not the main reason to join the trial.

I e-mailed dhr Rutten a few weeks ago (in dutch). I asked if the regenerating could possibly lower tinnitus, and if there were be treatments on animals. He answered (in dutch):

Thanks for your e-mail. Currently we are working on a treatment against hearing loss. We dont target Tinnitus as main point. The first trials are for safety and doses. This trial is running in London. Possibly u could contact the study team via ---------.nl. Due to independenty Audion is not the factory to discuss which patient take place at the study. I can't do anything more then move you forward to ---------.nl and advice u to keep an eye on the trials.
Best regards,


Now i'm thinking of writing a letter to the clinic in London. Are there any suggestions?

Maybe this can be the first thing to see if hair cell generation can lead to lessen tinnitus. (if there will be any hair cells regenerated....) Find this really exciting for some reason.. Although I think Frequency has better arrows, but this seems to be something.

 

There's a thread on the Audion trial https://www.tinnitustalk.com/threads/audion-therapeutics-trial.21830/ that discusses inclusion/exclusion criteria etc.

 

I would never try other persons HA ! Amplification with HA can be around 85 dB, and total SPL near 130 dB ! Yes, amplification can be fine adjusted, but only + - 10 dB (at least with my HA). Luckily you didn’t get any damage ?

 

That’s why I went into a silent room to test them. There was no input to amplify. I use in-ear monitors for a living, so I know how dangerous loud input directly into the ear is.

 

Are you a musician?

 

Think you're right indeed. Thought it was already bound to happen, but now also read ethics commission just approved.

 

I am, yes. I do my best to avoid loud situations, but hearing loss is the opportunity cost of loving my job.

 

Some toilet reading please leave on external server: docdroid

Amin0glycoside D@mage and Hair Cell R3gn3ration 1n the Chicken Utricle (H*ller) 2017.pdf
http://docdro.id/aVGmXWB

Delivery of Aden0-Ass0ciated Vir@l Vect0rs 1n Adult M@mmalian Inner E@r Ce11Subtypes without Audit0ry Dy5functi0n.
http://docdro.id/iaBk2Bt

 

Does anyone know what PSCC stands for? I have been reading the discussion part of the second article from the links @jeff W posted.

 

It is defined on page 5 in the paper: posterior semicircular canal.

 

Have a look at what they look like with his Majesty I@n Curth0ys.

The Otoliths - A Revised Understanding -...

 

It's why we hear the tinnitus. The brain's auditory processing center is built to handle all the frequencies across it's physical layout itself. It's our limbic system that miscalculates and doesn't filter out the busted signal to the brain. I think the whole tinnitus being memorized thing is pure baloney. Neuroscientists aren't even 100% sure of what specific neuronal connections mean sometimes and to date they've never shown definitely the difference between chronic and acute tinnitus. The brain is a complicated system and it's constantly changing. Bring back the signals, the brain re calibrates back to normal.

 

So there is a way to get these AAV vectors in the cochlea without adversely effect hearing thresholds. Also without opening the middle ear. I didn't realise it is possible to get al the way to the apex side of the cochlea. I still think the surgery was quite invasive, yet only 20 minutes. Drilling a whole and see the perylimph fluid leaking out. BRRRR

 

My question is more likely: Inner Ear Hair Cell Damage - Maybe we can know more...

Usually no tinnitus sufferer can be completely sure to have inner ear hair cell damage....

Sorry for offtopic

 

Speak for yourself. I'm 100% sure my ears were destroyed at cellular level and thus tinnitus (and severe sudden hearing loss, which lasted 16-18 hours) appeared.

 

Thank you for making this thread here is something related I stumbled upon today ..

https://www.pri.org/stories/2017-03...generating-hair-cells-inner-ear?itok=loggedin

 

They have an update on an "siHes1" nano particle they have been working with. It looks like a direct transdifferentiation from SC to HC similar to what Audion/REGAIN are testing, but a different molecule. I would say at this point in time they are "very early" in development and nowhere near any clinical trials.

Also appears you can support them through your amazon purchases using amazon smile.

http://houghear.org/cause/amazon-smile/

The more players there are in the this space, the better off everyone will be.

http://houghear.org/wp-content/uploads/2017/10/Newsletter-3rd-Quarter.pdf

Here is a copy of their poster summary from the 2017 Mid-Winter Meeting for the Association in Research in Otolaryngology

PS 218 Coordinated Wnt/β-catenin Activation and Inhibition of Hes1-Mediated Notch Signaling Induces Synergistic Increases in Cochlear Hair Cell Numbers Richard D. Kopke; Matthew B. West; Xiaoping Du; Wei Li; Ibrahima Youm; Jianzhong Lu; Weihua Cheng; Qunfeng Cai Hough Ear Institute Background The sensory epithelium of the inner ear is composed of a complex mosaic of auditory hair cells (HCs) and supporting cells (SCs). Although HC loss in mammals is irreversible, recent studies have demonstrated that a subpopulation of postnatal SCs retain stem cell-like properties that imbue them with the phenotypic plasticity to transdifferentiate into new HCs in response to genetic or pharmacologic manipulation. The observation that these responsive SCs are competent for canonical (β-catenin-dependent) Wnt pathway signaling suggests that it may be possible to potentiate the HC regenerative response induced by pharmacogenetic manipulation of the Notch pathway, using Hes1 siRNA (siHes1) nanoparticle (NP) technology, by priming the sensory epithelium of the OC with agents that amplify Wnt/β-catenin signaling throughout the SC population. Methods Postnatal murine cochleae were exposed to the ototoxic aminoglycoside, neomycin, in vitro and then cultured under conditions in which Wnt pathway activation and inhibition of Hes1 signaling were alternately manipulated. This was carried out by pharmacologic inhibition of glycogen synthase kinase 3β, which promotes activation of Wnt/β-catenin signaling, and pharmacogenetic inhibition of Hes1, using siHes1 biomolecules, delivered by either a transfection reagent or poly(lactide-co-glycolide acid) (PLGA) NPs. A combination of molecular and immunohistological examinations were then employed to discern the degree and manner in which these manipulations impacted phenotypic plasticity and HC transdifferentiation. Results Pharmacologic inhibition of GSK3β was sufficient to induce Wnt/β-catenin signaling and a mitotic response among SCs in cultured OCs. Combined inhibition of GSK3β and siRNA-mediated knockdown of the Notch effector protein, Hes1, led to synergistic increases in HC numbers following ototoxic neomycin exposure. From our comparative analyses, we found that staged inhibition of GSK3β followed by Hes1 knockdown resulted in the most robust increases in HC numbers, consistent with a priming effect induced by Wnt pathway activation. Conclusions The observation that staged inhibition of GSK3α/β and Hes1 can lead to synergistic increases in HC numbers in ototoxin-damaged murine cochlea provides an important insight into the development of therapeutic strategies for regenerating lost mammalian auditory sensory epithelia. As substantial loss of SCs through siHes1-mediated transdifferentiation may limit the long-term viability of regenerated HCs or adversely affect auditory function, the ability of Wnt pathway activation to either potentiate the regenerative efficiency of siHes1 NPs or mitotically repopulate SCs may enhance the long-term therapeutic efficacy of this approach. This research was supported by grant AR15-005 from The Oklahoma Center for the Advancement of Science and Technology.

 

How many years until product in the market?

 

No idea. They don't even have a published paper yet, only a poster presentation and a paper could take a couple years by itself. So I would say we are talking quite awhile.

 

Had to post it again. It´s just too relevant and darkish humorous.
Nice that someone is doing something though.

 

I doubt anyone was growing hair cells in a petri dish 20yrs ago. So definitely progress

 

A nice power point that summarizes the research going on over the last 30yrs.

https://www.audiology.org/sites/default/files/conferences/Ryals ARC handout.pdf

 

Otonomy: Advance Development of Multiple Programs for Hearing Loss and Tinnitus: Otonomy plans to continue the development of multiple programs for the prevention and treatment of sensorineural hearing loss, and the treatment of tinnitus. The hearing loss programs, currently in preclinical development, involve the anatomical and functional repair of ribbon synapses, protection of hair cells from chemotoxicity, and regeneration of hair cells. Otonomy is also developing gacyclidine, a potent and selective NMDA receptor antagonist, for the treatment of tinnitus. Hearing loss and tinnitus affect large patient populations and are important unmet medical needs because they have a significant burden on patients and lack effective treatments.

 

This is from Hough Institute's 3rd Quarter Newsletter.

BABY HAIR CELLS! BY DR. MATTHEW WEST The loss of auditory hair cells in the cochlea is a major underlying cause of hearing loss in humans of all ages. Unlike other parts of the body that are programmed for spontaneous regeneration, the cochlea is unable to replace lost hair cells after injury. This can result in both acute and chronic loss of hair cells and permanent hearing loss. At HEI, we are developing therapeutic strategies to reprogram the cochlea to replace lost hair cells and restore hearing function in deafened ears. In a previous newsletter report, we described exciting pre-clinical results for hair cell regeneration in guinea pigs following prolonged treatment with our proprietary siHes1 nanoparticle technology. In these experiments, noise-deafened animals with pervasive hair cell loss were treated with sustained infusion of siHes1 nanoparticles over the course of one week, resulting in pronounced improvements in hearing function in comparison to placebo-treated control animals. These ground-breaking results propelled HEI researchers to validate these discoveries and investigate whether shorter treatment periods were possible without compromising the quality of the restorative effects. From these evaluations, our research staff have been able to demonstrate that clinically-significant hair cell regeneration and hearing recovery are, in fact, achievable using a dramaticallyabbreviated (24-hour) treatment interval. The degree of recovery realized under these conditions replicated the original proof-of-concept results achieved from the continuous one-week infusion. Moreover, the restorative effects were durable and sustainable, revealing long-term preservation of the acquired hearing function. Examination of treated ears at early time points after the one-day infusion interval captured the appearance of regenerating hair cells bearing immature stereocilia, the hair-like structures that bend back and forth in response to sound waves. These “baby hair cells” were uniquely observed in siHes1 nanoparticle-treated ears and provide a fascinating snap-shot of the regenerative process in motion. This confirmation of the restorative attributes of our nanoparticle technology in noise-deafened animals and the demonstration that this therapeutic effect is achievable from a single (one-day) application is a game-changer, as it expands the playbook for the clinical development of this regenerative approach and suggests that lower doses than anticipated are capable of inducing the desired effect. As a localized, middle-ear outpatient procedure is the ideal goal for widespread clinical implementation of this technology, the reduced exposure time and dosing achieved in these studies are key findings, indeed.