Inner Ear Hair Cell Regeneration — Maybe We Can Know More

@tomytl Thanks for sharing! Very interesting development! So now we have 15 companies (according to my own count), across a half dozen of countries, that are all working on pharmaceuticals to either protect or regenerating the inner ear. Something very good is bound to come out of all this interest and activity going on.

 

That relates to Bionure. They expect to get "Clinical Trial Authorization for BN201 in the UK in Q2 2017".

This means that Spiral will complete the "feasibility assessment" by Q3 2017. In simple English, Spiral will see if they can use BN201 and BN119 for the inner ear.

So Bionure will start a clinical trial for BN201 for eye problems in the UK by Q2 2017. Spiral will know if they can use BN201 and BN119 for ear problems by Q3 2017.

 

Could it be the motorcycle accident he had? The same affliction that caused him tinnitus? Look under his user name.

@dan26 I admire your strong spirit, for keeping up with this for such a long time. Don't give up hope now! We are entering a new age now where we will be able to restore many types of hearing damage. It was only in 1980s that scientists discovered that birds can regenerate their hair cells.

You don't think it can be repaired? It may be more difficult to repair if it's cut higher up, near the root of the branch. But nothing is impossible! The impossible is what keeps us motivated and going forward.

 

AHELO project:
EU-funded research breakthrough offers hope to millions with hearing impairments

I know it's been mentioned before, but I don't see anyone citing the final results.

"Spiral ganglion neurons (SGN) are major players in hearing conveying electrical signal from cochlear sensory cells (hair cells) to the central auditory pathway. Since SGN degeneration has been extensively described as a cause of hearing loss, neuroactive compounds are potential therapeutic drugs for sensorineural hearing loss (SNHL).

Affichem company, in close collaboration with academic researchers, has discovered a new family of original compounds called Dendrogenins that display potent neurotrophic and neuroprotective properties on cellular models of neuronal differentiation. These effects led Affichem to evaluate Dendrogenins potency on an in vivo model of chemo-induced deafness, used for cochlear implant testing, during FP6 Eurohear project. These studies demonstrate the efficacy of Dendrogenins to restore electrical responsiveness of auditory nerve in guinea pig exposed to aminoglycosides.

On this basis, Affichem is developing AF243, an effective member of Dendrogenins family, as a drug candidate for the prevention/treatment of hearing loss and to improve cochlear implant efficacy. For this purpose, our objective during AFHELO project is to finalize the preclinical study at the level of determination of the mechanism of action, in vivo efficacy in mice models of noise induced hearing loss, ADME and toxicology to support the clinical evaluation of AF243 in hearing loss.

Intensive studies performed during AFHELO project have lead to major advances for the preclinical development of our drug candidate. First, the chemical synthesis procedure, allowing the preparation of a water soluble AF243 hydrochloride salt at the gram scale, is optimized.

In second step, we have identify that Liver X Receptor (LXR), a nuclear receptor involved in cholesterol homeostasis, inflammation, neuronal differentiation and neuroprotection, is a pharmacological target of AF243 involved in its neurotrophic property.

We also showed that AF243 induced SGN branching in vitro and protect mice from noise induced hearing loss when given orally (a mode of administration suitable in clinic).

Finally, we demonstrate the safety of AF243 at the effective dose given orally on mice

Data obtained during AFHELO project highlight that AF243 is an innovative drug for the prevention and the treatment of deafness and afford a better knowledge of its mechanism of action. Considering the efficacy and the novelty of our drug candidate, AF243 is prone to afford a therapeutic option for patients suffering from hearing loss that remain actually without satisfactory treatment."

Source: http://cordis.europa.eu/result/rcn/193425_en.html

"Potential beneficiaries of this breakthrough from the EU-funded AFHELO project include people exposed to noise – in particular through accidents, hazardous working conditions or exposure to military operations (...)

Recent studies – such as the EU-funded EUROHEAR project – demonstrated that this compound could help maintain and restore auditory nerve functionality, and thus improve the effectiveness of cochlear implants. (...)

Preclinical studies carried out by the project team confirmed the neurotrophic and neuroprotective properties of AF243, along with its ability to restore the functionality of auditory nerves and prevent noise-induced hearing loss. (...)

The AFHELO project will be completed in mid-2016, and work will continue to ensure that the potential of AF243 is fully exploited. The next step will be to validate the efficacy of the drug in larger cohorts of animals and in parallel develop a local delivery approach. This will then be followed by regulatory studies, which is a prerequisite before human trials can begin. (...)

Another goal of this project was to obtain a better understanding of the causes of the early onset of hearing loss. Good hearing depends on the integrity of the sensory epithelia in the inner ear, while hearing impairment occurs when sensory hair cells die and spiral ganglion neurons degenerate. (...)

Since these hair cells and spiral ganglion neurons develop from the same origin, the team saw that the growth factors that affect their differentiation could present a potential target for therapeutic applications. The AFHELO project therefore focused on the effects of AF243 on cell differentiation and neuron survival, and found that the compound was highly effective. The team also found that folic acid deficiency resulted in premature hearing loss, showing that bad eating habits can have an impact on hearing."

Source: http://cordis.europa.eu/news/rcn/123985_en.html

 

Dendrogenins!

Study: Dendrogenin A and B two new steroidal alkaloids increasing neural responsiveness in the deafened guinea pig

"Following immediate or delayed Dendrogenin treatment the electrical responsiveness was significantly maintained, in a similar extent as has been shown using neurotrophic factors. (...)

Our results suggest that Dendrogenins constitute a new class of drugs with strong potential to improve cochlear implant efficacy and to treat neuropathy/synaptopathy related hearing loss. That electrical responsiveness was maintained despite a significantly reduced neural population suggests that the efficacy of cochlear implants is more related to the functional state of the spiral ganglion neurons than merely their number."

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513558/

Also, take note of this:

"AF243 induces neuron survival and neuronal differentiation.

The non-peptide nature of AF243 gives it a competitive advantage over the currently known neurotrophic factors. In addition, its synthesis by chemical means, not by biotechnological processes, guarantees its biological safety."

Source: http://www.affichem.com/af243

They have tested the oral approach so far. They plan on testing the local approach next. I'm not sure if they have done it yet. Either way, this is a company to keep an eye on.

 

Perhaps more importantly, it allows for oral administration.

NT-3 and BDNF are also used to improve cochlear implants, but it doesn't mean that people with minor synaptic loss can't benefit from the same treatment.

"AF243 induced SGN branching in vitro and protect mice from noise induced hearing loss when given orally"

"Preclinical studies carried out by the project team confirmed the neurotrophic and neuroprotective properties of AF243, along with its ability to restore the functionality of auditory nerves and prevent noise-induced hearing loss."

They don't exactly use the word "regrowth". But how do you explain "SGN branching"? Ganglion is a cluster of nerve cell bodies. Even if they cannot regrow these cell bodies, they may not need to in order to restore auditory nerve function. SGN have been shown to survive for a long time. If by branching they mean that they can send out dendrite projections to contact the hair cells, then it may be just what we need. Synaptopathy is the loss of contact with the hair cells. Neuropathy is the loss of neurons, or nerve cell bodies. Even if this does occur, improving the function of the remaining cells may still be worth the effort and restore auditory nerve function.

 

@Jim51042 You will find some additional info on Affichem's website for their US subsidiary.

http://affichemusa.com/

"Affichem USA Inc. is developing small molecule Dendrogenins for the treatment of cancer, hearing loss, and other neurodegenerative disorders."

"Dendrogenins were first named for their ability to stimulate neurally derived cells to form dendrites."

"AF243 is a revolutionary regenerative drug which stimulates differentiation of neural progenitors and promotes the functional state of neurons or neuron-derived cells, including spiral ganglion neurons, that transmit sound information from the cochlea to the brain."

"Prior regenerative approaches have focused on growth factors which bind to membrane receptors to trigger the growth, proliferation and differentiation. These proteins demonstrated secondary effects such as neuropathic pain and abnormal proliferation of Schwann cells in the clinic.

In contrast to AF243, an oxysterol metabolite, acts by modulating transcriptional activity of LXR nuclear receptor and stimulating the expression of proteins involved in the regulation of neuronal development, differentiation and cell survival."

So this drug may actually have less side effects than NT-3 and BDNF. Assuming that it's true what they say about neuropathic pain and abnormal proliferation.

 

Affichem S.A. pipeline:


Affichem USA Inc. pipeline:

Looks like they are getting close to first clinical trials. I think they might get something out there before Decibel Therapeutics does. We don't even know yet what kind of drugs Decibel is working on. Here we have a concrete example of what Affichem is working on, and the lab testing strongly indicated that it works. It's also targeting nerve cells, rather than sensory cells like everyone else.