A recently published special issue of International Journal of Molecular Science reviewed a variety of therapeutic interventions currently being studied as novel strategies to restore hearing.
One of these strategies involves the use of “KCNQ4 activators” as a way to keep the inner ear functioning properly. And according to the paper, existing drugs (or combinations thereof) that are already approved could potentially be repurposed as therapies for sensorineural hearing loss.
From the May 26, 2021 paper titled, “Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics”:
The voltage-gated potassium channel KCNQ4 has an essential role in regulating auditory function in the inner ear, by contributing to potassium recycling and maintenance of cochlear homeostasis. Reduced activity of the KCNQ4 channel has been associated with a genetic form of hearing loss, noise-induced hearing loss, and age-related hearing loss. Rim and colleagues presented a comprehensive review of 90 publications looking at the KCNQ4 as a potential therapeutic target for the treatment of hearing loss. In this review, the authors updated the current concepts of the physiological and pathophysiological roles of KCNQ4 in the inner ear and focused on the role of KCNQ4 activators in therapeutic management of different forms of hearing loss. They propose that the simultaneous application of two activators with distinct modes of action may result in synergistic effects and reduced off-target effects. It was also suggested that drug repurposing may be an attractive option for clinical development of KCNQ4 activators as therapies for hearing loss.
Another recent paper, from three months ago (published March 2, 2021) titled, “Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss”, stated:
Therefore, the discovery of small compounds activating or potentiating KCNQ4 is an important strategy for the curative treatment of hearing loss.
The authors concluded by recommending that “KCNQ4 activators should be validated in clinical trials, as there is no ongoing clinical trial targeting hearing loss by KCNQ4 activators currently.”
But do not let the fact that KCNQ4 activators have not yet entered human clinical trials mislead you. Despite the current lack of trials, that does not automatically mean these drugs are far, far away.
Because, as the authors also pointed out earlier in the same paper: “Drug repurposing and optimization for applicable specific KCNQ4 mutation might also be an option for clinical application of KCNQ4 activators […] with advantages of reducing the cost and shortening the time when compared to de novo drug discovery.”
As far as what to keep an eye out for next, on the topic of KCNQ4, the researchers also tip us off as to which company is working on this mechanism most closely:
Acousia Therapeutics, which is a biotech company aiming for the development of small-molecule drugs for sensory neuronal hearing loss, has eight compounds targeting KCNQ4 in its pipeline.
Company website here (comment: Acousia seems to keep a low profile, so for now don’t expect to find any additional details about these eight compounds): http://www.acousia.com/
Last but not least, a fun fact.
Aside from the repurposed drugs that might hold hearing restoration potential, there is another compound related to KCNQ4 mentioned in the paper. An exotic one, as described in one of the cited papers: Subtype-Selective Activation of Kv7 Channels by AaTXKβ(2–64), a Novel Toxin Variant from the Androctonus australis Scorpion Venom.
Scorpion venom. Hmmm…
AUTHOR’S NOTE: There is something oddly reassuring about the thought of researchers from around the world leaving no stone unturned (and no tiny venomous creature unexamined) in search of a potential hearing loss cure.
A good reminder that we never know where (or from what) the next big discovery will arise. Nature is full of secrets and science is constantly uncovering these surprises…
More updates to follow…
How to get KCNQ4 activator updates
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Inhalation of Molecular Hydrogen, a Rescue Treatment for Noise-Induced Hearing Loss
Front Cell Neurosci. 2021 Jun 1;15:658662. doi: 10.3389/fncel.2021.658662. eCollection 2021.
Noise exposure is the most important external factor causing acquired hearing loss in humans, and it is strongly associated with the production of reactive oxygen species (ROS) in the cochlea. Several studies reported that the administration of various compounds with antioxidant effects can treat oxidative stress-induced hearing loss. However, traditional systemic drug administration to the human inner ear is problematic and has not been successful in a clinical setting. Thus, there is an urgent need to develop rescue treatment for patients with acute acoustic injuries. Hydrogen gas has antioxidant effects, rapid distribution, and distributes systemically after inhalation.The purpose of this study was to determine the protective efficacy of a single dose of molecular hydrogen (H2 ) on cochlear structures. Guinea pigs were divided into six groups and sacrificed immediately after or at 1 or 2 weeks. The animals were exposed to broadband noise for 2 h directly followed by 1-h inhalation of 2% H2 or room air. Electrophysiological hearing thresholds using frequency-specific auditory brainstem response (ABR) were measured prior to noise exposure and before sacrifice. ABR thresholds were significantly lower in H2 -treated animals at 2 weeks after exposure, with significant preservation of outer hair cells in the entire cochlea. Quantification of synaptophysin immunoreactivity revealed that H2 inhalation protected the cochlear inner hair cell synaptic structures containing synaptophysin. The inflammatory response was greater in the stria vascularis, showing increased Iba1 due to H2 inhalation.Repeated administration of H2 inhalation may further improve the therapeutic effect. This animal model does not reproduce conditions in humans, highlighting the need for additional real-life studies in humans.
PMID:34140880 | PMC:PMC8205059 | DOI:10.3389/fncel.2021.658662
Frontiers in cellular neuroscience
DATE – PUBLISHED:
Fri, 18 Jun 2021 06:00:00 -0400
DATE – DOI:
DATE – ADDED:
LINK – PUBMED:
LINK – DOI:
LINK – PUBLISHER:
Hearing Loss Treatment Report, Urgent Research, 2021-06-18T17:25:36+00:00, https://www.hearinglosstreatmentreport.com.
Effects of Insulin-Like Growth Factor (IGF-1) in Patients with Sensorineural Hearing Loss
J Int Adv Otol. 2021 May;17(3):207-214. doi: 10.5152/iao.2021.8549.
OBJECTIVES: (1) To test the effect of local administration of insulin-like growth factor-1 (IGF-1) in patients with sensorineural hearing loss (SNHL). (2) To test the effect of local administration of IGF-1 in patients with ototoxicity.
METHODS: Forty patients with SNHL were included in the study. Their hearing thresholds at different frequencies (0.5, 1, 2, and 4 kHz) along with the average hearing threshold were noted. The patients were then randomly allocated to 2 groups and were treated with IGF-1 via one of the following routes: (1) intratympanic injection and (2) Gelfoam. Patients were followed-up at weekly intervals for 6 weeks but follow-up PTA was done at 3 weeks, 6 weeks, and 6 months only.
RESULTS: Forty patients (25 male, 15 female) participated in the study. Their age ranged from 13 to 63 years, with a mean of 31.3 years. Nineteen (47.5%) patients exhibited some degree of recovery after 6 months of follow-up, while 21 (52.5%) did not exhibit any recovery. Fourteen (35%) patients showed slight recovery (SR), 1 (4%) patient showed marked recovery, and complete recovery was observed in 4 (10%) patients. Twelve of the 20 patients who underwent treatment using Gelfoam showed improvement in hearing (measured as a reduction in hearing threshold), while only 7 of the 20 patients who underwent intratympanic injection showed such improvement. Among adverse reactions, the most common was pain (88%) which typically did not last beyond 3 days. Other adverse reactions observed were dizziness (24%) and headache (20%). One patient suffered from acute suppurative otitis media (ASOM) and had a perforation in the tympanic membrane. However, this was treated successfully with medications.
CONCLUSION: Intratympanic IGF-1 is a novel drug that has shown early promise in controlling and reversing SNHL.
PMID:34100744 | DOI:10.5152/iao.2021.8549
The journal of international advanced otology
DATE – PUBLISHED:
Tue, 08 Jun 2021 06:00:00 -0400
DATE – DOI:
DATE – ADDED:
LINK – PUBMED:
LINK – DOI:
LINK – PUBLISHER:
Hearing Loss Treatment Report, Urgent Research, 2021-06-08T18:54:02+00:00, https://www.hearinglosstreatmentreport.com.
A noteworthy abstract from The Association for Research in Otolaryngology (ARO) 44th Annual MWM held a few months ago:
Attenuation of Age-Related Hearing Loss in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice Treated With Fatty Acid Synthase Inhibitor CMS121
The senescence-accelerated prone strain 8 (SAMP8) mouse model provides opportunities to investigate potential therapies for age-related hearing loss (ARHL), the most common sensory disorder in older humans. In SAMP8 mice, oxidative stress leads to chronic inflammation, apoptosis, and premature senescence. CMS121 is a fatty acid synthase inhibitor previously shown to improve cognitive function in SAMP8 mice through anti-inflammatory and antioxidative effects in the hippocampus. Given the common cellular pathways leading to age-related dysfunction inthe hippocampus and cochlea, the aim of our study is to determine whether CMS121 is protective against ARHL in SAMP8 mice.
Auditory brainstem responses (ABRs) across six frequencies (4, 8, 12, 16, 24, and 32 kHz) were used to assess baseline hearing in sixteen 4-week-old SAMP8 mice, which were then split into age-matched groups with similar average hearing thresholds. The control group was then fed a vehicle diet, while the experimental group was fed a diet with CMS121. ABR measurements were repeated at seven, ten, and thirteen weeks of age. Cochlear immunohistochemistry was then performed using Ctbp2, GluR2, and Myo7a to analyze the number of paired ribbon-receptor synapses per inner hair cell (IHC). Descriptive statistics are provided with mean ±SEM (Standard Error of the Mean). Two-sample t-tests were performed to compare hearing thresholds and paired synapse count across the two groups, with alpha = 0.05.
Baseline hearing thresholds across the six frequencies in the control group (77.5± 5.9, 59.0 ± 9.5, 44.2 ± 6.1, 47.5 ± 7.8, 36.8 ± 6.0, and 35.0 ± 7.2) were statistically similar to those of the CMS121 group (74.9 ± 2.3, 51.4 ± 3.7, 42.3 ± 3.3, 45.8 ± 5.0, 37.8 ± 4.6, and 33.3 ± 4.7.) While the control group showed progressive ARHL (hearing thresholds at 13 weeks were 84.0 ± 6.4, 63.8 ± 10.0, 56.5 ± 6.1, 64.8 ± 7.4, 37.0 ± 6.4, and 38.3 ± 6.1), the CMS121 group maintained stable hearing thresholds at 13 weeks (73.1 ± 4.0, 50.0 ± 4.5, 39.8 ± 3.8, 43.8 ± 4.4, 31.6 ± 4.3, and 35.8 ± 7.1). At that time, the control group had significantly worse hearing thresholds at 12 kHz (56.5 vs. 39.8, p = 0.044) and 16 kHz (64.8 vs. 43.8, p = 0.040) compared to the CMS121 group. Immunohistochemistry showed a significantly lower synapse count per IHC in the control group (15.7) compared to the CMS121 group (18.4), p = 0.014.
Our study shows a significant reduction in hearing loss and increased preservation of ribbon synapses in the mid-range frequencies among mice treated with CMS121 compared to untreated mice. These findings support expanding the scope of current research on CMS121 to further investigate the promising role of this compound as a protective agent against ARHL.
Further study will be needed to explore whether CMS121 can reverse any pre-existing hearing loss. But considering how nearly all forms of hearing loss are progressive (albeit some are slower than others), a decibel saved is a decibel
As far as mechanism is concerned, it seems to show potential in combating the damaging effects of noise-induced lipid peroxidation. But there’s likely a few things going on.
“But human trials must be years away.”
Fortunately this drug candidate has a bit of a head start, as it is being studied in Alzheimer’s disease:
That’s all for now. More information to follow.
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New findings published in the Journal of Pharmacological Sciences outline the effectiveness of vinpocetine, a sodium channel blocker, as a treatment for sensorineural hearing loss.
“…with the use of vinpocetine, the hearing capacity improved. It is concluded that vinpocetine helps to stop hearing impairment and even improve hearing.”
Source: J Pharmacol Sci. 2021 Apr;145(4):313-318. doi: 10.1016/j.jphs.2021.01.010. PMID: 33712282.
Researchers conducted a phase 2 trial to determine if treatment with 30mg/day of vinpocetine could stop or reverse hearing deterioration in patients with sensorineural hearing loss.
Quick background from Wikipedia:
“Vinpocetine (ethyl apovincaminate) is a synthetic derivative of the vinca alkaloid vincamine. Vincamine is extracted from either the seeds of Voacanga africana or the leaves of Vinca minor (lesser periwinkle).”
Obligatory photo of the flowering plant:
The results, which were recently printed in the April issue of JPS, in a paper titled, “Evaluation of vinpocetine as a therapy in patients with sensorineural hearing loss: A phase II, open-label, single-center study”, appear promising.
Here is the abstract (emphasis ours):
The progressive degeneration of the excitable cells of the ear depends on the sustained excitation of the voltage-sensitive sodium channels, so the negative pharmacological modulation could be a rational therapeutic strategy against the damage of these cells. The objective was to demonstrate the effectiveness of Vinpocetine (VPC), a potent sodium channel blocker, as a treatment for acquired sensorineural hearing loss. A phase II, longitudinal and prospective open clinical study, was conducted over a period of 12 months with patients older than 18 years, to demonstrate the effectiveness of Vinpocetine (VPC) as a treatment for acquired sensorineural hearing loss, using evoked potentials, otoacoustic emissions, audiometry and logoaudiometry, analyzing the results at 6 and 12 months of treatment with Vinpocetine (30 mg/day in 3 doses). It was observed that from 0 to 6 months there was hearing impairment (which was already expected due to the age of the patients). From 6 to 12 months and from 0 to 12 months there were significant differences with a tendency towards improvement, indicating that the aforementioned deterioration not only stopped, but that with the use of vinpocetine, the hearing capacity improved. It is concluded that Vinpocetine helps to stop hearing impairment and even improve hearing.
Link to the full-text version of the paper plus a backup link to the entry on PubMed:
More information on vinpocetine will follow.
For now, here are some quick notes followed by links to further reading:
- semisynthetic natural product
- derived from the periwinkle plant
- has anti-inflammatory properties
- has the ability to modulate sodium and channel channels
- is used as a vasodilator for cerebrovascular and age-related memory disorders
- regulates levels of toll-like receptors
- subject of debate, controversy, and FDA activity/memos [comment: to anyone reading this, be very careful of vinpocetine for sale on the internet. This article is not meant to suggest any treatment and especially not a do-it-yourself vinpocetine regimen. Furthermore, one of the studies I read tested supplement products that listed vinpocetine as an ingredient… and found that many of these products actually contained no vinpocetine (and/or worse, “replacement” ingredients that were not listed on the bottle).]
- a search for vinpocetine on PubMed shows a lot of results, quite recent too… hmmm…
Some interesting articles on vinpocetine [author’s note: this “drug” keeps getting more interesting the more I read about it…]:
- Vinpocetine: drug or dietary supplement?
FDA signals intent to regulate semisynthetic dietary ingredient as a drug
- Vinpocetine: An Unapproved Drug Sold as a Dietary Supplement
- Vinpocetine – Wikipedia
Two more scientific papers, related to vinpocetine and the auditory system:
That’s all for now.
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Researchers at the University of Utah’s Mansour Lab are studying the Fibroblast Growth Factor signaling pathway with the long-term goal of harnessing developmental signals to drive hearing restoration.
“Our results will contribute new knowledge to the long-term goal of harnessing developmental signals to drive hearing restoration.”
The project has received funding from the National Institute on Deafness and Other Communication Disorders (NIDCD) and will continue through January 2022.
According to investigators, the results “will facilitate future efforts to manipulate the FGF signaling system for hearing restoration.”
First, they will use mouse models to investigate the role of the Fibroblast Growth Factor signaling pathway and its critical role in the inner ear.
But the findings could uncover key development signals that could potentially be commandeered to restore hearing function.
The team is being led by Dr. Suzanne L. Mansour (Molecular Biology Program – FGFs and Inner Ear Development, Mouse models of hearing loss and restoration), who has been studying these FGF signals since the early 2000s.
Here is the full abstract and public health relevance statement:
Regulation of inner ear development by FGF signals and effectors
Mansour, Suzanne L.
University of Utah, Salt Lake City, UT, United States
Morphogenesis of the inner ear epithelium requires coordinated deployment of several signaling pathways and disruptions cause abnormalities of hearing and/or balance. With the advent of cochlear implantation to treat hearing loss even in cases of inner ear malformation, it is critical to understand exactly how such malformations affect the auditory ganglia and innervation. Also, in light of the intense focus on in vitro generation of inner ear cell types for transplantation and in vivo manipulation of developmental signaling molecules to promote differentiation of various inner ear cells for hearing restoration, elucidating the roles and regulation of such signals and their effectors governing otic differentiation and morphogenesis are necessary to advance treatment. The genes encoding FGF3 and FGF10, ligands that signal through FGFR2b and FGFR1b, are expressed dynamically throughout otic development in both epithelial and ganglion domains. Studies conducted by the Mansour Lab of both conventional Fgf3 and Fgf10 conditional knockout mice and those expressing a doxycycline-inducible ligand trap (dnFGFR2b) that rapidly inhibits signaling through both FGFR1b and FGFR2b, showed that Fgf3 and Fgf10 are not required in the placode lineage for otocyst formation, but are required subsequently for otocyst patterning, neuroblast maintenance, epithelial proliferation and both vestibular and cochlear morphogenesis. Furthermore, the first genome wide analyses of otocyst mRNA revealed FGFR2b/1b signaling targets that define novel candidates for genes involved in otic morphogenesis and function. This proposal has two Aims addressing the hypotheses that 1) FGFR2b/1b signaling is required continuously for both otic neuroblast specification and maintenance, and that at later stages, mesenchymal signaling, as well as that in the epithelial and ganglion domains, is required for cochlear epithelial differentiation and ganglion maintenance and 2) FGFR2b/1b downstream target genes mediate some or all of the effects of FGFR2b/1b signaling on otic morphogenesis and gangliogenesis. To determine the early role of FGFR2b/1b signaling in otic ganglion formation and its later role in epithelial differentiation and ganglion maintenance, DOX-induced ubiquitous and CRE-limited expression of dnFGFR2b will be employed and morphology and molecular markers of otic patterning, proliferation and survival in both tissues will be assessed. To determine the roles of downstream targets of FGFR2b/1b signaling, two genes encoding transcription factors that are activated by FGFR2b/1b signaling and one gene encoding a BMP signaling regulator that is repressed by FGFR2b/1b signaling will be studied. Otic conditional mutants will be generated for each gene, and their morphologic and functional development will be assessed. In addition, the extent to which the BMP regulator contributes to the dnFGFR2b phenotypes and the effects of overexpressing the BMP regulator will be assessed. The results will contribute new knowledge that will facilitate future efforts to manipulate the FGF signaling system for hearing restoration.
Public Health Relevance
Permanent hearing loss caused by malformation of the inner ear or congenital or progressive loss of its sensory or neural cells affects up to one third of individuals by the age of 80 and generates significant social and healthcare costs. In this proposal, we use mouse models to investigate the role of the Fibroblast Growth Factor signaling pathway in forming the inner ear epithelium and neurons. Our results will contribute new knowledge to the long-term goal of harnessing developmental signals to drive hearing restoration.
For updates on Mansour’s FGF signaling system (and other hearing restoration research/treatments) sign up for free email updates (our newsletter) here.
Project #: 1R01DC019127-01
Researchers at University of California-Irvine are testing the effects of nicotine to see if it will reduce or reverse auditory decline.
The research is part of a new project funded by the NIA division of the U.S. National Institutes of Health.
The project was recently awarded $640,473 in grant money for 2021 to determine, in humans and mice, whether nicotine’s effects can restore auditory function.
It began a few months ago and will continue until at least the end of 2021. (If successful, it could continue to receive more funding every year, until the end of 2025.)
Worth pointing out: nicotine, in this context, is NOT related to tobacco, smoking, or vaping. This is some sort of pharmaceutical nicotine, apparently:
“Because nicotine enhances cortical and cognitive function, pharmaceutical companies are developing nicotine-like drugs … These drugs are non-addictive (unlike nicotine in tobacco), yet nicotine also is non-addictive when given topically or orally.”
And, according to the project description, a positive outcome “will facilitate the translation of nicotine-based therapeutic treatments for hearing loss to clinical populations.”
Here is a shortened version of the project Abstract and Public Health Relevance Statement (formatting and emphasis ours):
Ideally, a combination of drug treatment with hearing aids and behavioral training could restore auditory function, but the development of pharmacological treatments requires a better understanding of the mechanisms by which candidate drugs improve hearing.
The goals of this proposal are to develop biomarkers of altered auditory processing in aging mice and humans, and using these biomarkers, to test the hypothesis that nicotine can normalize these age-related central auditory deficits.
Because nicotine enhances cortical and cognitive function, pharmaceutical companies are developing nicotine-like drugs to target cognitive deficits in aging. These drugs are non-addictive (unlike nicotine in tobacco), yet nicotine also is non-addictive when given topically or orally. However, its clinical benefits have not been exploited except as an aid to stop smoking.
We hypothesize that: 1) acute nicotine compensates for the age-related decline in inhibition by exciting the remaining inhibitory neurons; 2) chronic nicotine exposure (CNE) upregulates nicotinic acetylcholine receptors (nAChRs); and, as a result, 3) acute nicotine and/or CNE will reduce or reverse the age-related auditory decline.
We will test these hypotheses in both mouse and human at the level of cells (mouse in vitro brain slice), neural systems (mouse in vivo physiology; human brain imaging and EEG) and behavior (human psychoacoustics).
- Aim 1 will determine in mouse whether age-related decline in auditory spectrotemporal processing is reversed by acute nicotine or CNE, and characterize the associated cellular mechanisms.
- Aim 2 will identify, in humans, age-related changes in receptive field properties in auditory cortex using novel fMRI techniques and determine if nicotine reverses these changes using psychoacoustics, fMRI and EEG.
This project features a multifaceted, parallel approach in mouse and human. Each Aim will:
- examine auditory processing at multiple adult ages;
- use similar acoustic stimuli in both species, accounting for species differences in hearing, to target common mechanisms;
- test the effects of nicotine.
A successful outcome will promote an integrated understanding across levels, from cellular mechanisms to perception, and facilitate translation of nicotine-based therapeutic treatments to clinical populations.
Public Health Relevance Statement
Nicotine enhances auditory and cognitive functions because it mimics the brain’s system for “paying attention” to important sounds amid distractions (for example, understanding speech in a noisy environment). In part, nicotine does this by activating inhibitory neurons in the auditory cortex. Since age-related hearing deficits result in part from the loss of inhibitory neurons, this project will determine, in humans and mice, whether nicotine’s effects can compensate for reduced inhibition in aging and thereby restore auditory function.
For some more background on the science and theory behind nicotine and hearing, here is a good paper from last year:
Nicotine Enhances Auditory Processing in Healthy and Normal-Hearing Young Adult Nonsmokers March 2020
Nicotine improves auditory performance in difficult listening situations. The present results support future investigation of nicotine effects in clinical populations with auditory processing deficits or reduced cholinergic activation.
The UC Irvine project described in this post is part of the story. There is also a separate project, also at UC Irvine, titled, “Nicotinic enhancement of auditory-cognitive processing.” (Also awarded a grant worth over $600,000.)
From the project narrative section of the description:
The drug nicotine enhances auditory-cognitive function because it “hijacks” the brain’s endogenous system for directing attention to important sounds (for example, understanding speech in a noisy environment). This project seeks to determine if one kind of nicotine receptor (a2 subtype) and one kind of neuron (VIP) in two key regions of the cerebral cortex (auditory cortex and prefrontal cortex) play essential roles in nicotine’s effects. The long-term goal is to understand brain mechanisms of auditory processing and guide development of novel drug treatments for auditory-cognitive disorders.
We will be following this research and these nicotine/hearing improvement projects and posting updates as important milestones are met.
This article is an unfinished draft and a work in progress. You are accessing it early because this not-yet-public link is sent to email subscribers.
Exported on 05/01/2021 from the HHS Tracking Accountability in Government Grants System (TAGGS), http://taggs.hhs.gov, Project Number 1R01AG067073-01A1
An unofficial update on Decibel Therapeutics’ secretive gene therapy program to treat sensorineural hearing loss by regenerating cochlear outer hair cells…
First, the official story, followed by a big “unofficial” update on “DB-301″…
Laurence Reid, CEO of Decibel Therapeutics, had this to say during a recent presentation at the 20th Annual Needham Virtual Healthcare Conference – from April 15, 2021:
Laurence Reid: We have an earlier stage program with respect to the cochlea. The goal is to drive differentiation of the supporting cell, through an immature hair cell, and then on particularly to either generate the outer hair cell or potentially the inner hair cell – for treating different types of patient populations with different cellular bases for their hearing loss.
Here is a slide from the presentation:
Officially, we also have some background information thanks to a recent Decibel Therapeutics, Inc SEC filing (emphasis ours):
Cochlear Hair Cell Regeneration
Age-related hearing loss and noise-induced hearing loss affect millions of people in the United States and Europe. Research has shown that the degree of hearing loss in these populations is best predicted by the amount of outer hair cell loss. We believe that restoring outer hair cells could restore hearing in these individuals. In our cochlear hair cell regeneration program, we are designing an AAV-based gene therapy that utilizes cell-selective expression of reprogramming factors to convert supporting cells into outer hair cells. We are currently conducting preclinical in vitro and in vivo rodent studies to evaluate the cell-selectivity of certain proprietary promoters and the ability of certain reprogramming factors that may drive an outer hair cell fate.
In that same filing, we learn that Decibel Therapeutics plans to announce the targets for this cochlear hair cell regeneration program in 2022. Excerpt and pipeline snapshot:
In addition, we are advancing our cochlear hair cell regeneration program to treat acquired hearing loss by regenerating cochlear outer hair cells. We plan to announce the targets for our cochlear hair cell regeneration program in 2022.
However, we might not need to wait until 2022 for that update, because…
Our independent research has uncovered what appear to be details related to Decibel’s “Cochlear Hair Cell Regeneration Program” (a.k.a. the gene therapy program which could potentially be given the name “DB-301”)…
That’s our unofficial code name, inferred from Decibel’s naming scheme (“AAV.RF301” or “AAV.301” + “DB” = DB-301).
From a Decibel Therapeutics corporate overview presented during Citi’s 15th Annual BioPharma Virtual Conference:
As you can see, this slide looks like a perfect match for the cochlear hair cell regeneration program. (Which is why we’re calling this an “early update” on the program.)
The presentation has the word “confidential” written on page 19.
However, the source of this information – a PDF document – is currently available on Decibel’s website. (It is indexed by search engines and accessible to the public. We have archived it digitally as well, for record-keeping purposes.)
Furthermore, within this PDF – on page 19, in very, very, very tiny text – is a list of what appear to be outer hair cell candidate targets (copy+pasted):
Hdac3 Kdm4a Mtpn Htatip2 Dnmt3a Mlxip Foxo3
oxn3 Prnp Sall1 Pknox2 Klf9 Rora Six2 Trps1 Actn4 Mef2a Pdcd11 Nfkb1 Hlcs Zfp410 Banp Zbtb7b Esrra E2f3 Zfp740 Zkscan3 Creb3l1 Ighm Zfp324 Arnt Lig1 Elk3 Zbtb40 Crem Smarca2 Nfatc2 Rest Nfib Zfp608 Nfix Smad7 Mafk Adarb1 Irf6 Nacc2 Rorb Bhlhe40 Ikzf2 Jun Zfp423 Nr3c1 Tppp Cat Zfp637 Zfp777 Kmt2a Nr2f2 Zfp592 Pura Zfp365 Zbtb46 Zfp654 BC005561 Zfp516 Cic Zhx3 Rxra Zfp106 Zfp277 Thra Tmem33 Zc3h7a Srrm3 Pds5a Zbtb4 Ube2k Ctbp2 Id4 Srebf1 Nfat5 Ddit3 Sall3 Mdm2 Srebf2 Gtf2i Prdx5 Smap2 Zbtb7a Zfp618 Gata3 Irf9 Mef2d Taf1 Zfp523 Kdm2a Abcf2 Zfp398 Zfp638 Hmg20a Msi2 Nmral1 Tead1 ead2 H2afy Irx3 Ezh2 Rfxap Sox9 Tgif2 Egr4 Egr3 Npas4 Sox11 Fhl2 Prox1 Sox2 Cers2 Gm10093 Dazap1 Dnajc21 Isl1 Ran Ebf1 Atoh1 Hes6 Rpl35 Rps10 Psma6 Akr1a1 Barhl1 Smarca5 Ruvbl1 U2af1 Gtf2a2 Zfp428 Ssbp3 Zfp326 Nuak1 Pknox1 Cyb5r1 Tceal5 Msra Cers6 Zmat4 Bcl11b Npdc1 Bcl2 Ybx1 Stub1 Zmat2 Zfp667 Yeats4 Tfdp2 Hnrnpa1 Tfdp1 Rbm17 Hmgn3 Lhx3 Cers4 Ugp2 Bax Mrps25 H1fx Nap1l1 Pax2 Traf4 Mcm6 Neurod6 Rab2a Cd59a Ptcd1 Klf7 Las1l Cdk2ap1 Mycl Nono Zfp330 Insm1 Irx2 Id1 Id2 Magoh Nr2f6 Zbtb20 Diablo Gar1 Snrpb2 Rps4x Zmiz1 Hnrnpc Nr2f1 Rbpj Lsm6 Hmgb2 Tbpl1
Is this a short list of targets that Decibel is planning to choose from and announce in 2022?
Time will tell.
But, taken together, all this information leads us to believe that Decibel Therapeutics could have an earlier update for us about all these “unofficial” details (including the name “DB-301”, which is just one possibility).
COMMENT: This article was made available to email subscribers several days early. If you want early access to updates like this one, join the email updates list. It’s free, no spam, and your information is kept private.
Hough Ear Institute is developing a new drug that uses RNA technology to regenerate inner ear hair cells and restore lost hearing.
The name of the drug is AOK-1.
Unlike Hough’s first drug, NHPN-1010, AOK-1 is not a pill.
Instead, it is an injection.
And the way it works is equally different.
New: Breakthrough Number Two from Hough Crew
The Hough pill aims to restore hearing by repairing and reestablishing the connections to hair cells. It is designed to rescue or salvage “stranded” sensory cells.
This AOK-1 injection, on the other hand, aims to restore hearing by regenerating, repairing and regrowing the sensory cells themselves. Perhaps even from virtually scratch.
The dream? That AOK-1 could someday give hearing to people affected by even the most severe forms of noise-induced hearing loss.
“…like releasing a ‘parking brake’ on the regenerative process”
Hough Ear Institute CEO Dr. Richard Kopke recently shared the first details on AOK-1, including the big idea behind its mechanism.
From the video (transcribed and lightly edited for clarity and brevity):
The next technology is the one that is injected into the ear and we call it AOK-1. And it’s a regenerative therapeutic. It’s a regenerative drug and it’s an RNA technology. It’s an RNA molecule that eliminates a protein that keeps the hair cells from regenerating in the cochlea. So it’s like a parking brake on the whole regenerative process in the cochlea. When we get rid of that protein, then the hair cells can generate.
In short, AOK-1 is being developed to awaken the human body’s innate ability to repair and regrow its lost or damaged inner ear hair cells. The same way many animals, including birds, frogs, and fish, can naturally regenerate lost sensory cells and hearing. AOK-1, a small interfering RNA achives this by interfering with the protein that is responsible for keeping this regenerative power “asleep” in humans.
A “same-day” hearing restoration procedure?
Dr. Richard Kopke also explained how the drug is being designed as an outpatient “same-day” procedure. It does not require an overnight stay at the hospital. Rather, you get it and go home shortly after. The procedure involves some numbing drops for the ear drum, followed by a minimally invasive injection of thermosensitive hydrogel that contains the active drug.
This delivery method is discussed during the presentation:
Importantly, the science appears to be getting there. In vivo animal model experiments are showing lots of promise. (The research behind AOK-1, by the way, is supported by a $1.9 million Department of Defense CDMRP grant.)
And although AOK-1 is still in preclinical development, Dr. Richard Kopke concluded his presentation with a “hint” at the possibility of upcoming human clinical trials…
His exact words:
Currently we’re under talks and negotiations with another pharmaceutical company that would like to take this technology, license it, and bring it to the clinic. It seems to be a robust, reproducible technology that restores hearing.
The full presentation from Dr. Richard Kopke is available on YouTube: March 2021 – Hough Institute Breakthrough – Member Meeting (uploaded on April 15, 2021). The AOK-1 part of the presentation starts at the 33 minutes, 56 seconds (33:56) timestamp.
For updates on the progress of AOK-1 and its progress toward human studies, subscribe to our free email newsletter (updates).
For those of you who are eager to dive deeper into the science behind AOK-1, here are links to the original research papers:
- https://houghear.org/wp-content/uploads/2020/07/Shibata-Gene-therapy-for-hair-cell-regeneration-Review-and-new-data.pdf [PDF]
Source: Hearing Loss Association of America – Oklahoma Central Chapter. (2021, April 15). March 2021 – Hough Institute Breakthrough – Member Meeting [Video]. YouTube. https://www.youtube.com/watch?v=WCed87H92S4
Acknowledgements: Credit belongs to reddit user u/filleorange for finding and sharing the link to this informative video. (When it was first posted to reddit, the video only had a measly 4 views!)
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