Is tinnitus all in the genes?
Is tinnitus all in the genes?
How much will FX-322 cost? David Lucchino, Frequency Therapeutics CEO, talks pricing and value…
Frequency Therapeutics Completes Enrollment of FX-322 Phase 2a Study for Sensorineural Hearing Loss
Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies.
The Neural Bases of Tinnitus: Lessons from Deafness and Cochlear Implants
Journal of Neuroscience 16 September 2020, 40 (38) 7190-7202; DOI: https://doi.org/10.1523/JNEUROSCI.1314-19.2020
The new study identifies candidate genes that could reveal the underlying causes and molecular mechanisms involved in tinnitus and ultimately lead to new targeted treatments.
“Our study has identified a number of interesting candidate genes for further investigation, most notably RCOR1,” write the study authors.
The preprint, which was posted to medRxiv on September 13, 2020, has not yet been certified by peer review but it was supported by funding from some big names such as Action on Hearing Loss and NIHR UCLH BRC (Deafness and Hearing Problems).
Researchers performed a genome-wide association study of tinnitus involving 172,608 volunteers.
Identification of the genetic variants involved in tinnitus would help reveal the nature of the mechanisms involved in generating tinnitus after hearing loss, a requisite for development of treatments. Previous pilot genome-wide association studies and candidate gene studies for tinnitus have lacked sufficient power to establish specific genetic risk factors but the relatively high heritability demonstrates there is potential to use such approaches to reveal the underlying mechanisms.
“Three variants in close proximity to the RCOR1 gene reached genome wide significance,” according to the study.
Worth a read.
Link to study abstract:
Link to full text [PDF]:
The authors responsible for this fascinating paper (preprint) now at the forefront of the genetics of tinnitus: Helena Rose Rees Wells, Fatin N Zainul Abidin, Maxim Freydin, Frances MK Williams, Sally J Dawson.
It is therefore possible that the association of MYO3B, ARID5B and ZNF318 with tinnitus is secondary to their role in hearing since tinnitus is usually manifested when there is a hearing loss present. However, it may be that the nature of the hearing loss caused by these genes variants creates a deficit which particularly potentiates the generation of tinnitus.
More “tinnitus gene” coverage to follow. How to follow this research? Keep checking the front page or subscribe to email updates and get a once-weekly summary (list) of new links that were recently added.
From a case report that was published earlier this summer. The use of a spinal cord stimulator provided a patient with “near total relief of otalgia, total relief of tinnitus, and mild improvement in sensorineural hearing loss.”
How did it work? Will it work for you? What type of tinnitus does this work for?
Way too soon to even speculate.
If you want a good discussion topic, look at the last sentence in the abstract (quoted below):
Neuromodulation continues to grow in its scope and application in the relief of chronic and debilitating disorders. Both otalgia and tinnitus can be multifactorial in etiology, with diagnostic and treatment challenges. This is a case of spinal cord stimulator placement providing a patient with near total relief of otalgia, total relief of tinnitus, and mild improvement in sensorineural hearing loss. We believe that this is the first report showing benefit of high spinal cord stimulation in tinnitus, and we consider whether there are neuronal connections between upper cervical nerve roots and the auditory pathways.
Do neuronal connections between the upper cervical nerve roots and the auditory pathways exist?
For all tinnitus patients or just some (i.e. is it common or rare)?
Would people with this subtype of tinnitus be treatable with high spinal cord stimulation?
Could they expect the same “total relief” as the patient in the case study?
We don’t know yet.
But it sure is exciting to think about.
Wouldn’t it be nice if answering these research questions helped uncover a treatable “cervical nerve root” tinnitus subtype?
… all thanks to a case report that could have just as easily been forgotten?
Case reports are like tiny seeds.
If planted and watered enough, they can sometimes sprout into new research.
Your attention is the water.
Whenever you discuss a case report or ANY OTHER research topic or paper online… whenever you share it with others in the tinnitus community… whenever you post about it online…
You are watering that seed of an idea, helping it grow.
Then it can start to take root.
Other people notice.
They start to water it.
It becomes bigger, now with branches of its own… it becomes a ‘thing’ within the tinnitus community.
Researchers and the people who control the funding dollars [you know who you are, hi] begin to take notice. And while they might not comment*, they see it on their radar. The attention of the community is important. They monitor it. It is a factor they must consider.
* too busy reading My Posting Place?
The “voice of the patient” is an increasingly-important element of publicly funded projects and grant decisions.
You influence policy by sharing links to research and ideas with the community. I’m talking about places like Reddit (r/tinnitus and r/tinnitusresearch) and, of course, TinnitusTalk.
These forums are effectively a “public record” of research topics and things like views, comments, posts… are quietly becoming metrics that influence decisions and literally help researchers get grant money more easily.
Meanwhile, ideas and papers and topics that are NOT discussed by the community… certainly not helpful. Without a public record or the support of the “voice of the patient”, a paper or research topic could be totally ignored. Simply because it did not have enough people to vouch for it and those responsible for deciding what to fund understandably had no idea it was important to anyone.
So remember to pay attention and join the discussion somewhere because your share, your comment, your post… is a lot like a vote, and that will continue to become more and more relevant in the future.
One more thing…
Remember to subscribe to email updates so that you never miss exciting case reports like this spinal cord stimulation one… plus, some other exclusive tinnitus treatment-related updates that are ignored everywhere else. (COMMENT: the weekly newsletter digest is ALMOST READY and if you have submitted your email address you will get the first issue as soon as it is sent. Totally free, one email per week, no spam, privacy respected.)
Feedback? Comments? Requests? Send an email to firstname.lastname@example.org and say hello.
Dr. Will Sedley discusses role of “predictive brain processing” in tinnitus in latest interview – via Tinnitus Talk [PDF]
Did you mean: tinnitus talk podcast will sedley
Tinnitus and the Power of Prediction — Dr. Will Sedley
ANNOUNCEMENT – Tinnitus Treatment Report now includes tinnitus preprints. You can find these “preprints” (early not-yet-published research papers) in the Research section of the home page. Just look for the word [Preprint] next to the article title!
What is a preprint?
In academic publishing, a preprint is a version of a scholarly or scientific paper that precedes formal peer review and publication in a peer-reviewed scholarly or scientific journal. The preprint may be available, often as a non-typeset version available free, before and/or after a paper is published in a journal. Source: Wikipedia
Where can you find tinnitus preprint papers?
You could run custom searches for tinnitus at bioRxiv, medRxiv, Preprints.org, PMC, Research Square, EuropePMC, and other preprint servers – or – you can skip all the digging and simply visit the front page of TinnitusTreatmentReport.com, which uses a system that automatically monitors those same sources… automatically identifies, filters, and retrieves the newest tinnitus-related preprints… and automatically adds them to its great (and convenient) wall of tinnitus research.
Your only job? Just keep an eye on the #research section and look for the [Preprint] label!
Here are two recent tinnitus preprints from this month (August 2020):
Preprints will also be included in the weekly newsletter when it is ready (very soon). So remember to join the email updates list while it is still open if you want to get email updates.
Questions, comments, suggestions? Send an email to email@example.com and say hello.
Frequency Therapeutics Provides Business Updates and Reports Second Quarter 2020 Financial Results
Expects to Complete Enrollment of FX-322 Phase 2a Study for Sensorineural Hearing Loss by Early Q4 2020; Study Readout Anticipated in Q2 2021
Recently Announced Clinical Data Show FX-322 Delivery to the Cochlea and Preliminary Evidence of a Durable Clinical Benefit; Plans New Studies in Additional Patient Populations
Raised $42.3 Million Private Placement, Providing Company Runway into 2023
August 12, 2020 07:30 AM Eastern Daylight Time
WOBURN, Mass.–(BUSINESS WIRE)–Frequency Therapeutics, Inc. (Nasdaq: FREQ), a clinical-stage biotechnology company focused on harnessing the body’s innate biology to repair or reverse damage caused by a broad range of degenerative diseases, today announced business updates and financial results for the second quarter ended June 30, 2020.
“We are pleased with the steady progress in our Phase 2a study, despite the challenges of the pandemic, and we anticipate completing enrollment early in the fourth quarter of 2020 and sharing data from the study in the second quarter of 2021,” said Frequency Therapeutics Chief Executive Officer David L. Lucchino. “In the last quarter, we generated compelling cochlear drug delivery data for FX-322, as well as important durability data suggesting that some patients who were given a single injection of FX-322 in our original Phase 1/2 study maintained statistically significant improvements in word recognition between 12 and 21 months following administration. We believe that these clinical advances are important building blocks as we work to further our understanding of FX-322 drug activity and the patient populations we hope to treat.
The name of the leading tinnitus drug candidate is tetrandrine (TET) and researchers believe it could prevent and treat tinnitus by targeting both inflammatory and calcium signaling pathways.
Recent media coverage of Bao’s efforts to develop the first human treatment for tinnitus left many people itching to know more about the mysterious new drug.
The articles teased at the possibility of a cure… but did not provide specific details or even hint at how it might work.
The website for Bao’s company, Gateway Biotechnology, appeared to be equally secretive. The only reference to an upcoming tinnitus treatment in their pipeline was a code name: GW-201.
Sadly, a search for GW-201 on Google did not fill in the blanks.
But today, we have finally tracked down those elusive details concerning Bao’s tinnitus research and GW-201 – including a copy of the official project abstract.
The information was found by searching through a U.S. Department of Health & Human Services (HHS) grant-award program database for new entries with “Gateway Biotechnology Inc” as the recipient name.
TARGETING MULTIPLE SIGNALING PATHWAYS FOR TINNITUS PREVENTION AND TREATMENT
Award Number: R44DC018759
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH
Subjective tinnitus is the perception of a phantom sound, which negatively impacts the quality of life for millions of people worldwide. Despite the great demand for remedy, there are no FDA-approved drugs to prevent or treat tinnitus. Possible causes of tinnitus are complicated. The current view is that hyperactivity in the central auditory nervous system contributes to the majority of tinnitus cases. This abnormal electrical activity, including an increase in delta-band activity, may be the direct result of an increase in T-type calcium channel activity. Other studies suggest that inflammatory responses within the brain may be involved in the development and persistence of tinnitus; therefore, drug candidates targeting both inflammatory and calcium signaling pathways may act synergistically to prevent and treat tinnitus. Tetrandrine (TET), an approved drug used in China, exhibits both anti-inflammatory and calcium channel-blocking properties. Using a new tinnitus detection method in mice, we have shown that both salicylate-induced and noise-induced tinnitus can be effectively treated by TET in a dose-dependent manner. Our hypothesis is that TET or its chemical analogs can be developed as drugs to prevent and treat tinnitus. In our proposed experiments, we have two parallel goals: (1) obtain investigational new drug (IND)-enabling toxicity and pharmacokinetics data for TET (Aim 1) and (2) optimize second-generation products with structure-activity relationship studies of TET and its chemical analogs (Aim 2). Successful accomplishment of Aim 1 will enable TET to advance into clinical development. In addition, the studies of Aim 2 will enable us to identify additional candidates in case TET fails at clinical stages. By targeting multiple cellular signaling pathways that impinge upon tinnitus, our study will open new areas for the treatment and prevention of tinnitus. The extensive body of data publicly available for TET and its analogs will help us significantly reduce development time and costs.
SOURCE: HHS Tracking Accountability in Government Grants System (TAGGS)
From a U.S. patent assigned to Gateway Biotechnology…
In some cases, the therapeutically effective amount of TET or salt thereof is in a supplement product. In some cases, the therapeutically effective amount of TET or salt thereof is comprised in an herb extract. In some cases, the herb is Stephania tetrandra. In some cases, the herb is Stephania tetrandra S Moore. In some cases, the therapeutically effective amount of TET or salt thereof is isolated and purified. In some cases, the therapeutically effective amount of TET or salt thereof is a diastereoisomer having a diastereomeric excess of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or from at least about 50% to about 100%.
Gateway Biotechnology, Inc., a biotechnology company that repurposes drugs with established safety records to prevent and treat hearing disorders, today announced that is has been assigned U.S. patent number 10,434,097 to develop a compound isolated from a Chinese medicinal plant for the prevention and treatment of noise-induced hearing loss.
Developing story… more information about GW-201, tetrandrine (TET), and Stephania tetrandra will be added to this post…
This exclusive update is brought to you by Tinnitus Treatment Report. If you have a question, comment, or correction for this article, send an email to firstname.lastname@example.org and say hello. For email updates about GW-201, tetrandrine (TET), and other promising new treatments in the pipeline for tinnitus, subscribe.
DISCLAIMER: This website does not offer medical advice. The information, media, and content featured on this website is for information, educational, and entertainment purposes only. Do not use this information instead of consulting with a doctor or qualified professional healthcare provider responsible for your care. This website does not endorse, recommend, suggest, or offer any advice related to healthcare decisions, symptoms, nutrition, wellbeing, or choice of medical interventions. Do not use any of the information on this website to guide your treatment plan or make decisions regarding your personal health. Always talk to your doctor or a qualified healthcare professional before making a decision affects your health. In case of a medical emergency, contact your local emergency services provider or the appropriate authorities.
NEOMED researcher receives federal grant for first human tinnitus treatment
NIH FUNDS NEOMED TINNITUS RESEARCHER
Categories: Innovation & Research | Tags: Anatomy & Neurobiology, Hearing Research
Tinnitus affects millions in the United States, and yet as of today, there is no treatment for this uncomfortable and disruptive hearing impairment. Northeast Ohio Medical University researcher Jianxin Bao, Ph.D., a professor in the Department of Anatomy and Neurobiology and a member of the Hearing Research focus area, has spent his 20-year career looking for a treatment. Now, as the Principal Investigator on a research proposal for Gateway Biotechnology, Inc., a company he co-founded, Dr. Bao has received a major boost from the federal government.
Otonomy Reports Positive Top-Line Results from Phase 1/2 Clinical Trial of OTO-313 in Patients with Tinnitus
Otonomy Provides Update on Clinical Trials and Development Programs
June 15, 2020 16:05 ET | Source: Otonomy, Inc.
SAN DIEGO, June 15, 2020 (GLOBE NEWSWIRE) — Otonomy, Inc. (Nasdaq: OTIC), a biopharmaceutical company dedicated to the development of innovative therapeutics for neurotology, today provided an update on its product pipeline and the timeline to results for the company’s three ongoing clinical trials, including the Phase 3 trial of OTIVIDEX in Ménière’s disease. The company will host a conference call and webcast today at 4:30 p.m. ET to review these updates.
Congressman Tim Ryan Announces National Institute on Deafness and Other Communications Disorders Grant for Tinnitus Prevention and Treatment
Frequency Therapeutics Shares Clinical Data From Exploratory Study Confirming Delivery of FX-322 to the Cochlea – Top-Line Results Show Consistent Drug Entry in All Patients
Causes of tinnitus
FAU team of researchers uses computer-based model to explain chronic ringing in the ears
This new paper titled, The Stochastic Resonance model of auditory perception: A unified explanation of tinnitus development, Zwicker tone illusion, and residual inhibition, is a must-read for anyone interested in a fascinating “big picture” explanation of tinnitus.
The 25-page PDF document (see link below) is a pre-print that is dated March 27, 2020. A “pre-print” is a paper that has not yet been published and has not yet gone through the peer review process. Think of it like an “unofficial” copy of a paper that is waiting to be published and must still be verified.
Here is the link to the PDF of the paper:
Despite the pre-print status, it is worth sharing because it offers insight into the fundamental nature of tinnitus, including its various causes, why it’s hard to tell why tinnitus gets worse for some people but not for others, and… best of all… as the title mentions, this paper includes a a “unified explanation” of tinnitus development. A “big picture” model that could explain all the other models, and bring them together.
Here are some of the “big picture” visuals you will find inside:
The authors outline many of the current and widely-studied tinnitus models and theories. They describe how these models are similar, how they are different, and point out the apparent contradictions. And then they explain how all these models may fit within an even bigger model: a “big picture” theory and explanation of tinnitus – in many of its various forms – that is based on something called stochastic resonance (SR). (For more background on SR: see this post from May 14, 2019, which describes the SR model of tinnitus.)
As the authors mention, the study does have its limitations. The theory does not literally explain everything. But it lays some solid groundwork and provides new direction for researchers to continue their search for an “everything” model of tinnitus that has both explanatory and predictive power. Solid progress!
It appears that a serious amount of research and consideration went into creating this work, which draws from 122 relevant papers, many of which are quite recent. (In other words, this is NOT simply “recycled” theories from years ago, or a lazy, unoriginal review. It is the exact opposite!)
A unified explanation of tinnitus development… worthy of the community’s spotlight?
It is now up to the tinnitus community to decide if they wish to discuss stochastic resonance and highlight the work of Schilling et al to make sure high-quality research like this gets the attention it deserves. (Remember, if promising research gets ignored… if promising research does not get attention… the funding dollars will either dry up, or – if history is any indication – be swallowed by “mainstream” studies involving TRT, etc. So, do your part and share original research! The community’s attention can be a remarkably powerful force in steering the direction of future research.)
Acknowledgements: A special thank you to the team of authors responsible for this noteworthy research: Achim Schilling, Konstantin Tziridis, Holger Schulze, Patrick Krauss.
The Stochastic Resonance model of auditory perception: A unified explanation of tinnitus development, Zwicker tone illusion, and residual inhibition
Achim Schilling, Konstantin Tziridis, Holger Schulze, Patrick Krauss
bioRxiv 2020.03.27.011163; doi: https://doi.org/10.1101/2020.03.27.011163
Some new research that brings in to question how cortical plasticity relates to tinnitus.
Is cortical plasticity a cause of tinnitus or the key to reversing it?
Some interesting developments from the paper, Cortical Tonotopic Map Changes in Humans are Larger in Hearing Loss than in additional Tinnitus:
This observation suggests a connection between tinnitus and an incomplete form of central compensation to hearing loss, rather than excessive adaptation. One implication of this may be that treatments for tinnitus shift their focus towards enhancing the cortical plasticity on track, instead of reversing it.[…]
Tinnitus, a common and potentially devastating condition, is the presence of a ‘phantom’ sound that often accompanies hearing loss. Hearing loss is known to induce plastic changes in cortical and sub-cortical areas. Although plasticity is a valuable trait that allows the human brain to rewire and recover from injury and sensory deprivation, it can lead to tinnitus as an unwanted side effect. In this large fMRI study, we provide evidence that tinnitus is related to a more conservative form of reorganization than in hearing loss without tinnitus. This result contrasts with the previous notion that tinnitus is related to excessive reorganization. As a consequence, treatments for tinnitus may need to enhance the cortical plasticity, rather than reversing it.
Here is a sneak preview “summary” of the most recent Lenire (Neuromod) device clinical trial results.
It is an abstract.
It is from the Association for Research in Otolaryngology’s 43rd Annual MidWinter Meeting’s Abstract Book: Abstracts 488 Volume 43, 2020 (PS 767).
It is exciting.
But remember to keep a few important points in mind while reading:
Here it is:
Safety and Efficacy of Combined Sound and Trigeminal Nerve (Tongue) Stimulation to Treat Tinnitus: Effects of Different Stimulation Settings over Time
Hubert H. Lim, Caroline Hamilton, Stephen Hughes, Emma Meade, Martin Schecklmann, Thavakumar Subramaniam, Sven Vanneste, Deborah Hall, Berthold Langguth, Brendan Conlon
University of Minnesota, Minneapolis, USA, St. James’s Hospital/Trinity College Dublin, Neuromod Devices Limited, University of Regensburg, The University of Texas at Dallas, University of Nottingham
Tinnitus affects 10-15% of the population. Unfortunately, there are limited treatment options. Recent animal and pilot human research has demonstrated the ability to drive extensive auditory plasticity and potentially treat tinnitus by pairing sound with trigeminal or somatosensory nerve activation, such as with tongue stimulation. A non-invasive device (Lenire) using auditory and tongue (bimodal) stimulation was evaluated in two large randomized and blinded clinical trials in over 500 participants with tinnitus in Ireland and Germany. The first study (TENT-A1) investigated three stimulation settings (PS1, PS2, PS3) presented for 12 weeks (60 minutes recommended per day) and evaluated during treatment and up to 12 months post-treatment (326 enrolled participants). Primary outcome measures included the Tinnitus Handicap Inventory (THI) and Tinnitus Functional Index (TFI). The second study (TENT-A2) investigated different stimulation settings over time across four treatment arms (191 enrolled participants). The first treatment arm consisted of the most effective stimulation setting from TENT-A1 during the first 6-weeks (PS1) followed by a new bimodal stimulation setting during the second 6-weeks (PS4). The second and third arms consisted of different bimodal settings than the first arm, while the fourth arm consisted of an acoustic only condition during the first 6-weeks followed by a bimodal condition during the second 6-weeks. All three stimulation settings in TENT-A1 resulted in statistically significant improvements in tinnitus for THI (p< 0.0001) and TFI (p< 0.0001) that were also clinically significant ( >7 THI points, >13 TFI points). Post-treatment, PS1 resulted in persistent improvements lasting 12 months after treatment ceased (p< 0.0001). The treatment was safe and well-tolerated with a high compliance rate (84%; >36 hours of usage). The largest therapeutic effects occurred within the first 6-weeks. In TENT-A2, similar results were observed for PS1 during the first 6-weeks as in TENT-A1. Changing the stimulation setting from PS1 to PS4 led to a greater improvement (p< 0.001) than observed in TENT-A1 that also persisted for 12 months post-treatment, as well as reaching a higher compliance rate of 91%. Post-hoc analyses showed that different bimodal stimulation settings over time could be as effective as the PS1-to-PS4 condition and that specific bimodal stimuli consistently outperformed the acoustic only condition for both THI and TFI. Overall, these findings demonstrate that the Lenire treatment provides safe, fast-acting (within 6 weeks) and reproducible therapeutic effects that can last at least 12 months. Furthermore, adjusting the stimulation settings time can drive greater therapeutic effects.
The complete results and supporting data will probably only be available (published in a peer-reviewed journal) in Q1 2021 or Q2 2021.
This information is presented without further comment.
What do you think of this Lenire update? Discuss it in the Tinnitus Talk forums, on Reddit (r/tinnitus and r/tinnitusresearch), in Facebook groups, and on Twitter. Ask lots of questions. Or send an email to email@example.com with your opinion and commentary.
To get more exclusive tinnitus treatment-related updates delivered to your inbox, subscribe to the Tinnitus Treatment Report email updates list. It is a free once-weekly link roundup and newsletter that will be sending out its first issue very soon.
Toward Tinnitus Subtyping: or Finding a Key for Each Keylock
Toward Tinnitus Subtyping: or Finding a Specific Personalized Treatment for Each Patient
Why Tinnitus Needs Citizen Science: A Researcher’s Perspective
Developing effective treatments or even a cure for tinnitus
Published on February 3, 2020, added to TinnitusTreatmentReport.com manually on September 7, 2020
Resaphene Suisse AG: Charité Ethics Committee in Berlin Approves Study on Tinniwell Tinnitus Therapy
Published: Jan 21, 2020
Cognosetta, Inc receives funding to test whether treatment with BMS-191011, a calcium-activated potassium (BK) channel opener, can reduce behavioral and neurophysiological manifestations of chronic tinnitus. The project started on December 15, 2019 and is expected to continue until June 30, 2020.
Project Number: 1R43DC018487-01
Contact PI / Project Leader: SCOTT, LUISA L
Title: DEVELOPING A NOVEL THERAPEUTIC FOR TREATING TINNITUS Awardee Organization: COGNOSETTA, INC.
Tinnitus or “ringing in the ears” is a hearing disorder that disproportionately impacts those who are or have served in the military. There is currently no effective cure for tinnitus. Patients with tinnitus exhibit broad changes in brain activity in the auditory system and elsewhere. One of the fundamental characteristics of tinnitus is a dysregulation in the excitatory/inhibitory balance in the central auditory system (CAS) leading to neuronal hyperexcitability and synchrony. The large conductance calcium-activated potassium (BK) channel is implicated in other neuronal excitability disorders like temporal lobe epilepsy, tonic-clonic seizures and alcohol withdrawal seizures. Gated by both voltage and intracellular calcium, and expressed throughout the peripheral and central auditory system, the BK channel is able to modulate auditory neuronal signaling across a wide variety of conditions. Recently, Lobarinas et al. found that two BK channel openers, Maxipost and its enantiomer, reduced behavioral evidence of salicylate-induced tinnitus in rats. Though Maxipost was originally developed as a BK channel opener, in fact it is a more potent KCNQ channel opener. Nonetheless, these findings provided the impetus for our preliminary studies showing that BMS-191011, a more specific BK channel opener, reduces behavioral manifestations of tinnitus in two mouse models. Consistent with a mechanistic aim of counteracting hyperactivity in the CAS, our preliminary data and other’s shows that BK channel openers reduce neuronal activity in the auditory midbrain. The overall aim of the proposed studies is to test whether treatment with a class of BK channel openers, exemplified by BMS-191011, can reduce behavioral and neurophysiological manifestations of chronic tinnitus. Behavioral assays will probe whether treatment with the BK channel opener modifies responses that can be linked to CAS function. Both invasive and non-invasive neurophysiological recordings in vivo will characterize treatment effects on neural correlates of tinnitus in the CAS to 1) provide cross-methodological confirmation for the behavioral effects, 2) facilitate preclinical target validation and engagement studies, and 3) allow translation to clinically-measurable markers of tinnitus. The studies will employ a mouse model of acoustic trauma-induced tinnitus that matches the etiology of a substantial portion of the patient population. The use of mice will enable a longitudinal study design in which treatment begins ~2-3 months after acoustic trauma. Many mammals preclude long duration studies or higher usage rates, but the CBA/CaJ mouse is both affordable and now considered a reliable model of tinnitus following noise trauma. Together, the proposed preclinical studies will explore whether administration of a class of BK channel openers exemplified by BMS-191011 is a valid strategy to counteract maladaptive CAS function underlying stable tinnitus. This therapeutic approach clinically would allow a lapse in time following noise trauma before treatment onset, in line with the practical needs of at-risk members of the Armed Forces who may develop tinnitus while deployed, and the many patients who already have acoustic trauma-related tinnitus.
Ion channels regulate neural processing; and, changes in ion channel function can underlie central nervous system disorders. tinnitus or “ringing in the ears”, which is characterized by hyperexcitability in the central auditory system, may be relieved by modulating the function of specific ion channels. This project will explore whether a specific class of potassium channel modulators can reduce the neural and behavioral manifestations of chronic tinnitus.
SOURCE: National Institutes of Health – NIH Research Portfolio Online Reporting Tool (RePORT)
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New ‘fast-track’ system for tinnitus and hearing loss
Auris Medical Announces Notice of Allowance for European Patent Application
Auris Medical Receives “Intention to Grant” notice from European Patent Office for New Oral NKCC1 inhibitor Treatment for Tinnitus
European Patent Office (EPO) issues notice of “Intention to Grant” for Auris Medical’s “Treatment of Tinnitus Through Modulation of Chloride Co-Transporter NKCC1 in the Auditory System”
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January 10, 2020 08:30 ET | Source: Auris Medical AG
Application covers invention of oral treatment for tinnitus
Hamilton, Bermuda, January 10, 2020 – Auris Medical Holding Ltd. (NASDAQ: EARS), a clinical-stage company dedicated to developing therapeutics that address important unmet medical needs in neurotology and central nervous system disorders, today announced that the European Patent Office (EPO) has issued a notice of “Intention to Grant” for its patent application entitled “Treatment of Tinnitus Through Modulation of Chloride Co-Transporter NKCC1 in the Auditory System” (European Patent Application 11 894 529.3).
The allowed claims cover compounds modulating the sodium potassium chloride co-transporter 1 (NKCC1) for use in the oral treatment or prevention of tinnitus. As demonstrated in an animal model of acute noise trauma, administration of an NKCC1 inhibitor resulted in a significant reduction of a biomarker for the presence of tinnitus (p<0.02). Inhibition of NKCC1 reduces trauma-induced excessive intracellular chloride ion levels in inner hair cells and the resulting neural hyperexcitability in the auditory system, which underlies the perception of tinnitus. The communication from the EPO concludes substantive examination of the patent application, which is now expected to issue as a patent once the issue fees are paid and the patent office concludes its respective administrative procedures. A corresponding patent application is currently pending before the US Patent and Trademark Office (USPTO) and was already granted in Japan. “We are very pleased with this new addition to our patent estate in tinnitus, which remains an area of great unmet medical need“, commented Thomas Meyer, Auris Medical’s founder, Chairman and CEO. “NKCC1 represents a new and promising target for tinnitus therapy, particularly because it may allow for oral treatment and thus complement Keyzilen®, our investigational tinnitus drug for intratympanic administration. We intend to develop a proprietary NKCC1 inhibitor through our new subsidiary, Zilentin Ltd., which we recently established in order to bundle our activities and assets within the therapeutic areas of tinnitus and hearing loss.” About Auris Medical Auris Medical is a biopharmaceutical company dedicated to developing therapeutics that address important unmet medical needs in neurotology and central nervous system disorders. The company is focused on the development of intranasal betahistine for the treatment of vertigo (AM-125) and for the treatment of antipsychotic-induced weight gain and somnolence (AM-201). These projects have gone through two Phase 1 trials and entered into proof-of-concept studies in 2019. In addition, Auris Medical has two Phase 3 programs under development: Sonsuvi® (AM-111) for acute inner ear hearing loss and Keyzilen® (AM-101) for acute inner ear tinnitus. The Company was founded in 2003 and is headquartered in Hamilton, Bermuda. The shares of Auris Medical Holding Ltd. trade on the NASDAQ Capital Market under the symbol “EARS.” Forward-looking Statements
Auris Medical Announces Formation of New Subsidiary for Development Projects in Tinnitus and Hearing Loss
American Tinnitus Association and British Tinnitus Association Partner to Spark Innovations in Tinnitus Treatments and Advance Global Discussion About Potential Tinnitus Breakthroughs
Sufficient proof of concept to support future investigation of MDMA as a treatment for tinnitus?
Frequency Therapeutics Provides Business Updates and Reports Third Quarter 2019 Financial Results
Initiated FX-322 Phase 2a clinical study for sensorineural hearing loss
Granted FDA Fast Track designation for FX-322
Completed an $88.6 million initial public offering in October 2019, providing Company runway into 2022
“This has been a tremendously productive period for Frequency as we commenced our Phase 2a study, received Fast Track designation for FX-322, and completed key financings that we believe will enable us to advance our hearing program and further diversify our portfolio as we apply our progenitor cell activation platform in numerous disease areas,” said Frequency Therapeutics Chief Executive Officer David Lucchino. “We have opened all U.S. sites for our Phase 2a study of FX-322 and remain on track to report top-line data in the second half of next year. We believe FX-322 has the potential to be a restorative, disease-modifying treatment for the millions of patients with hearing loss, with the aim of improving hearing function, including speech intelligibility. We also continue to advance our multiple sclerosis development efforts and remain focused on moving our remyelination program into the clinic in the second half of 2021.”
Neuromodulation for Tinnitus Relief: Interview with Neuromod Devices CEO Dr. Ross O’Neill
The cortisol awakening response: could this be an effective measure of tinnitus distress?
Frequency Therapeutics Commences Dosing in its Phase 2a Study of FX-322 for Sensorineural Hearing Loss; FDA Grants FX-322 Fast Track Designation
VIDEO: Susan Shore on Bimodal Stimulation for Tinnitus – #TRI2019 (via TinnitusHub)
When will Neuromod publish the results of their latest clinical trial, Treatment Evaluation of Neuromodulation for Tinnitus – Stage A2 (TENT-A2)?
It looks like we now have an answer…
The data collection and database lock are expected to be completed by February 2020, and the data analysis and manuscript submission are expected to be conducted in autumn of 2020.
The findings of this study will be disseminated to relevant research, clinical, and health services and patient communities through publications in peer-reviewed journals and presentations at scientific and clinical conferences.
The source of this information, published on September 27, 2019:
Conlon B, Hamilton C, Hughes S, Meade E, Hall DA, Vanneste S, Langguth B, Lim HH
Noninvasive Bimodal Neuromodulation for the Treatment of Tinnitus: Protocol for a Second Large-Scale Double-Blind Randomized Clinical Trial to Optimize Stimulation Parameters
JMIR Res Protoc 2019;8(9):e13176
Why the long wait?
The time between manuscript submission and publication is usually a matter of months.
For example, The Proceedings of the National Academy of Sciences (PNAS) website mentions that the average time from submission to online publication for their journal is 5.5 months and the average time from submission to issue publication is 6 months.
The wait time varies depending on the publication, but you get the idea…
Even if Neuromod submits their manuscript in late 2020 – as currently planned – that still means we probably won’t see the actual findings and published article until Q1 2021 or Q2 2021… or maybe later…
So despite all those exciting Hubert Lim videos and teasers, it seems like we are not going to get the TENT-A2 results for another year or more.
(Prove us wrong, Neuromod, prove us wrong!)
Meanwhile, the company continues to prepare for global commercialisation of their Lenire tinnitus treatment.
What do you think? Head on over to TinnitusTalk, r/tinnitus, r/tinnitusresearch, or your favorite tinnitus forum and/or Facebook group and discuss this update.
And remember to subscribe to TinnitusTreatmentReport.com email updates for more exclusive tinnitus treatment-related updates and the latest research. (First newsletter issue coming soon.)
Questions? Comments? Corrections? Email firstname.lastname@example.org and say hello.
Neuromod Successfully Closes €8 Million Capital Raise: proceedswill be used to accelerate ongoing commercialisation of the Company’s Lenire® tinnitus treatment device
A Breakthrough in Understanding Tinnitus: The Entire Hearing System Studied
Possible Link Between Marijuana Use, Tinnitus
Study added to conflicting information on the issue
Some more information about the upcoming presentation and study, Phase 1/2 Hearing Loss Trial of Intratympanic FX322, a Progenitor Cell Activator, has been posted on the AAO-HNSF 2019 conference website.
This information was previously embargoed (fully), but this abstract/preview has just been made public:
Background: Study Objectives: Although most species can regenerate hair cells, hair cell loss in mammals is permanent because the subset of supporting cells that serve as hair cell progenitors during development fail to divide and differentiate on their own. This work showed that two small molecules that now comprise FX322 restore the regenerative potential of mouse and human progenitor cells in vitro and regenerate hair cells when applied to ototoxin damaged mouse tissue. Importantly, a single intratympanic injection of FX322 restores hair cells and auditory function in mice with trauma within one month after treatment. Utilizing small molecules to regenerate hair cells could provide a therapeutic advantage over the complexities and challenges associated with gene and cell therapies. This preclinical body of data supported the start of the first clinical trial of FX322 in patients with sensorineural hearing loss. Methods: The trial was conducted at three private US otolaryngology practices to assess the systemic safety, plasma PK, and effects on otoscopy, audiometry, and word testing of locally-delivered FX322. The trial was double-blinded, placebo-controlled and enrolled 23 patients with medical histories consistent with either noise-induced hearing loss or sudden sensorineural hearing loss which was considered stable (no change ≥10dB at any frequency, ≥6 months, PTA ≤70dB). Patients were randomized to either placebo or FX322 at two different dose volumes, and treatment was given as a single intratympanic dose. Patients were monitored overnight for safety and PK, and returned at months 0.5, 1, 2 and 3 for otoscopy, audiometry and word testing. Results: As of the date of this writing the study remains blinded and final results will be presented at the annual AAO-HNS meeting.
Expect more information on the day of the presentation: September 17, 2019.
For more tinnitus treatment/cure updates, subscribe to the weekly digest/newsletter (first issue will be sent out soon). Also check out Hearing Loss Treatment Report for more treatment-related updates. Questions/Comments/Suggestions – email email@example.com and say hello.
Thank you to Reddit user /u/pandoira for finding this update and bringing it to the attention of the tinnitus and hearing loss community!
The image below shows delivery of FX-322 that turns to a gel in the middle ear. The drug diffuses into the cochlea and is expected to create the greatest concentration of drug in the high frequency region of the cochlea.
Phase 1/2 clinical trial
We conducted a Phase 1/2 clinical trial of FX-322 in which we enrolled 23 adult patients aged 33 to 64 with an established diagnosis of mild to moderately severe stable SNHL, defined as the average pure tone value of 26 to 70 dB at the 500, 1000, 2000 and 4000 Hz frequencies, who had no change of 10 db or more at any frequency for more than six months. Fourteen patients had mild SNHL and nine patients had moderate to moderately severe SNHL. Of the nine moderate to moderately severe patients, six were randomized to FX-322 and three to placebo. In this trial, 15 patients were treated with a single injection of FX-322 and eight patients received placebo. Each patient had a documented medical history consistent with either noise-induced hearing loss, or NIHL, typically from noise exposure at work, or sudden SNHL, or SSNHL, which is characterized as a loss of 30 dB at three adjacent frequencies occurring over a 72-hour period. All patients had stable SNHL, meaning their hearing function at study entry was not significantly different based on a documented audiogram from at least six months prior to the study. Hearing function, specifically speech intelligibility, was assessed using WR and WIN. Hearing loudness was also measured using pure tone audiometry. Patients were randomized to a single injection of FX-322 or placebo administered at one of two different dose volumes (0.05 mL and 0.2 mL) to assess the safety of FX-322 administration and systemic exposure to FX-322. Follow-up visits occurred at 15, 30, 60, and 90 days after injection.
The objectives of the trial were to assess:
the systemic safety of FX-322;
the plasma pharmacokinetic profile to determine the systemic exposure to FX-322; and
the effect of FX-322 on measures of ear health and hearing function.
FX-322 was observed to be well-tolerated in this trial. No serious adverse events were observed, and all treatment-related adverse events were mild, procedure-related, and generally resolved within minutes after dosing. We also observed limited concentrations of the FX-322 components in systemic circulation.
We also performed a post hoc analysis that showed a statistically significant improvement in WR by all FX-322-treated patients versus all placebo patients (p=0.01). A p value, as expressed in the data above, is the probability that the difference between two data sets was due to chance. The smaller the p value, the more likely the differences are not due to chance alone. In general, if the p value is less than or equal to 0.05, the outcome is statistically significant. The data are presented as adjusted mean relative percent change from baseline in the figure below. FX-322 treated patients saw improvements as early as 15 days after treatment that were sustained over 90 days.
We performed an additional post hoc analysis on WIN data. As shown in the figure below, the adjusted mean relative percent change from baseline was assessed at 15, 30, 60, and 90 days after injection, and a trend in improvement was seen in FX-322-treated patients versus placebo. Also, there were non-statistically significant trends in improved WIN scores at Day 90 in the four FX-322, treated patients that had statistically significant and clinically meaningful improvements in WR in the prospective statistical analysis.
We assessed audiometric changes from 250 Hz to 8000 Hz for all patients. Since drug enters closest to the high frequency region, the greatest drug exposure is expected to occur in the high frequency region. While no statistical differences were observed at any frequency when comparing pooled treatment groups, four of the moderate to moderately severe FX-322 patients showed a 10 dB threshold improvement at 8000 Hz at Day 90.
Planned Phase 2a clinical trial
Based on our analysis of the data from our Phase 1/2 clinical trial, we intend to initiate a randomized, double-blind, placebo-controlled, single- and repeat-dose Phase 2a clinical trial of FX-322 at approximately 12 sites in the United States in the fourth quarter of 2019. We plan to enroll approximately 96 adults aged 18 to 65 with stable SNHL. As in the Phase 1/2 clinical trial, patients must have a documented medical history consistent with either stable NIHL or stable SSNHL, with an average range of 26 to 70 dB loss measured by pure tone audiometry across four frequencies.
To explore how a single dose compares to multiple doses of FX-322, we plan to randomize patients to one of four groups, each of which will receive four injections, once per week at weekly intervals starting at the initial visit. Group 1 will receive one injection of FX-322 and three injections of placebo. Group two will receive two injections of FX-322 and two injections of placebo. Group three will receive four injections of FX-322. Group four will receive four injections of placebo. Patients will have follow-up visits two weeks after dosing and then monthly for seven months. The efficacy endpoints of this trial are expected to be WR, WIN, and pure tone audiometry in the range of 250 to 8000 Hz. The exploratory efficacy endpoints are expected to be the Tinnitus Functional Index, the Hearing Handicap Inventory for Adults, and pure tone audiometry in the range of 9000 to 16000 Hz. The selection of the efficacy endpoints in this study build on the learnings from the Phase 1/2 trial,
and we believe will add to our knowledge on the potential ways in which FX-322 may improve hearing function. We expect to report top-line data from this trial in the second half of 2020. We may also conduct clinical research in presbycusis.
Prior to commencing clinical trials, we tested FX-322 in multiple preclinical studies, including in human cells ex vivo and functional hearing tests in mice in vivo. In in vitro testing of isolated human inner ear progenitor cells with the compounds comprising FX-322, we observed the formation of new progenitor cells and their subsequent conversion into hair cells. We also observed translation across species in our in vitro studies of the inner ear progenitor cells from rhesus macaques in which a similar expansion of cell numbers were observed as in the in vitro studies of human cells.
We also conducted ex vivo testing in intact cochlea isolated from mice. To cause hair cell loss, we exposed the cochlea for 16 hours to an aminoglycoside antibiotic that is toxic to hair cells. We then treated the cochlea for 72 hours with the compounds comprising the active agents in FX-322. Aminoglycoside treatment (left panel in the figure below) killed more than 80% of the hair cells in the cochlea (shown in green). By contrast, cochlea treated with the compounds in FX-322 (shown in the middle panel) regenerated hair cells to a near native level, as shown graphically in the right panel.
Restoration of Hair Cells in Mouse Cochlea
We also tested FX-322 in a mouse model of severe noise-induced hearing loss. Following noise exposure, 47 mice were treated with FX-322 and 37 were treated with placebo. Hearing function was measured using auditory brainstem response, or ABR, in which the signal generated by the auditory nerve upon sensing sound is detected by electrodes on the scalp. We performed ABR testing after 24 hours, and measured hearing recovery after 30 days. The figure below shows the percentage of mice treated with FX-322 (shown in orange) or with placebo (shown in blue) that achieved a hearing recovery of at least 10 dB at 20000 Hz, a mid-range
frequency for mice. The improvement observed in the placebo-treated mice was due to recovery of temporary effects not related to hair cell death, which is typical following acute hearing loss.
Hearing Recovery in Mice Treated with FX-322
We have also conducted pharmacokinetic tests in multiple species in which we observed that FX-322 administration achieved therapeutic levels of the active pharmaceutical ingredients in the cochlea.
Auris Medical Announces Formation of Scientific Advisory Board for Tinnitus Programs
Brain Inflammation Identified as Potential Target to Treat Tinnitus
The discovery by UA associate professor of physiology Shaowen Bao and his colleagues could lead to new treatments to silence tinnitus for millions of sufferers.
Frequency will use the proceeds to support the clinical development of FX-322, a regenerative therapeutic for the treatment of sensorineural hearing loss that is moving into a Phase 2a study, and to advance discovery programs in other therapeutic areas using its proprietary Progenitor Cell Activation (PCA) platform.
FACT #1: Some people habituate to their tinnitus.
FACT #2: Some people do not habituate to their tinnitus.
FACT #3: Some people believe that EVERYONE can habituate to their tinnitus.
FACT #4: Some people believe that IT IS YOUR FAULT if you are unable to habituate to your tinnitus… that you CHOOSE not to habituate… and the reason you have not habituated like the others, is because there is a problem with your personality… because you are unwilling to habituate… because you are pretending you cannot habituate… because you are trying to not habituate… because you are lying about your habituation… or because you are depressed or have psychological “issues”…
Yes, it sounds crazy… but some people really do hold these disturbing beliefs. Sadly, you don’t even need to look very far to find evidence of this attitude within the tinnitus community. People arguing over habituation, as if they have all the answers. Alas…
We might not have to worry about these habituation-pushers (enemy NPCs) for much longer. Because more and more researchers are starting to find clues that could soon confirm what many “non-habituated” people in the tinnitus community already know from personal experience: NOT EVERYONE CAN HABITUATE TO THEIR TINNITUS – and, importantly… the cause of this “habituation-proof subtype” of tinnitus (or patient) has nothing to do with the “reasons” mentioned above (which are not only unscientific and lazy, but insulting and destructive).
The real reasons some people do not habituate are almost certainly physiological (i.e. they can be traced back to a physical process, outside of your control and/or independent of your thoughts). What, exactly? We do not know yet. But… it appears that the science is starting to support the obvious: that people who do not habituate are NOT just stubborn or self-sabotaging or defective.
So, if YOU can’t habituate, don’t worry. The science is finally starting to confirm what you already knew. It is NOT your fault and it is NOT “all in your head” or imaginary.
Instead, there is probably a physiological cause. At least, that seems to be the big picture that is emerging from the newest studies. And the most recent of these studies, exploring the cause of habituation-proof tinnitus and/or patients, is from July 12, 2019. The title of the study is Toward An Exploration of Habituating to Tinnitus: Perspectives on Sensory Gating and it is from the the American Academy of Audiology.
Here is a link to this latest habituation-related study on PubMed:
You can read the abstract. The full paper is not yet available (the link to the journal site is appears to be broken or is not yet active).
Here is an excerpt:
The purpose of this study was to compare behavioral aspects of sensory gating in normal and tinnitus participants to search for the reason why some tinnitus participants habituate to their tinnitus but some others do not.[…]
These results suggested that tinnitus associated with behavioral aspects of sensory gating and decompensated tinnitus may be a result of deficient sensory gating.
PMID: 31304914 DOI: 10.3766/jaaa.18038
The next time someone argues about habituation or gives you a hard time, politely refer them to this recent study which explores deficient sensory gating as the reason why some people cannot habituate… or… you can also refer them to another recent study, previously mentioned on this website, which examines The potential role of auditory prediction error in preventing habituation to tinnitus.
And remember… if scientists can prove not all tinnitus patients can habituate… then groups/organizations such as the VA will be “forced” to seek other solutions – for all those patients who cannot be helped by habituation – and this could lead to more resources being put toward finding an ACTUAL cure. You never know!
Astellas picks up Frequency’s regenerative hearing loss med outside U.S. for $80M
Tinnitus experts Susan Shore and Calvin Wu discuss the future of tinnitus research and the approaches that are most likely to provide reliable therapies…
The new paper, titled “Mechanisms of Noise-Induced Tinnitus: Insights from Cellular Studies,” was published in Neuron on July 3, 2019. It is a thorough review of 161 different scientific papers… and the concluding remarks provided by authors Susan Shore and Calvin Wu are insightful and exciting.
Here is a link to the full text:
Studies of single neurons and how ensembles of neurons produce population responses are likely to be the most effective route to unraveling the mechanisms of this elusive disease. To enable us to develop methods to alleviate the bothersome or debilitating symptoms of tinnitus, we need to understand the cellular underlying mechanisms.
Here is the abstract:
Tinnitus, sound perception in the absence of physical stimuli, occurs in 15% of the population and is the top-reported disability for soldiers after combat. Noise overexposure is a major factor associated with tinnitus but does not always lead to tinnitus. Furthermore, people with normal audiograms can get tinnitus. In animal models, equivalent cochlear damage occurs in animals with and without behavioral evidence of tinnitus. But cochlear-nerve-recipient neurons in the brainstem demonstrate distinct, synchronized spontaneous firing patterns only in animals that develop tinnitus, driving activity in central brain regions and ultimately giving rise to phantom perception. Examining tinnitus-specific changes in single-cell populations enables us to begin to distinguish neural changes due to tinnitus from those that are due to hearing loss.
NOTE: The article has a delayed release embargo on PMC until July 2020. However, the full text is now public and online. It was tracked down by TinnitusTreatmentReport.com’s automated research gathering system. To get the latest tinnitus research – without waiting months and months for it to become “public” (or easily found) – remember to sign up for our free weekly email updates. You will receive these weekly email summaries every Saturday, which will be sent out in the coming weeks.
Evolution, Revolution, Stagnation? – Exclusive Insights from #TRI2019
Research Roundup: 20+ field reports from the Tinnitus Research Initiative (TRI) 2019 Conference in Taipei
This new model of tinnitus is NOT directly linked to hearing loss and primary auditory cortex abnormalities… but with a simultaneous premotor ear-eye disturbance…
Could this “disturbed crosstalk between the ear and eye systems” also explain why so many tinnitus patients also suffer from visual snow? Hmmmm…
Here is a link to the full pre-print paper (not yet peer-reviewed):
Tinnitus mechanisms remain poorly understood. Our previous functional MRI (fMRI) studies demonstrated an abnormal hyperactivity in the right parietal operculum 3 (OP3) in acoustic trauma tinnitus and during provoked phantom sound perceptions without hearing loss, which lead us to propose a new model of tinnitus. This new model is not directly linked with hearing loss and primary auditory cortex abnormalities, but with a proprioceptive disturbance related to middle-ear muscles. In the present study, a seed-based resting-state functional MRI method was used to explore the potential abnormal connectivity of this opercular region between an acoustic trauma tinnitus group presenting slight to mild tinnitus and a control group. Primary auditory cortex seeds were also explored because they were thought to be directly involved in tinnitus in most current models. In such a model, hearing loss and tinnitus handicap were confounding factors and were therefore regressed in our analysis. Between-groups comparisons showed a significant specific connectivity between the right OP3 seeds and the potential human homologue of the premotor ear-eye field (H-PEEF) bilaterally and the inferior parietal lobule (IPL) in the tinnitus group. Our findings suggest the existence of a simultaneous premotor ear-eye disturbance in tinnitus that could lift the veil on unexplained subclinical abnormalities in oculomotor tests found in tinnitus patients with normal vestibular responses. The present work confirms the involvement of the OP3 subregion in acoustic trauma tinnitus and provides some new clues to explain its putative mechanisms.
New research from Susan Shore presented at last month’s 4th International Hearing Loss Conference…
Cochlear damage may be necessary but not sufficient to induce tinnitus
While hearing loss is associated with tinnitus, the relationship is not causal as people without audiometric hearing loss can develop tinnitus and not all people with audiometric hearing loss develop tinnitus.
Likewise, in animal models, noise exposures that produce only temporary threshold shifts result in behavioral evidence of tinnitus only in about half of the exposed animals. Following tinnitus-induction using narrow band noise exposures, we have demonstrated that dorsal cochlear nucleus fusiform cells show BF-specific alterations in stimulus-timing dependent plasticity, increased spontaneous synchronization, and increased spontaneous firing rates (SFR) in animals with behavioral evidence of tinnitus [1, 2].
Conversely, animals without plasticity-induced changes in fusiform cells, but equivalent degrees of cochlear damage, did not show evidence of tinnitus. Similarly, bushy cells in ventral cochlear nucleus showed BF-restricted increased SFR and cross-unit synchrony in animals with behavioral evidence of tinnitus but not in those without such behavioral evidence, even though ABR thresholds and suprathreshold wave-1 amplitudes were equivalent , suggesting similar cochlear damage in the two groups. Changes in glutamatergic and cholinergic transmission were also changed in these animals in a tinnitus-specific manner [4, 5].
Conclusions: These results suggest that hearing loss, whether visible or ‘hidden’, is insufficient by itself to produce a tinnitus phenotype. Changes in cochlear output after noise exposure require accompanying plastic changes in recipient neurons in the CNS in order to result in the physiological and behavioral signatures of tinnitus.
References:  C. Wu, D.T. Martel, S.E. Shore, Increased Synchrony and Bursting of Dorsal Cochlear Nucleus Fusiform Cells Correlate with Tinnitus, J Neurosci, 36 (2016) 2068-2073.  K.L. Marks, D.T. Martel, C. Wu, G.J. Basura, L.E. Roberts, K.C. Schvartz-Leyzac, S.E. Shore, Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans, Sci Transl Med, 10 (2018).  D. Martel, S. Shore, Ventral cochlear nucleus bushy cells contribute to enhanced auditory brainstem response amplitudes in tinnitus., ARO, 2019, DOI (2019).  A.N. Heeringa, C. Wu, C. Chung, M. West, D. Martel, L. Liberman, M.C. Liberman, S.E. Shore, Glutamatergic Projections to the Cochlear Nucleus are Redistributed in Tinnitus, Neuroscience, DOI 10.1016/j.neuroscience.2018.09.008(2018).  L. Zhang, C. Wu, D.T. Martel, M. West, M.A. Sutton, S.E. Shore, Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs, Hippocampus, DOI 10.1002/hipo.23058(2018).
This information is from page 17 of the [PDF] International Hearing Loss Conference 2019 Program.
Drug to reduce brain inflammation CURED tinnitus in mice – paving the way towards a pill for humans
Reducing brain inflammation could treat tinnitus and other hearing loss-related disorders
New breakthrough pill could cure tinnitus
Condition : Meniere’s Disease
Interventions : Drug: 200mg SPI-1005 BID; Drug: 400mg SPI-1005 BID; Other: Placebo
Sponsor : Sound Pharmaceuticals, Incorporated
SPI-1005 for the Treatment of Patients With Meniere’s Disease
Mon, 30 Oct 2017 12:00:00 EDT
Latest FX-322 study results… earlier than expected?
The upcoming presentation, “Phase 1/2 Hearing Loss Trial of Intratympanic FX322, a Progenitor Cell Activator,” was previously scheduled for September 18, 2019.
But according to the AAO-HNSF Annual Meeting website, the presentation date has been changed from September 18 to September 17.
Here is the updated schedule and a link to the page where this information can be found:
Title: Phase 1/2 Hearing Loss Trial of Intratympanic FX322, a Progenitor Cell Activator
Session: Late Breaking Scientific Oral Presentations
Location: Ernest N. Morial Convention Center, Room 286/287
Date: Tuesday, Sep 17 8:24 AM
Could the date of the presentation be changed again? It’s possible. But the conference takes place between September 15 – 18, 2019… so, any scheduling changes should still stay within that date range.
Check the front page of this site for more updates OR sign up for free email updates, which will be sent out once-a-week starting June 21. (Note from admin: I’m still setting up the newsletter system, it will be ready soon!)
What’s really going on in the world of tinnitus research? Seven “big picture” insights from the #TRI2019 Conference…
Seven Things I Learned at the #TRI2019 Conference
Lead FX-322 study investigator, Susan King, will be presenting the latest FX-322 clinical trial results publicly, for the first time, this September. She will be joined by her six co-authors – including Will McLean, Co-Founder of Frequency Therapeutics.
The new FX-322 results and supporting data that will be referenced in Susan King’s scientific presentation, “Phase 1/2 Hearing Loss Trial of Intratympanic FX322, a Progenitor Cell Activator,” are not yet public. They have not yet been published. Both abstract and full text are currently “embargoed information” (and unlikely to be available online or in print until mid September, at the earliest).
Where FX-322 is “at” right now…
Last month, on April 9th, Frequency Therapeutics announced in a press release the positive results of their Phase 1/2 safety trial of FX-322. The company also shared its plans to present these very exciting human trial results “at a major otolaryngology meeting in 2019.”
This was great news… but they did not give us any other details. They did not tell us which otolaryngology meeting. They did not give us a date. They did not give us much. Instead, all we got was a hint…
Which is perhaps why so many people have been feeling in the dark about FX-322 recently… and also why so many people are getting hungry for updates.
Well, now we have an update that eliminates some of this looming uncertainty…
UPDATE: The date has been changed from September 18 to September 17. The information in this post, including location, date, and time, have been changed since this post was first published.
Title: Phase 1/2 Hearing Loss Trial of Intratympanic FX322, a Progenitor Cell Activator
Session: Scientific Oral Presentations: Otology/ Neurology
Location: Ernest N. Morial Convention Center, New Orleans Theater A
Date: Wednesday, Sep 18 9:21 AM
The most exciting part?
September 18 and the official release of the study results will act as a trigger for some even bigger updates. For example, the FX-322 Phase 2a clinical trial can only be initiated once the previous part of the study’s results are submitted for review and confirmed. So, we can probably expect yet another announcement about the status of Phase 2a, shortly after this presentation.
That’s all for now.
More information about AAO-HNSF 2019:
September 15 – 18, 2019
New Orleans, LA
About the Meeting:
The AAO-HNSF Annual Meeting & OTO Experience is “the world’s best gathering of otolaryngologists.” Held each fall, the AAO-HNSF Annual Meeting & OTO Experience provides an opportunity for thousands of Academy members, non-member physicians, allied health professionals, administrators, and exhibiting companies to converge for an exhilarating four days.
UPDATE (schedule has been changed):
For exclusive updates about FX-322 and other not-yet-available tinnitus treatments, subscribe to email updates. For a full list of previous FX-322 updates, all on one page, go here: https://www.tinnitustreatmentreport.com/tag/fx-322/
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Is this ancient “flower infusion” a forgotten herbal tinnitus remedy?
Sounds too good to be true, but you never know…
From a recent (April 2019) paper, Ethnobotanical Study of Medicinal Plants Used in Central Macedonia, Greece:
Satureja montana subsp. macedonica, in addition to the common use of the flower infusion for the treatment of flu and cough, is also used in the study area by Pontians informants to relieve tinnitus and improve hearing. Generally, Satureja spp. have been used since ancient times as flavorings for food and for the treatment of various diseases; their essential oils have been documented for antimicrobial, antidiarrheal, fungicidal, and antioxidant activities . However, the specific use for tinnitus treatment and for hearing improvement is particularly unusual and, to our knowledge, has never been previously reported.
Another interesting excerpt:
Despite growing erosion of existing European tradition ethnobotanical knowledge, population groups in this region maintain some exclusive folk remedies such as the use of Cuscuta campestris against bee stings reported only by Dopioi informants and that of Satureja montana subsp. macedonica cited by Pontians to relieve tinnitus and improve hearing. Such local knowledge is culturally significant and can provide information for developing future researches and promoting ethnopharmacological advances.
As exciting as this information may seem, it’s important to remember that it is too early to make any conclusions.
However, despite a lack of concrete evidence, there is something else to keep in mind: this supposed folk remedy was “successful” enough to be passed down, culturally, for generations…
So perhaps it worked for some people, in certain situations. And hopefully now it will be studied further, by scientists. Who knows, maybe it could lead to a new molecule, new discovery, drug candidate, or even human clinical trials.
Except the flower in question, Satureja montana, is already being studied for a variety of other health conditions (example: https://www.ncbi.nlm.nih.gov/pubmed/24868886)… so why can’t tinnitus be next?
MORE INFORMATION about Satureja montana:
… but could “SR Model of Tinnitus Development” someday lead to a potential cure?
This study was published online on April 23, 2019. However, until a few days ago, it was not “public” or indexed online. (A search for the title on PubMed returns no results.)
But now that it has been found, it deserves the tinnitus community’s attention…
Yet another root cause of tinnitus discovered?
According to researchers in Germany:
The brain constantly optimizes information transmission into the hearing system by physiological neuronal processes (stochastic resonance, SR) which can diminish hearing loss. Tinnitus develops as a side product. This hypothesis is supported by animal model data as well as by data from a collective of more than 40.000 patients with and without tinnitus.
More information about this will be posted here soon.
Until then, here is a link to the study:
And here is a link to further reading on stochastic resonance (SR):
A mysterious update related to Neuromod’s neuromodulation device…
Last Tuesday, Neuromod Devices Ltd. quietly updated the official study records of its two active neuromodulation device clinical trials.
The update changed the anticipated Study Completion date from February 2019 to July 2019 – a five month delay.
A similar update occurred back in late December, too. That update also delayed the anticipated Study Completion date for the neuromod device study.
Considering July 2019 is only two months away, this does not appear to be cause for concern.
However, one can’t help but wonder what this means. Without an explanation or comment from Neuromod, this mysterious “delay” could fuel some
This post will be updated if and/or when Neuromod provides an update or clarifies the situation.
Dr. Ross O’Neill, CEO of Neuromod commented: “This is a very exciting time for Neuromod as we move towards commercialisation, supported by encouraging data from our recent clinical trials. I am delighted that industry leaders of the calibre of Deb, Suzanne and Cathal have agreed to join our team. Neuromod is investing in growing our organisation; we have been working tirelessly to ensure that all systems are in place to bring our much-anticipated breakthrough treatment to the large population of people living with tinnitus globally.”
Full video presentation from Dr. Hubert Lim, Chief Scientific Officer of Neuromod Devices, at last month’s American Auditory Society Scientific and Technology Meeting.
The 29-minute video is jam-packed with new details about the much-anticipated Neuromod device (also known as Lenire).
Video: RP308 – Reproducible and Long-Term Efficacy of a New Treatment for Tinnitus Evaluated in over 500 Patients”
UPDATE: May 18, 2019 – The link to the video is broken. It looks like the source file was recently removed or deleted.
UPDATE: This article seems to have been removed from the University of Michigan website. What happened? Was it moved? Deleted? Posted too early? Original URL: https://labblog.uofmhealth.org/body-work/ringing-ears-where-sound-coming-from Here is a screenshot: SOURCE: https://labblog.uofmhealth.org/body-work/ringing-ears-where-sound-coming-from Here is an excerpt:
“By moving the treatment to humans, we were able to also reduce the tinnitus in a randomized, double-blinded crossover study, the first of its kind.”
Susan Shore, Ph.D.
Can you share more about your ongoing research at U-M regarding tinnitus, as well as its impact on patients?
Our treatment, targeted auditory-somatosensory stimulation, was developed directly from basic science studies on guinea pigs, in which we were able to record activity from hundreds of single neurons in the first part of the brain that is connected to the ear, the cochlear nucleus.
These cells, called fusiform cells, showed increased firing rates and they synchronized together in guinea pigs that showed behavioral evidence of tinnitus. Building from our previous research on multisensory stimulation of these neurons, we were able to reduce the spontaneous firing of these neurons, which resulted in reduction of the tinnitus.
This approach uses specially timed sounds and mild electric pulses that are designed to reduce the activity of the circuit, specifically in animals with tinnitus, whose brain circuits differ from the animals without tinnitus.
By moving the treatment to humans, we were able to also reduce the tinnitus in a randomized, double-blinded crossover study, the first of its kind. The promising results led us to run a second trial, which is in process right now. And we hope to have results by the end of 2019. The targeted bimodal treatment was developed here at U-M in the Shore laboratory, located in the Kresge Hearing Research Institute in our Department of Otolaryngology. This is also where the current trial is being conducted. Fortunately, the system behind Tinnitus Treatment Report automatically archives all the pages it links to – for situations just like this. Multiple copies of this article were saved, archived, and converted to .pdf before it was unexpectedly removed from the University of Michigan website.
This exciting information was found in a local news story about Frequency Therapeutics and FX-322 posted last night.
Local company working on treatment to reverse hearing loss
The article appears to have been published online yesterday, and it is
dated “Updated: 7:58 PM EST Mar 1, 2019″…
I have not had a chance to investigate, but I am wondering…
Was this clever plan to fast track FX-322 (if all goes well) by connecting it with dementia and other fast-track-friendly conditions mentioned anywhere else… before yesterday?
Was this real news or recycled news? Either way, it’s exciting to consider…
If all goes well, Frequency Therapeutics plans on asking the FDA to fast track the drug, citing recent studies that link hearing loss to other diseases like depression and dementia.
Can this “loophole” apply to other drugs, not just FX-322? and allow pharma companies to fast track promising tinnitus treatments as long as they are somehow related to “more serious” conditions and risks of withholding the drug (e.g. risk of suicide)? All these questions would certainly make for an eye-opening discussion.
This podium presentation preview was uncovered on the American Academy of Audiology’s AAA 2019 Conference Planner website.
It appears to be a public post (i.e. not a “leak” or “accidental release”), but judging by its view count (33 views as of 02/22/2019 2:40 pm EST), it has not
been heavily publicized or received much attention.
At a glance, this podium abstract doesn’t look much different than the recently-uncovered Neuromod Device study result abstract dated March 2, 2019.
However, there is one small (but significant) detail that is worth pointing out…
Something that offers us insights into the current status of the Neuromod Device and whether or not the company is actively preparing for its public release and distribution to doctors and clinics.
Small abstract, big clues… (take another look)
Top right corner:
The CE stands for Continuing Education. The 0.05 is the number of CE credits this presentation offers attendees.
Think about it.
Hubert Lim, PHD – the Chief Scientific Officer of Neuromod – is traveling across the country… but NOT simply to present and hype up the exciting study results…
Rather, he is on a mission to TEACH audiologists how to “implement this treatment” in their clinics for their tinnitus patients.
Which might have you wondering…
Would he be doing that if Neuromod’s study results were clinically insignificant?
Would he be doing that if the device was not very close to a commercial release?
Would audiologists get CE credits for a presentation about a device that did not work?
Time will tell.
Neuromod Device study results
accidentally posted online or just very hard to find?
This information was discovered within a .pdf document hosted on the American Auditory Society website. The 19-page document is a collection of podium abstracts for the upcoming American Auditory Society Scientific and Technology Meeting (February 28 – March 2, 2019). And one of these abstracts is for the long-awaited Neuromod Device study results.
Interestingly, the web address where this information was found is “public” and indexed by Google (see screenshot). However, for some reason it is post-dated March 2, 2019.
Was this abstract supposed to be public so soon?
Reproducible and Long-Term Efficacy of a New Treatment for Tinnitus
Tinnitus affects ~10-15% of the population. Unfortunately, there are limited treatment options. A new non-invasive neuromodulation device using auditory (sound) and trigeminal nerve (tongue) stimulation has been evaluated in more than 500 tinnitus patients across two randomized and blinded clinical trials. The first study explored the effects of three MBT stimulation settings (PS1, PS2, PS3) that were presented for 12 weeks (~30-60 minutes per day) and evaluated during treatment and up to 12 months posttreatment (326 enrolled patients). Pre-specified primary outcome measures included the Tinnitus Handicap Inventory (THI) and Tinnitus Functional Index (TFI). All three MBT settings resulted in statistically and clinically significant improvements in tinnitus during treatment. Post-treatment, PS1 resulted in long-term improvements lasting 12 months that clinically outperformed the other stimulation settings. The treatment was safe and well-tolerated with a high compliance rate (84%). Encouragingly, the greatest therapeutic effects were observed within the first 6 weeks of treatment, which was repeatable for PS1 in an ongoing second clinical trial in 191 patients. These two clinical trials represent one of the largest clinical trial datasets for tinnitus treatments, demonstrating safe, fast-acting (within 6 weeks) and reproducible therapeutic effects that can last at least 12 months with appropriate stimulation settings.
Professor earns award for tinnitus research
January 25, 2o19
The future of neurostimulation: Smart neuromodulation
A first step in adaptive flexible neuromodulation is the decoding of symptoms, thoughts, memories, actions, perceptions, and so on. Recently, AI using machine learning has been capable of finding an objective signature for symptoms such as pain, tinnitus, tremor, depression,15 but also for memories,16,17 which can even be used for restoring memories and even transplanting them in other animals.18
Frequency Therapeutics Completes $42 Million Series B Financing
>>> original quote from article = Proceeds from the financing will support the advancement of the Company’s clinical candidate, FX-322, for hearing regeneration. Top-line results from an ongoing Phase 1/2 study are expected in the first half of 2019. The financing will also support the continued expansion of Frequency’s pipeline with new therapeutic applications from the Company’s PCA Regeneration platform.
>>> modified quote from article = Top-line results from FX-322 Phase 1/2 study are expected in the first half of 2019
Frequency Therapeutics to Present at the 37th Annual JP Morgan Healthcare Conference
Horizon 2020 backs major push to tackle tinnitus
https://markets.businessinsider.com/news/stocks/sensorion-announces-positive-topline-results-from-seliforant-phase-2a-study-1027808912Sensorion Announces Positive Topline Results From Seliforant Phase 2a Study
Pitt Researchers Awarded $2 Million Grant to Develop Drug for Tinnitus
>>> nov 12 2018, nov 29 ata article
Frequency Therapeutics Completes Enrollment in Single Dose Safety Trial to Evaluate FX-322, a First-in-Class Drug Candidate for Hearing Restoration
WOBURN, Mass.–(BUSINESS WIRE)–Frequency Therapeutics, a clinical stage biotechnology company, today announced the completion of enrollment in the single dose safety trial to evaluate FX-322, a first-in-class drug candidate for hearing restoration from the company’s Progenitor Cell Activation (PCA) Regeneration platform. The randomized, double-blind, placebo-controlled trial is assessing the safety of a single dose of FX-322 given by intratympanic administration in adult patients with stable sensorineural hearing loss (SSHL) who have a medical history consistent with either noise exposure or sudden hearing loss.
Discovery of new neurons in the ear could lead to treatments for tinnitus