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Frequency Therapeutics Highlights Clinical Advancement of FX-322 and Unveils FX-345, a New Potential Restorative Treatment for Hearing Loss

Frequency Therapeutics Highlights Clinical Advancement of FX-322 and Unveils FX-345, a New Potential Restorative Treatment for Hearing Loss
November 9, 2021
https://investors.frequencytx.com/news-releases/news-release-details/frequency-therapeutics-holds-virtual-rd-event-highlighting

Comments from the CEO:
“We will also unveil two new research programs that demonstrate the potential of our progenitor cell activation (PCA) approach. First, we will introduce FX-345, a new hearing restoration candidate designed for greater distribution through the cochlea, potentially enabling the treatment of expanded SNHL patient populations.”

Highlights from the press release, copy+pasted:

“FX-345
Introduction of new SNHL investigational therapeutic program, including a more potent GSK3 inhibitor designed to achieve broader exposure of the cochlea.

Frequency Therapeutics Announces First Subject Dosed in FX-322 Phase 2b Acquired Sensorineural Hearing Loss (SNHL) Study

https://www.businesswire.com/news/home/20211021005166/en/Frequency-Therapeutics-Announces-First-Subject-Dosed-in-FX-322-Phase-2b-Acquired-Sensorineural-Hearing-Loss-SNHL-Study-and-FDA-Agreement-on-Speech-Perception-as-Primary-Endpoint

Frequency Therapeutics Announces First Subject Dosed in FX-322 Phase 2b Acquired Sensorineural Hearing Loss (SNHL) Study and FDA Agreement on Speech Perception as Primary Endpoint

FX-322 in Adults With Acquired Sensorineural Hearing Loss

CATEGORY:
Clinical Trials

TITLE:
FX-322 in Adults With Acquired Sensorineural Hearing Loss

INTERVENTION/TREATMENT:

PHASE:

DESCRIPTION:
Conditions :   Hearing Loss, Sensorineural;   Noise Induced Hearing Loss;   Sudden Hearing Loss

Interventions :   Drug: FX-322;   Drug: Placebo

Sponsor :   Frequency Therapeutics

Recruiting

ID:
NCT05086276

STATUS:

DATE – FIRST POSTED:
Wed, 20 Oct 2021 12:00:00 EDT

DATE – LAST UPDATE POSTED:
10/20/21 06:28AM

DATE – RETRIEVED:
10/20/21 06:28AM

LINK – STUDY HISTORY:
https://clinicaltrials.gov/ct2/history/NCT05086276

LINK – STUDY RECORD:
https://clinicaltrials.gov/ct2/show/NCT05086276

REFERENCE:
Hearing Loss Treatment Report, Urgent Research

Eli Lilly-Backed Audion Therapeutics Initiates Phase 2 Clinical Trial of AUD1001 (LY3056480) in Patients with Sensorineural Hearing Loss

The official record for the study, “A Phase 2 Double Blind, Randomized, Placebo Controlled Trial inVEstigating the Effect and Safety of Several Dosing Regimens of LY3056480 in Patients With STAble Sensorineural Hearing Loss”, was added to ClinicalTrials.gov on September 30, 2021.

The name of this new study is “VESTA”, the name of the drug is “AUD1001” (also known as “LY3056480”), and it is sometimes referred to as the “REGAIN treatment” for hearing loss.

aud1001 study record phase 2 teaser

Official description from the new study record (9/30/2021):

VESTA is a double blinded, randomized, placebo controlled, multi center efficacy phase 2 study comparing three dosing regimens of 250 µg LY3056480. Adult volunteers with stable mild to moderately-severe SNHL will be recruited through Adult Otolaryngology – Head & Neck Surgery Services in the US. Four injections of 250µg LY3056480 or placebo administered trans-tympanically into one ear (worse hearing ear).

Source —link to the study record:

LY3056480 in Patients with Sensorineural Hearing Loss (NCT05061758)
https://clinicaltrials.gov/ct2/show/NCT05061758

More background and context — from Audion’s website:

AUD1001 was shown to be safe and well tolerated, and provided early indications of efficacy in speech in noise, a key clinical outcome parameter. Importantly, the efficacy signals persisted a year after the treatment.

[…]

Audion is preparing for initiation of new clinical trials of AUD1001 for sensorineural hearing loss at multiple sites in Europe and in the US in H2 2021. The planned Phase 2b double blind, placebo controlled trials will be conducted in adults with demonstrated loss of clarity, using a standardized local drug delivery.

Source: https://audiontherapeutics.com/development/

More details about the AUD1001 study:

  • phase 2 study will enroll 135 participants
  • recruitment has NOT started yet
  • three recruitment locations listed so far: Illinois, New York, Virginia
  • company website mentions sites in Europe but the study record says participants will be recruited through sites in the US
  • that does not rule out Europe sites (since the study record could be updated when new sites are added in the future)
  • so, right now there is a slightly confusing inconsistency — but nothing is contradictory or set in stone

As for timeline…

  • Start Date: September 2022
  • Primary Completion Date : September 2024
  • Study Completion Date : March 2025

Keep in mind, these are Estimated dates, and subject to change.

The key date here, for most people, is the September 2022 start date.

As for when RECRUITING will begin…

Not sure yet.

But I will send out an email when the status changes from “Not yet recruiting” to “Recruiting” — as soon as I find out. Nothing to report just yet and no estimates or opinions to share.

If you are not subscribed and want AUD1001 updates, I have a strongly-biased (and very good) recommendation: subscribe to the Hearing Loss Treatment Report email newsletter. Email updates for people who want “early access” to hearing loss treatment updates — like this one about AUD1001… in many cases, before the company has had time to issue a press release! (That is what happened here.) Expect between 1-3 emails per week, on average. Sometimes none. Sometimes four. It depends. But the important thing is, issues are only sent when something exciting and new is happening. No recycled stories or press releases. No blogspam. No advertorials or sneakiness. No spam, no nonsense. Unsubscribe instantly with one click.

More AUD1001 updates to follow… including an update whenever the trial opens its doors and begins recruiting. Which, hypothetically, could be any day now.

A Trial of LY3056480 in Patients With SNLH

CATEGORY:
Clinical Trials

TITLE:
A Trial of LY3056480 in Patients With SNLH

INTERVENTION/TREATMENT:

PHASE:

DESCRIPTION:
Condition :   Sensorineural Hearing Loss

Intervention :   Drug: LY3056480

Sponsor :   Audion Therapeutics BV

Not yet recruiting

ID:
NCT05061758

STATUS:

DATE – FIRST POSTED:
Thu, 30 Sep 2021 12:00:00 EDT

DATE – LAST UPDATE POSTED:
09/30/21 05:28PM

DATE – RETRIEVED:
09/30/21 05:28PM

LINK – STUDY HISTORY:
https://clinicaltrials.gov/ct2/history/NCT05061758

LINK – STUDY RECORD:
https://clinicaltrials.gov/ct2/show/NCT05061758

REFERENCE:
Hearing Loss Treatment Report, Urgent Research

The Hunt for Drugs That Promote Ear Hair Cell Regeneration: Nanjing University researchers use cochlear organoids to identify drugs that can promote the regeneration of hair cells

https://www.technologynetworks.com/drug-discovery/news/treating-hearing-loss-the-hunt-for-drugs-that-promote-hair-cell-regeneration-353641

The Hunt for Drugs That Promote Ear Hair Cell Regeneration

“Nanjing University researchers use cochlear organoids to identify drugs that can promote the regeneration of hair cells”

miR-153 inhibition significantly restores KNCQ4 in cochlea after noise exposure, which attenuates sensorineural hearing loss

CATEGORY:
Research

SCREENSHOT:
miR-153/KCNQ4 axis contributes to noise-induced hearing loss in a mouse model

TITLE:
miR-153/KCNQ4 axis contributes to noise-induced hearing loss in a mouse model

CONTENT:
J Physiol Sci. 2021 Sep 3;71(1):28. doi: 10.1186/s12576-021-00814-0.

ABSTRACT

Damage to the cochlear sensory epithelium is a key contributor to noise-induced sensorineural hearing loss (SNHL). KCNQ4 plays an important role in the cochlear potassium circulation and outer hair cells survival. As miR-153 can target and regulate KCNQ4, we sought to study the role of miR-153 in SNHL. 12-week-old male CBA/J mice were exposed to 2-20 kHz broadband noise at 96 dB SPL to induce temporary threshold shifts and 101 dB SPL to induce permanent threshold shifts. Hearing loss was determined by auditory brainstem responses (ABR). Relative expression of miR-153 and KCNQ4 in mice cochlea were determined by Real-Time quantitative PCR. miR-153 mimics were co-transfected with wild type or mutated KCNQ4 into HEK293 cells. Luciferase reporter assay was used to validate the binding between miR-153 and KCNQ4. AAV-sp-153 was constructed and administrated intra-peritoneally 24- and 2-h prior and immediately after noise exposure to knockdown miR-153. The KCNQ4 is mainly expressed in outer hair cells (OHCs). We showed that the expression of KCNQ4 in mice cochlea was reduced and miR-153 expression was significantly increased after noise exposure compared to control. miR-153 bound to 3’UTR of KNCQ4, and the knockdown of miR-153 with the AAV-sp-153 administration restored KCNQ4 mRNA and protein expression. In addition, the knockdown of miR-153 reduced ABR threshold shifts at 8, 16, and 32 kHz after permanent threshold shifts (PTS) noise exposure. Correspondingly, OHC losses were attenuated with inhibition of miR-153. This study demonstrates that miR-153 inhibition significantly restores KNCQ4 in cochlea after noise exposure, which attenuates SNHL. Our study provides a new potential therapeutic target in the prevention and treatment of SNHL.

PMID:34479475 | DOI:10.1186/s12576-021-00814-0

SOURCE:
The journal of physiological sciences : JPS

PUBLISHER:

PMID:
pubmed:34479475

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:34479475

DOI:
10.1186/s12576-021-00814-0

DATE – PUBLISHED:
Sat, 04 Sep 2021 06:00:00 -0400

DATE – DOI:
2021-09-03T15:08:12Z

DATE – ADDED:
09/04/21 09:14AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/34479475/

LINK – DOI:
https://doi.org/10.1186/s12576-021-00814-0

LINK – PUBLISHER:
https://jps.biomedcentral.com/articles/10.1186/s12576-021-00814-0?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-09-04T13:14:45+00:00, https://www.hearinglosstreatmentreport.com.

The expression of PHB2 in the cochlea: a new target for age-related hearing loss

CATEGORY:
Research

SCREENSHOT:
The expression of PHB2 in the cochlea: possible relation to age-related hearing loss

TITLE:
The expression of PHB2 in the cochlea: possible relation to age-related hearing loss

CONTENT:
Cell Biol Int. 2021 Aug 26. doi: 10.1002/cbin.11693. Online ahead of print.

ABSTRACT

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly, but its mechanism remains unclear. Scaffold protein Prohibitin 2 (PHB2) has been widely involved in aging and neurodegeneration. However, the role of PHB2 in ARHL is undeciphered to date. To investigate the expression pattern and the role of PHB2 in ARHL, we used C57BL/6 mice and HEI-OC1 cell line as models. In our study, we have found PHB2 exists in the cochlea and is expressed in hair cells, spiral ganglion neurons and HEI-OC1 cells. In mice with ARHL, mitophagy is reduced and correspondingly the expression level of PHB2 is decreased. Moreover, after H2 O2 treatment the mitophagy is activated and the PHB2 expression is increased. These findings indicate that PHB2 may exert an important role in ARHL through mitophagy. Findings from this work will be helpful for elucidating the mechanism underlying the ARHL and for providing a new target for ARHL treatment. This article is protected by copyright. All rights reserved.

PMID:34435719 | DOI:10.1002/cbin.11693

SOURCE:
Cell biology international

PUBLISHER:

PMID:
pubmed:34435719

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:34435719

DOI:
10.1002/cbin.11693

DATE – PUBLISHED:
Thu, 26 Aug 2021 06:00:00 -0400

DATE – DOI:
2021-08-26T11:36:01Z

DATE – ADDED:
08/26/21 02:11PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/34435719/

LINK – DOI:
https://doi.org/10.1002/cbin.11693

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/cbin.11693?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-08-26T18:11:08+00:00, https://www.hearinglosstreatmentreport.com.

Downregulation of Cav3.1 T-type Calcium Channel Expression in Age-related Hearing Loss Model

CATEGORY:
Research

SCREENSHOT:
Downregulation of Cav3.1 T-type Calcium Channel Expression in Age-related Hearing Loss Model

TITLE:
Downregulation of Cav3.1 T-type Calcium Channel Expression in Age-related Hearing Loss Model

CONTENT:
Curr Med Sci. 2021 Aug;41(4):680-686. doi: 10.1007/s11596-021-2416-0. Epub 2021 Aug 17.

ABSTRACT

OBJECTIVE: Age-related hearing loss (AHL), characterized by degeneration of cochlea structures, is the most common sensory disorder among the elderly worldwide. The calcium channel is considered to contribute to normal hearing. However, the role of the T-type voltage-activated calcium channel, Cav3.1, remains unclear in AHL. Here, we investigate the age-related change of Cav3.1 expression in the cochlea and D-gal-induced senescent HEI-OC1 cells.

METHODS: Cochleae from C57BL/6 mice at 2 months and 12 months of age were assessed. Senescence in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells was induced by D-gal treatment. The immunofluorescence technique was employed to investigate the distribution of Cav3.1 in vivo and in vitro. Quantitative assessment was achieved by Western blotting and real-time PCR.

RESULTS: In comparison with 2-month-old animals, 12-month old C57BL/6 mice exhibited great loss of hair cells and elevated auditory brainstem threshold. The Cav3.1 was located in hair cells, spiral ganglion cells, lateral walls, and the expression of Cav3.1 protein and mRNA decreased in the aged cochleae. D-gal-induced senescence assay confirmed the down-regulation of Cav3.1 expression in senescent HEI-OC1 cells.

CONCLUSION: Our results show that age-related down-regulated expression of Cav3.1 in the cochleae is associated with AHL and may contribute to the pathogenesis of AHL.

PMID:34403092 | DOI:10.1007/s11596-021-2416-0

SOURCE:
Current medical science

PUBLISHER:

PMID:
pubmed:34403092

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:34403092

DOI:
10.1007/s11596-021-2416-0

DATE – PUBLISHED:
Tue, 17 Aug 2021 06:00:00 -0400

DATE – DOI:
2021-08-17T10:36:41Z

DATE – ADDED:
08/17/21 07:00PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/34403092/

LINK – DOI:
https://doi.org/10.1007/s11596-021-2416-0

LINK – PUBLISHER:
https://link.springer.com/10.1007/s11596-021-2416-0?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-08-17T23:00:52+00:00, https://www.hearinglosstreatmentreport.com.

Sneak preview of AP-001, a novel therapeutic for hearing loss from Anida Pharma

Some early details on AP-001 (also known as neuroprotectin D1 or NPD1), a novel therapeutic currently being studied by Anida Pharma to treat noise-related and age-related hearing loss.

AP-001 anida pharma pipeline hearing loss july 2021 annotated

Background:

Anida Pharma is a private biotech company based in Cambridge, Massachusetts, focused on developing new drugs “to prevent and restore sensory organ dysfunction.”

The company’s lead drug candidate is a compound called “AP-001” and… what makes AP-001 special is that it works on multiple pathways all at once: e.g., “inflammation, cell death and tissue repair, both epithelial and nerve regrowth” — all of which are known to be associated with hearing impairment, to different degrees, in varying contexts.

AP-001 (also known as neuroprotectin D1 or NPD1), it seems, has the potential to treat hearing loss — including noise-related, drug-related, and/or age-related causes.

Rough draft copy of explanation [work-in-progress]:

Worth mentioning: AP-001 is endogenous. In other words, the body makes it naturally. And, even more interesting, is the role it plays…

Basically, AP-001’s normal job is to clean up any messes caused by the body’s immune system. So the body’s immune system recognizes a threat. Attacks said threat. And sometimes there is a mess. Collateral damage. Well, when that happens, the body releases AP-001… which is deployed to fix, repair, restore any destruction caused during the immune response and battle.

You can think of AP-001 as the body’s own cleanup crew… and a function within the body that has evolved as a tool to repair the chaos and damage following a immune attack damage. It is referred to as a “counter-mechanism” in the science section of the Anida Pharma website. I like that.

Anyway, the main reason this counter-mechanism exists is… because the body wants to make sure important functions (such as sight or hearing) are not permanently lost after getting caught up in the crossfire of an immune system battle.

And so, a special mechanism evolved to handle that “messy” repair and cleanup job. Before the damaged system collapsed to a point of no return.

Now, here is how this relates to hearing restoration…

Scientists believe they have discovered a way to harness that “counter-mechanism” and its special “rebuilding” toolset… and extend its purpose beyond that of “clean up crew” in wake of a big immune system battle… and instead deploy it in response to any sort of damage, for various purposes.

So, with respect to hearing loss… the “repair job” could be using AP-001 to fix any sort of trauma or loss… not just an immune warzone… e.g. it could be noise trauma, ototoxicity/drug-induced, or even be used to reverse age-related damage and progression.

The idea here is, this natural “counter-mechanism” (a.k.a. AP-001) might still be effective beyond its original duty (which was limited to immune attack rebuilding)… and applicable to situations where it might not have been released naturally, in great enough volume.

[DRAFT]

Some hearing loss-related tidbits from the official Anida Pharma company website:

“Anida is also working at identifying treatments to restore the hearing in individuals suffering age- and noise-related hearing loss.”

“Anida is a preclinical-stage biopharmaceutical company leveraging the knowledge around the body’s own homeostatic and protective mechanisms to develop targeted therapeutics in the fields of vision and hearing.”

“AP-001, is an endogenous lipid-derived agonistic small molecule from the DHA metabolome.”

Le “annotated Anida Pharma pipeline” snapshot:

AP-001 anida pharma pipeline hearing loss july 2021 annotated
Much wow. Such pipeline.

(Image credit and source of original image: https://www.anidapharma.com/)

This article is a work in progress. [Last updated on 7/25/2021 at 5:09pm EST.] For now, I just wanted to share news of “AP-001” ASAP and add it to the hearing loss treatment radar. (So more people know that it exists.) Also…

Remember to subscribe if you want early access to updates on stuff like this. See link below. (Email subscribers receive links to articles like this one several days before the article is added to the front page of this website.)

AP-001 updates

Sign up for the Hearing Loss Treatment Report email newsletter to get updates on promising new hearing loss drugs on the horizon. It’s free, your information is kept private, you will not receive promotional emails, and you can easily unsubscribe at any time with one click. Expect between 1-2 emails per week, but only if something interesting is happening.

References

Researchers at University of Maryland School of Medicine (UMSOM) launch new online tool to advance medical discoveries to reverse progressive hearing loss

https://www.news-medical.net/news/20210719/New-online-tool-launched-to-accelerate-discoveries-for-reversing-progressive-hearing-loss.aspx

New online tool launched to accelerate discoveries for reversing progressive hearing loss

Researchers at University of Maryland School of Medicine (UMSOM) launch a new tool to advance medical discoveries to reverse progressive hearing loss.

FX-322 in Adults With Severe Sensorineural Hearing Loss

CATEGORY:
Clinical Trials

TITLE:
FX-322 in Adults With Severe Sensorineural Hearing Loss

INTERVENTION/TREATMENT:

PHASE:

DESCRIPTION:
Conditions :   Hearing Loss, Sensorineural;   Noise Induced Hearing Loss;   Sudden Hearing Loss

Interventions :   Drug: FX-322;   Other: Placebo

Sponsor :   Frequency Therapeutics

Recruiting

ID:
NCT04629664

STATUS:

DATE – FIRST POSTED:
Mon, 16 Nov 2020 12:00:00 EST

DATE – LAST UPDATE POSTED:
07/06/21 07:55AM

DATE – RETRIEVED:
07/06/21 07:55AM

LINK – STUDY HISTORY:
https://clinicaltrials.gov/ct2/history/NCT04629664

LINK – STUDY RECORD:
https://clinicaltrials.gov/ct2/show/NCT04629664

REFERENCE:
Hearing Loss Treatment Report, Urgent Research

Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss [Completed]

CATEGORY:
Clinical Trials

TITLE:
Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss

INTERVENTION/TREATMENT:

PHASE:

DESCRIPTION:
Condition :   Sensorineural Hearing Loss

Interventions :   Drug: PIPE-505;   Drug: Diluent alone

Sponsor :   Pipeline Therapeutics, Inc.

Completed

ID:
NCT04462198

STATUS:

DATE – FIRST POSTED:
Wed, 08 Jul 2020 12:00:00 EDT

DATE – LAST UPDATE POSTED:
06/24/21 11:34AM

DATE – RETRIEVED:
06/24/21 11:34AM

LINK – STUDY HISTORY:
https://clinicaltrials.gov/ct2/history/NCT04462198

LINK – STUDY RECORD:
https://clinicaltrials.gov/ct2/show/NCT04462198

REFERENCE:
Hearing Loss Treatment Report, Urgent Research

OTO-413 in Subjects With Speech-in-Noise Hearing Impairment

CATEGORY:
Clinical Trials

TITLE:
OTO-413 in Subjects With Speech-in-Noise Hearing Impairment

INTERVENTION/TREATMENT:

PHASE:

DESCRIPTION:
Condition :   Sensorineural Hearing Loss

Interventions :   Drug: OTO-413;   Drug: Placebo

Sponsor :   Otonomy, Inc.

Recruiting

ID:
NCT04129775

STATUS:

DATE – FIRST POSTED:
Thu, 17 Oct 2019 12:00:00 EDT

DATE – LAST UPDATE POSTED:
06/18/21 05:20PM

DATE – RETRIEVED:
06/18/21 05:20PM

LINK – STUDY HISTORY:
https://clinicaltrials.gov/ct2/history/NCT04129775

LINK – STUDY RECORD:
https://clinicaltrials.gov/ct2/show/NCT04129775

mTOR Signaling in the Inner Ear as Potential Target to Treat Hearing Loss

CATEGORY:
Research

SCREENSHOT:
mTOR Signaling in the Inner Ear as Potential Target to Treat Hearing Loss

TITLE:
mTOR Signaling in the Inner Ear as Potential Target to Treat Hearing Loss

CONTENT:
Int J Mol Sci. 2021 Jun 14;22(12):6368. doi: 10.3390/ijms22126368.

ABSTRACT

Hearing loss affects many people worldwide and occurs often as a result of age, ototoxic drugs and/or excessive noise exposure. With a growing number of elderly people, the number of people suffering from hearing loss will also increase in the future. Despite the high number of affected people, for most patients there is no curative therapy for hearing loss and hearing aids or cochlea implants remain the only option. Important treatment approaches for hearing loss include the development of regenerative therapies or the inhibition of cell death/promotion of cell survival pathways. The mammalian target of rapamycin (mTOR) pathway is a central regulator of cell growth, is involved in cell survival, and has been shown to be implicated in many age-related diseases. In the inner ear, mTOR signaling has also started to gain attention recently. In this review, we will emphasize recent discoveries of mTOR signaling in the inner ear and discuss implications for possible treatments for hearing restoration.

PMID:34198685 | DOI:10.3390/ijms22126368

SOURCE:
International journal of molecular sciences

PUBLISHER:

PMID:
pubmed:34198685

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:34198685

DOI:
10.3390/ijms22126368

DATE – PUBLISHED:
Fri, 02 Jul 2021 06:00:00 -0400

DATE – DOI:
2021-06-15T02:31:04Z

DATE – ADDED:
07/02/21 08:07AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/34198685/

LINK – DOI:
https://doi.org/10.3390/ijms22126368

LINK – PUBLISHER:
https://www.mdpi.com/1422-0067/22/12/6368?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-07-02T12:07:25+00:00, https://www.hearinglosstreatmentreport.com.

KCNQ4 Activators as a Potential Treatment for Hearing Loss

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…

KCNQ4 activators meme hearing loss scorpion

More updates to follow…

How to get KCNQ4 activator updates

  • Join the free email newsletter to get updates related to repurposed drugs targeting KCNQ4 (plus, news about other promising treatments in development for hearing restoration). Expect between 1 and 3 emails per week. But only when something interesting appears on the radar. No spam, no promotional emails, no third parties, and one-click unsubscribe. Privacy respected.

References

Inhalation of Molecular Hydrogen, a Rescue Treatment for Noise-Induced Hearing Loss

CATEGORY:
Research

SCREENSHOT:
Inhalation of Molecular Hydrogen, a Rescue Treatment for Noise-Induced Hearing Loss

TITLE:
Inhalation of Molecular Hydrogen, a Rescue Treatment for Noise-Induced Hearing Loss

CONTENT:
Front Cell Neurosci. 2021 Jun 1;15:658662. doi: 10.3389/fncel.2021.658662. eCollection 2021.

ABSTRACT

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

SOURCE:
Frontiers in cellular neuroscience

PUBLISHER:

PMID:
pubmed:34140880

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:34140880

DOI:
10.3389/fncel.2021.658662

DATE – PUBLISHED:
Fri, 18 Jun 2021 06:00:00 -0400

DATE – DOI:
2021-06-01T05:34:01Z

DATE – ADDED:
06/18/21 01:25PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/34140880/

LINK – DOI:
https://doi.org/10.3389/fncel.2021.658662

LINK – PUBLISHER:
https://www.frontiersin.org/articles/10.3389/fncel.2021.658662/full?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
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

CATEGORY:
Research

SCREENSHOT:
Effects of Insulin-Like Growth Factor (IGF-1) in Patients with Sensorineural Hearing Loss

TITLE:
Effects of Insulin-Like Growth Factor (IGF-1) in Patients with Sensorineural Hearing Loss

CONTENT:
J Int Adv Otol. 2021 May;17(3):207-214. doi: 10.5152/iao.2021.8549.

ABSTRACT

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

SOURCE:
The journal of international advanced otology

PUBLISHER:

PMID:
pubmed:34100744

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:34100744

DOI:
10.5152/iao.2021.8549

DATE – PUBLISHED:
Tue, 08 Jun 2021 06:00:00 -0400

DATE – DOI:
2021-06-04T13:09:30Z

DATE – ADDED:
06/08/21 02:54PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/34100744/

LINK – DOI:
https://doi.org/10.5152/iao.2021.8549

LINK – PUBLISHER:
https://www.advancedotology.org/en/effects-of-insulin-like-growth-factor-igf-1-in-patients-with-sensorineural-hearing-loss-131632?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-06-08T18:54:02+00:00, https://www.hearinglosstreatmentreport.com.

CMS121, a fatty acid synthase inhibitor, reduced hearing loss and increased preservation of ribbon synapses in the mid-range frequencies

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

Background

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.

Methods

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.

Results

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.

Conclusions

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 earned gained.

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:

https://www.sciencedirect.com/science/article/pii/S2213231720308533

That’s all for now. More information to follow.

These unfinished notes on CMS121 are for email subscribers. Sign up here.

FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway

CATEGORY:
Research

SCREENSHOT:
FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway

TITLE:
FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway

CONTENT:
Autophagy. 2021 May 19:1-22. doi: 10.1080/15548627.2021.1916194. Online ahead of print.

ABSTRACT

Presbycusis is the cumulative effect of aging on hearing. Recent studies have shown that common mitochondrial gene deletions are closely related to deafness caused by degenerative changes in the auditory system, and some of these nuclear factors are proposed to participate in the regulation of mitochondrial function. However, the detailed mechanisms involved in age-related degeneration of the auditory systems have not yet been fully elucidated. In this study, we found that FOXG1 plays an important role in the auditory degeneration process through regulation of macroautophagy/autophagy. Inhibition of FOXG1 decreased the autophagy activity and led to the accumulation of reactive oxygen species and subsequent apoptosis of cochlear hair cells. Recent clinical studies have found that aspirin plays important roles in the prevention and treatment of various diseases by regulating autophagy and mitochondria function. In this study, we found that aspirin increased the expression of FOXG1, which further activated autophagy and reduced the production of reactive oxygen species and inhibited apoptosis, and thus promoted the survival of mimetic aging HCs and HC-like OC-1 cells. This study demonstrates the regulatory function of the FOXG1 transcription factor through the autophagy pathway during hair cell degeneration in presbycusis, and it provides a new molecular approach for the treatment of age-related hearing loss.Abbreviations : AHL: age-related hearing loss; baf: bafilomycin A1; CD: common deletion; D-gal: D-galactose; GO: glucose oxidase; HC: hair cells; mtDNA: mitochondrial DNA; RAP: rapamycin; ROS: reactive oxygen species; TMRE: tetramethylrhodamine, ethyl ester.

PMID:34006186 | DOI:10.1080/15548627.2021.1916194

SOURCE:
Autophagy

PUBLISHER:

PMID:
pubmed:34006186

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:34006186

DOI:
10.1080/15548627.2021.1916194

DATE – PUBLISHED:
Wed, 19 May 2021 06:00:00 -0400

DATE – DOI:
2021-05-19T07:55:51Z

DATE – ADDED:
05/19/21 12:19PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/34006186/

LINK – DOI:
https://doi.org/10.1080/15548627.2021.1916194

LINK – PUBLISHER:
https://www.tandfonline.com/doi/full/10.1080/15548627.2021.1916194?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-05-19T16:19:43+00:00, https://www.hearinglosstreatmentreport.com.

Vinpocetine Improves Hearing in Patients with Sensorineural Hearing Loss: Results from a Phase 2 Study

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:

periwinkle photo
“Lesser Periwinkle (Vinca minor)” (Photo credit: Ryan Kaldari)

More information:

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):

Abstract
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:

Journal of Pharmacological Sciences front cover
Journal of Pharmacological Sciences (JPS) is an international open access journal that publishes research on “novel and exciting pharmacological findings.” (Source: ScienceDirect)

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…]:

Two more scientific papers, related to vinpocetine and the auditory system:

That’s all for now.

Michael Sutton

P.S. This article is a DRAFT COPY (work in progress). An early access link is provided to HearingLossTreatmentReport.com email subscribers. Not signed up? It’s free. Subscribe to the newsletter here »

P.P.S. You can email me at michael@urgentresearch.com if you have feedback/comments or just want to say hello.

Discovery of new hearing loss gene in humans [GAS2]

https://medicalxpress.com/news/2021-05-discovery-genetic-loss-illuminates-ear.html

Discovery of new hearing loss gene in humans – the first one known to affect the mechanical properties of inner ear support cells

FGF signaling system for hearing restoration

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.

Dr. Mansour photo
TEAM LEADER a.k.a. Professor Mansour (Photo credit: University of Utah website)

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

Abstract

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.

References

Project #: 1R01DC019127-01

UC-Irvine researchers studying nicotine-like drugs to improve hearing and restore auditory function

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:

  1. examine auditory processing at multiple adult ages;
  2. use similar acoustic stimuli in both species, accounting for species differences in hearing, to target common mechanisms;
  3. 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.

nicotine for hearing improvement grant screenshot
Image source: HHS Tracking Accountability in Government Grants System (TAGGS), 5/1/2021

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
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039769/

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.

References

Exported on 05/01/2021 from the HHS Tracking Accountability in Government Grants System (TAGGS), http://taggs.hhs.gov, Project Number 1R01AG067073-01A1

DB-301: Update on Decibel Therapeutics’ cochlear hair cell regeneration program for hearing loss

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″…

Officially:

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.

Deceibel Therapeutics 2022 cochlear hair cell regeneration program target date

However, we might not need to wait until 2022 for that update, because…

Unofficially:

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”)…

“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:

Possibly DB-301 Decibel Therapeutics

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.)

Confidential?

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.)

But Wait There's More meme
Was the information below included in the presentation on purpose? or accidentally? Hmmm…

Intentional?

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).

References

https://wsw.com/webcast/needham107/deci/2205522

http://www.decibeltx.com/wp-content/uploads/ARO-2021_Inner-Ear-Tropism_Poster-1.pdf

https://www.sec.gov/Archives/edgar/data/1656536/000156459021016167/0001564590-21-016167.txt

http://www.decibeltx.com/wp-content/uploads/Decibel-Corp-Overview-Q320-CITI-conference.pdf

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.

AOK-1 for hearing loss: a new regenerative drug from Hough Ear Institute

Hough Ear Institute is developing a new drug that uses RNA technology to regenerate inner ear hair cells and restore lost hearing.

AOK-1 siRNA therapeutic from Hough Ear Institute slide
The source of this information is a video recording of a meeting between Hough Hearing Institute CEO Dr. Richard Kopke and members of the Central Oklahoma Chapter of the Hearing Loss Association of America. The recording was uploaded to YouTube and shared with the public on April 15, 2021.

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:

AOK-1 injection delivery method photograph

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.)

AOK-1 before and after

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:

References:

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!)

Comments? Questions? Feedback?

Send an email to:

michael@hearinglosstreatmentreport.com

… and say hello!

Primary Neural Degeneration in Noise-Exposed Human Cochleas: Implications for Regenerative Therapeutics

https://www.jneurosci.org/content/early/2021/04/19/JNEUROSCI.3238-20.2021

Research Articles, Systems/Circuits
Primary Neural Degeneration in Noise-Exposed Human Cochleas: Correlations with Outer Hair Cell Loss and Word-Discrimination Scores

Journal of Neuroscience 21 April 2021, JN-RM-3238-20; DOI: https://doi.org/10.1523/JNEUROSCI.3238-20.2021

Abstract
Animal studies suggest that cochlear nerve degeneration precedes sensory cell degeneration in both noise-induced hearing loss (NIHL) and age-related hearing loss (ARHL), producing a hearing impairment that is not reflected in audiometric thresholds. Here, we investigated the histopathology of human ARHL and NIHL by comparing loss of auditory nerve fibers (ANFs), cochlear hair cells and the stria vascularis in a group of 52 cases with noise-exposure history against an age-matched control group. Although strial atrophy increased with age, there was no effect of noise history. Outer hair cell (OHC) loss also increased with age throughout the cochlea but was unaffected by noise history in the low-frequency region (<2 kHz), while greatly exacerbated at high frequencies (≥2 kHz). Inner hair cell (IHC) loss was primarily seen at high frequencies but was unaffected by noise at either low or high frequencies. ANF loss was substantial at all cochlear frequencies and was exacerbated by noise throughout. According to a multivariable regression model, this loss of neural channels contributes to poor word discrimination among those with similar audiometric threshold losses. The histopathological patterns observed also suggest that, whereas the low-frequency OHC loss may be an unavoidable consequence of aging, the high-frequency loss, which produces the classic down-sloping audiogram of ARHL, may be partially because of avoidable ear abuse, even among those without a documented history of acoustic overexposure. Statement of Significance As regenerative therapeutics in sensorineural hearing loss enter clinical trials, it becomes critical to infer which cochlear pathologies are present in addition to hair cell loss. Here, by analyzing human autopsy material, we show that acoustic injury accelerates age-related primary neural degeneration, but not strial degeneration, neither of which can be inferred from audiometric thresholds. It exacerbates outer hair cell (OHC) loss only in the high-frequency half of the cochlea, suggesting that the apical loss is age-related, whereas the basal loss is partially noise induced, and therefore avoidable. Statistical analysis suggests that neural loss helps explain differences in word-recognition ability among individuals with similar audiometric thresholds. The surprising correlation between neural loss and OHC loss in the cochlea’s speech region also implicates neural loss in the well-known decline in word scores as thresholds deteriorate with age. Custom Title Primary Neural Degeneration in Noise-Exposed Human Cochleas: Implications for Regenerative Therapeutics

Rinri Therapeutics Raises £10 million to Advance its Novel Stem Cell Therapy to Reverse Sensorineural Hearing Loss

https://www.prnewswire.com/news-releases/rinri-therapeutics-raises-10-million-from-existing-investors-and-uk-future-fund-to-advance-its-novel-stem-cell-therapy-to-restore-hearing-loss-301271469.html

Rinri Therapeutics Raises £10 million from Existing Investors and UK Future Fund to Advance its Novel Stem Cell Therapy to Restore Hearing Loss

Rinri Therapeutics Raises £10 million to Advance its Novel Stem Cell Therapy to Reverse Sensorineural Hearing Loss

The proceeds will support the development of the Company’s novel stem cell therapy to reverse sensorineural hearing loss (SNHL).

Nox3 might serve as a molecular target for the development of therapeutics for sensorineural hearing loss

CATEGORY:
Research

SCREENSHOT:
Nox3-derived superoxide in cochleae induces sensorineural hearing loss Mechanisms of Nox3-dependent hearing loss

TITLE:
Nox3-derived superoxide in cochleae induces sensorineural hearing loss Mechanisms of Nox3-dependent hearing loss

CONTENT:
J Neurosci. 2021 Apr 13:JN-RM-2672-20. doi: 10.1523/JNEUROSCI.2672-20.2021. Online ahead of print.

ABSTRACT

Reactive oxygen species (ROS) produced by NADPH oxidases (Nox) contribute to the development of different types of sensorineural hearing loss (SNHL), a common impairment in humans with no established treatment. Although the essential role of Nox3 in otoconia biosynthesis and its possible involvement in hearing have been reported in rodents, immunohistological methods targeted at detecting Nox3 expression in inner ear cells reveal ambiguous results. Therefore, the mechanism underlying Nox3 -dependent SNHL remains unclear and warrants further investigation. We generated Nox3-Cre knock-in mice, in which Nox3 was replaced with Cre recombinase (Cre ). Using Nox3-Cre;tdTomato mice of either sex, in which tdTomato is expressed under the control of the Nox3 promoter, we determined Nox3-expressing regions and cell types in the inner ear. Nox3 -expressing cells in the cochlea included various types of supporting cells (SC), outer hair cells (OHC), inner hair cells (IHC), and spiral ganglion neurons (SGN). Nox3 expression increased with cisplatin, age, and noise insults. Moreover, increased Nox3 expression in SC and OHC, especially at the basal turn of the cochlea, played essential roles in ROS-related SNHL. The extent of Nox3 involvement in SNHL follows the following order: cisplatin-induced HL (CIHL) > age-related HL (ARHL) > noise-induced HL (NIHL). Here, on the basis of Nox3-Cre;tdTomato , which can be used as a reporter system (Nox3-Cre+/- ;tdTomato+/+ and Nox3-Cre+/+ ;tdTomato+/+ ), and Nox3 -KO (Nox3-Cre+/+ ;tdTomato+/+ ) mice, we demonstrate that Nox3 inhibition in the cochlea is a promising strategy for ROS-related SNHL, such as CIHL, ARHL, and NIHL.SIGNIFICANCE STATEMENT: We found Nox3-expressing regions and cell-types in the inner ear, especially in the cochlea, using Nox3-Cre;tdTomato mice, a reporter system generated in this study. Nox3 expression increased with cisplatin, age, and noise insults in specific cell-types in the cochlea and resulted in the loss (apoptosis) of outer hair cells. Thus, Nox3 might serve as a molecular target for the development of therapeutics for sensorineural hearing loss, particularly cisplatin-induced, age-related, and noise-induced hearing loss.

PMID:33849947 | DOI:10.1523/JNEUROSCI.2672-20.2021

SOURCE:
The Journal of neuroscience : the official journal of the Society for Neuroscience

PUBLISHER:

PMID:
pubmed:33849947

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33849947

DOI:
10.1523/JNEUROSCI.2672-20.2021

DATE – PUBLISHED:
Wed, 14 Apr 2021 06:00:00 -0400

DATE – DOI:
2021-04-13T18:12:49Z

DATE – ADDED:
04/14/21 09:45AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33849947/

LINK – DOI:
https://doi.org/10.1523/JNEUROSCI.2672-20.2021

LINK – PUBLISHER:
http://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.2672-20.2021?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-04-14T13:45:44+00:00, https://www.hearinglosstreatmentreport.com.

PBM/NAC treatment may reduce hair cell loss associated with noise-induced hearing loss

PBM/NAC treatment may prevent hearing dysfunction caused by NIHL

CATEGORY:
Research

SCREENSHOT:
Combination photobiomodulation/N-acetyl-L-cysteine treatment appears to mitigate hair cell loss associated with noise-induced hearing loss in rats

TITLE:
Combination photobiomodulation/N-acetyl-L-cysteine treatment appears to mitigate hair cell loss associated with noise-induced hearing loss in rats

CONTENT:
Lasers Med Sci. 2021 Apr 6. doi: 10.1007/s10103-021-03304-2. Online ahead of print.

ABSTRACT

Sensorineural hearing loss is an intractable disease. Acoustic overstimulation creates hearing loss; many patients exhibit social and emotional dysfunctions. In a model of noise-induced hearing loss (NIHL), low-level laser photobiomodulation (PBM) at a near-infrared wavelength significantly improved auditory brainstem response (ABR) thresholds. In addition, both N-acetyl-L-cysteine (NAC) and acetyl-L-carnitine (ALCAR) attenuated NIHL, reducing the effects of noise trauma in the cochlea and the central auditory system. Here, we combined PBM with antioxidants to explore hearing threshold recovery and morphological hair cell changes after rats were exposed to noise. The average auditory brainstem response thresholds after PBM/NAC combination treatment were reduced from the apex to the basal turn at all of 8, 16, and 32 kHz compared to the noise-only group. The PBM/NAC combination treated group exhibited intact outer hair cells in all turns, and significantly greater hair cell numbers in the middle and basal cochlear turns, than did controls. Thus, PBM/NAC treatment may prevent hearing dysfunction caused by NIHL.

PMID:33822307 | DOI:10.1007/s10103-021-03304-2

SOURCE:
Lasers in medical science

PUBLISHER:

PMID:
pubmed:33822307

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33822307

DOI:
10.1007/s10103-021-03304-2

DATE – PUBLISHED:
Tue, 06 Apr 2021 06:00:00 -0400

DATE – DOI:
2021-04-06T07:04:00Z

DATE – ADDED:
04/06/21 07:30PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33822307/

LINK – DOI:
https://doi.org/10.1007/s10103-021-03304-2

LINK – PUBLISHER:
http://link.springer.com/10.1007/s10103-021-03304-2?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-04-06T23:30:28+00:00, https://www.hearinglosstreatmentreport.com.

Protective Effects of N(1)-Methylnicotinamide (MNAM) Against Hearing Loss via Moderate Overexpression of Sirtuin 1 Protein

CATEGORY:
Research

SCREENSHOT:
Protective Effects of N(1)-Methylnicotinamide Against High-Fat Diet- and Age-Induced Hearing Loss via Moderate Overexpression of Sirtuin 1 Protein

TITLE:
Protective Effects of N(1)-Methylnicotinamide Against High-Fat Diet- and Age-Induced Hearing Loss via Moderate Overexpression of Sirtuin 1 Protein

CONTENT:
Front Cell Neurosci. 2021 Apr 6;15:634868. doi: 10.3389/fncel.2021.634868. eCollection 2021.

ABSTRACT

Age-related hearing loss (ARHL) is the most common form of hearing loss and the predominant neurodegenerative disease associated with aging. Sirtuin 1 (SIRT1) is associated with the most complex physiological processes, including metabolism, cancer onset, and aging. SIRT1 protein levels are enhanced by the conversion of nicotinamide to N1 -methylnicotinamide (MNAM), independent of its mRNA levels. Moreover, MNAM has implications in increased longevity achieved through its mitohormetic effects. Nicotinamide N-methyltransferase (Nnmt) is an enzyme involved in MNAM metabolism, and its level increases under caloric restriction (CR) conditions. The CR condition has implications in delaying ARHL onset. In this study, we aimed to determine the relationship between diet, hearing function, SIRT1 and SIRT3 expression levels in the inner ear, and cochlear morphology. Mice fed with a high-fat diet (HFD), HFD + 1% MNAM, and low-fat diet (LFD) were monitored for age-related auditory-evoked brainstem responses, and changes in cochlear histology, metabolism, and protein and mRNA expressions were analyzed. Our results revealed that the HFD- and aging-mediated downregulated expression of SIRT1 and SIRT3 promoted hearing loss that was obfuscated by MNAM supplementation-induced upregulated expression of cochlear SIRT1 and SIRT3. Thus, our results suggest that MNAM can be used as a therapeutic agent for preventing ARHL.

PMID:33889076 | PMC:PMC8055820 | DOI:10.3389/fncel.2021.634868

SOURCE:
Frontiers in cellular neuroscience

PUBLISHER:

PMID:
pubmed:33889076

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33889076

DOI:
10.3389/fncel.2021.634868

DATE – PUBLISHED:
Fri, 23 Apr 2021 06:00:00 -0400

DATE – DOI:
2021-04-06T04:35:29Z

DATE – ADDED:
04/23/21 01:45PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33889076/

LINK – DOI:
https://doi.org/10.3389/fncel.2021.634868

LINK – PUBLISHER:
https://www.frontiersin.org/articles/10.3389/fncel.2021.634868/full?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-04-23T17:45:47+00:00, https://www.hearinglosstreatmentreport.com.

NLRP3 inhibitors such as Oridonin may provide new treatment strategy for noise-induced hearing loss

Some research that appeared on our radar recently: “Oridonin ameliorates noise-induced hearing loss by blocking NLRP3 – NEK7 mediated inflammasome activation” (March 23, 2021).

Link to the paper:

https://www.sciencedirect.com/science/article/pii/S1567576921002125

Excerpt:

Here, we further determined that treatment with oridonin could indeed interrupt the interaction between NLRP3 and NEK7 as well as inhibit the downstream inflammasome activation in mouse cochleae after noise exposure. Furthermore, we tested anakinra, another inflammatory inhibitor, and it was shown to partially alleviate the degree of hearing impairment in some frequencies in an NIHL mouse model. These discoveries suggest that inhibiting NLRP3 inflammasomes and the downstream signaling pathway may provide a new strategy for the clinical treatment of NIHL.

see it's simple toy story meme hearing loss oridoninWhat does that mean?

Here is an extremely loose – but simple – explanation of what this means:

  • inflammation is involved in noise-induced hearing loss (NIHL)
  • we aren’t sure how, exactly
  • but it seems that… sometimes… inflammation can go way too far
  • which might actually make things worse, or interfere with healing
  • this could be what happens in the ear after acoustic trauma
  • we aren’t sure about that either
  • but according to this theory…
  • maybe a drug that keeps the inflammation process from going way too far…
  • … might also help with the healing process and prevent further damage
  • (by making sure inflammation does not get carried away)
  • this might apply in the context of noise-induced hearing loss
  • Oridonin, anakinra are two drugs worth studying for this
  • but we aren’t sure… yet

Now, for those of you who prefer the nitty gritty details… diving deep into the science… and the technical side of things…

Here is some further reading about Oridonin – “a covalent NLRP3 inhibitor with strong anti-inflammasome activity” – from Nature:

https://www.nature.com/articles/s41467-018-04947-6

From that paper:

Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases.

Hmmm…

(I wonder if it has anything to do with osteoclasts…)

That’s all for now.

Estimated PIPE-505 Phase 2a Study Completion Date: June 12, 2021

Short but sweet update:

We now have an estimated completion date for the PIPE-505 phase 2a clinical trial: June 12, 2021.

Details below:

  • The PIPE-505 study record was updated on March 29, 2021.
  • The study completion date was changed from March 2021 [Anticipated] to June 2021 [Anticipated].
  • The June 12, 2021 date [Estimated] was calculated using information found within the study record and its history of changes, including: a) the submission date on which the Study Status was changed from “Recruiting” to “Active, not recruiting” and, b) the maximum follow-up Time Frame (“3 months after drug administration”) as detailed in the Outcome Measures section.
  • For a more conservative completion date, replace the last submitted update to Study Status date with the more recent last submitted update date of March 26, 2021. This gives us June 24, 2021.
  • Taken together, we are looking at a range of June 12 – June 24, with June 12th as the one to mark on your calendar.

PIPE-505 phase 2 completion date

Source: History of Changes for Study: NCT04462198 (Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss)

That’s all for now.

We will probably have the next PIPE-505 update for you before June 15th (and/or whenever Pipeline Therapeutics makes an announcement).

For ongoing PIPE-505 updates and news of other upcoming hearing loss treatments, sign up for the free email newsletter. No spam, no promotional emails, privacy respected. Between 1-3 emails per week (but only when something interesting is happening).

BREAKING: CGF166 Clinical Trial Results Posted Online…

CGF166 update: Results from the phase 1/2 study of the hearing loss drug are now available.

Developing story…

CGF166 has results clinical trial update

Two days ago, on March 30, 2021, the official study record of CGF166 was updated on ClinicalTrials.gov.

This update was not accompanied by a press release from Novartis nor any media coverage.

However, this “surprise” update had two important words: has results.

An unexpected update

These results came out of nowhere…

For anyone learning about CGF166 for the first time, here is some quick background info on the “mysterious” Novartis gene therapy drug candidate for hearing loss:

A Case Study: Using Regenerative Medicine to Treat Hearing Loss

In 1999, scientists singled out a gene called atonal as a “master switch” for turning on the growth of inner ear hair cells, which pick up sound waves and translate them into electrical signals in the brain. Humans are born with hair cells, but the atonal switch flips off at birth. Any subsequent damage to hair cells is permanent.

In collaboration with a biotech company, GenVec Inc, NIBR researchers have developed an experimental gene therapy called CGF166 to restore hearing function by regenerating hair cells. It consists of a viral vector carrying the atonal gene. The vector has been altered with the aim of making it harmless and is injected directly into the inner ear. CGF166 is now being tested in a limited number of patients with severe-to-profound hearing loss.

SOURCE: an old brochure from the Novartis Institute for Biological Research (NIBR), circa 2016.

Sounds promising, right?

Absolutely.

But that material was written 5 years ago and… since then – aside from the early buzz and media coverage on this holy grail treatment – CGF166 updates have been incredibly rare.

In fact, before today… the last credible update we got on CGF166 was from over a year ago when, on February 21, 2020, BioCentury pointed out that Novartis had “yet to publicly report data from its Phase I/II trial of gene therapy CGF166.”

SOURCE: Regenerative medicine for hearing loss makes quiet progress, BioCentury, https://www.biocentury.com/article/304491, dated February 21, 2020.

Well, now it looks like they (quietly) have.

The results were uploaded to the study record of the phase I/II clinical trial. Here is the official description:

The goal of the study was to evaluate the safety, tolerability, and the potential ability of CGF166 delivered through IL-infusion to improve hearing. CGF166 is a recombinant adenovirus 5 (Ad5) vector containing a cDNA encoding the human Atonal transcription factor (Hath1).

This study evaluated the safety, tolerability, and potential efficacy of CGF166 and the associated delivery procedures in patients with severe-to-profound unilateral or bilateral hearing loss. Eligible patients were required to have documented, non-fluctuating hearing loss.

SOURCE: https://clinicaltrials.gov/ct2/show/NCT02132130, last updated March 30, 2021.

CGF166 study results: Part 1

These results do not show all the data and numbers, but we expect to post a follow-up once we have some experts review them.

Here is the direct link to the study results that were uploaded on March 30, 2021: ClinicalTrials.gov Identifier: NCT02132130 – Study Results

It’s important to keep in mind that these results are NOT the same thing as an announcement or press release from the company. For that reason, there is no accompanying commentary or explanation of what these results mean.

CGF166 results sneak preview confusion emojiThis can be frustrating, but here at Hearing Loss Treatment Report we are currently working on a follow-up post that will provide a clear idea of what these numbers mean for people with hearing loss.

This is a developing story…

I wish we had more for you.

This is all we have, for now.

We will continue to monitor what is happening with CGF166 and post an update as soon as we know more. (The best way to get updates is by subscribing to our email newsletter – which we’ll be sending out very soon!)

cgf166 trial results meme

For now, we decided to share the link to these “raw” results because we believe in sharing early and sharing often. Information ASAP. Before the official press releases, before company Twitter announcements, before the media outlets, before before before.

And so, for that reason, we didn’t want to sit and wait on this long-awaited study result update just so we could organize it into a neatly-wrapped package with in-depth commentary.

That’s not our style.

“First”

The reason we believe in this post-first-question-later approach is because an increasingly large number of patients, organizations, and industry professionals use this site as a shortcut to the very latest hearing loss treatment updates.

Think of this site like a secret source of some of the fastest, earliest updates in the world of hearing loss drug development. And it’s meant to help inform people in situations like this: where this CGF166 phase I/II results story was missed, ignored, or simply too early (and thus unknown) to the mainstream media.

Which is also why you might want to subscribe to our email updates list… so you can get as-fast-as-we-can-find-them updates on experimental hearing restoration drugs and milestones… plus, sneak previews of what potential “cures” are really around the corner in 2021, 2022, and beyond…

But it’s not for everyone.

Questions? Comments? Corrections? Feedback:

Send an email to michael@urgentresearch.com and say hello.

Protective effects of vitamins/antioxidants on occupational noise-induced hearing loss: A systematic review

CATEGORY:
Research

SCREENSHOT:
Protective effects of vitamins/antioxidants on occupational noise-induced hearing loss: A systematic review

TITLE:
Protective effects of vitamins/antioxidants on occupational noise-induced hearing loss: A systematic review

CONTENT:
J Occup Health. 2021 Jan;63(1):e12217. doi: 10.1002/1348-9585.12217.

ABSTRACT

OBJECTIVES: Occupational noise-induced hearing loss (NIHL) due to industrial, military, and other job -related noise exposure can cause harmful health issues to occupied workers, but may also be potentially preventable. Vitamins/antioxidant have been studied as therapeutic strategies to prevent and/or delay the risks of human diseases as well as NIHL .So, this study was conducted to systematically review the protective effects of vitamins/antioxidants on occupational NIHL.

METHODS: Online databases including PubMed/Medline, Scopus, Web of Science, EMBASE, Science Direct, and Google Scholar were systematically searched up to 12 January 2021. Based on 6336 potentially relevant records identified through the initial search in the databases, 12 full-text publications were retrieved, one of which can be viewed as two separate trials, because it has studied the effects of two different antioxidants (ginseng and NAC) on NIHL, separately.

RESULTS: A review of the studies shows that vitamin B12, folic acid, and N-acetylcysteine (NAC) have a considerable protective effect on NIHL. However, these protective effects are not yet specified in different frequencies. The findings regarding the protective effects of other antioxidants are inconsistent in this field.

CONCLUSION: Vitamin B12, folic acid, and NAC may have a protective effect as an antioxidant on reducing occupational hearing loss. For a conclusive evidence of vitamin/antioxidant protective therapies, future studies with precise criteria for noise exposure and similar outcome parameters are required.

PMID:33788342 | DOI:10.1002/1348-9585.12217

SOURCE:
Journal of occupational health

PUBLISHER:

PMID:
pubmed:33788342

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33788342

DOI:
10.1002/1348-9585.12217

DATE – PUBLISHED:
Wed, 31 Mar 2021 06:00:00 -0400

DATE – DOI:
2021-03-31T14:18:59Z

DATE – ADDED:
03/31/21 07:53PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33788342/

LINK – DOI:
https://doi.org/10.1002/1348-9585.12217

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/1348-9585.12217?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-31T23:53:37+00:00, https://www.hearinglosstreatmentreport.com.

FX-322 in Sensorineural Hearing Loss [Completed]

CATEGORY:
Clinical Trials

TITLE:
FX-322 in Sensorineural Hearing Loss

INTERVENTION/TREATMENT:

PHASE:

DESCRIPTION:
Condition :   Sensorineural Hearing Loss

Interventions :   Drug: FX-322;   Drug: Placebo

Sponsor :   Frequency Therapeutics

Completed

ID:
NCT03616223

STATUS:

DATE – FIRST POSTED:
Mon, 06 Aug 2018 12:00:00 EDT

DATE – LAST UPDATE POSTED:
03/30/21 06:51AM

DATE – RETRIEVED:
03/30/21 06:51AM

LINK – STUDY HISTORY:
https://clinicaltrials.gov/ct2/history/NCT03616223

LINK – STUDY RECORD:
https://clinicaltrials.gov/ct2/show/NCT03616223

Transcription Factor Reprogramming in the Inner Ear: Turning on Cell Fate Switches to Regenerate Sensory Hair Cells

https://www.frontiersin.org/articles/10.3389/fncel.2021.660748/full

Front. Cell. Neurosci., 29 March 2021 | https://doi.org/10.3389/fncel.2021.660748
Transcription Factor Reprogramming in the Inner Ear: Turning on Cell Fate Switches to Regenerate Sensory Hair Cells

Abstract

Non-mammalian vertebrates can restore their auditory and vestibular hair cells naturally by triggering the regeneration of adjacent supporting cells. The transcription factor ATOH1 is a key regulator of hair cell development and regeneration in the inner ear. Following the death of hair cells, supporting cells upregulate ATOH1 and give rise to new hair cells. However, in the mature mammalian cochlea, such natural regeneration of hair cells is largely absent. Transcription factor reprogramming has been used in many tissues to convert one cell type into another, with the long-term hope of achieving tissue regeneration. Reprogramming transcription factors work by altering the transcriptomic and epigenetic landscapes in a target cell, resulting in a fate change to the desired cell type. Several studies have shown that ATOH1 is capable of reprogramming cochlear non-sensory tissue into cells resembling hair cells in young animals. However, the reprogramming ability of ATOH1 is lost with age, implying that the potency of individual hair cell-specific transcription factors may be reduced or lost over time by mechanisms that are still not clear. To circumvent this, combinations of key hair cell transcription factors have been used to promote hair cell regeneration in older animals. In this review, we summarize recent findings that have identified and studied these reprogramming factor combinations for hair cell regeneration. Finally, we discuss the important questions that emerge from these findings, particularly the feasibility of therapeutic strategies using reprogramming factors to restore human hearing in the future.

Congenital Deafness and Recent Advances Towards Restoring Hearing Loss

CATEGORY:
Research

SCREENSHOT:
Congenital Deafness and Recent Advances Towards Restoring Hearing Loss

TITLE:
Congenital Deafness and Recent Advances Towards Restoring Hearing Loss

CONTENT:
Curr Protoc. 2021 Mar;1(3):e76. doi: 10.1002/cpz1.76.

ABSTRACT

Congenital hearing loss is the most common birth defect, estimated to affect 2-3 in every 1000 births. Currently there is no cure for hearing loss. Treatment options are limited to hearing aids for mild and moderate cases, and cochlear implants for severe and profound hearing loss. Here we provide a literature overview of the environmental and genetic causes of congenital hearing loss, common animal models and methods used for hearing research, as well as recent advances towards developing therapies to treat congenital deafness. © 2021 The Authors.

PMID:33780161 | DOI:10.1002/cpz1.76

SOURCE:
Current protocols

PUBLISHER:

PMID:
pubmed:33780161

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33780161

DOI:
10.1002/cpz1.76

DATE – PUBLISHED:
Mon, 29 Mar 2021 06:00:00 -0400

DATE – DOI:
2021-03-29T13:07:03Z

DATE – ADDED:
03/30/21 12:08AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33780161/

LINK – DOI:
https://doi.org/10.1002/cpz1.76

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/cpz1.76?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-30T04:08:44+00:00, https://www.hearinglosstreatmentreport.com.

HLAA to Hold Patient-Focused Drug Development Webinar for People and Families Living with Sensorineural Hearing Loss (April 8)

HLAA Webinar: Externally-Led Patient-Focused Drug Development Meeting for People and Families Living with Sensorineural Hearing Loss

hlaa-pfdd

This one-hour webinar will provide an overview of the FDA drug development process as well as the value of Patient-Focused Drug Development (PFDD) meetings. We hope this webinar will spike your interest in being part of this important virtual meeting for the hearing loss community taking place on Tuesday, May 25, 2021.

HLAA to Hold Patient-Focused Drug Development Webinar and Meeting

Externally-Led Patient-Focused Drug Development Meeting for People and Families Living with Sensorineural Hearing Loss

Oridonin ameliorates noise-induced hearing loss by blocking NLRP3 – NEK7 mediated inflammasome activation

CATEGORY:
Research

SCREENSHOT:
Oridonin ameliorates noise-induced hearing loss by blocking NLRP3 - NEK7 mediated inflammasome activation

TITLE:
Oridonin ameliorates noise-induced hearing loss by blocking NLRP3 – NEK7 mediated inflammasome activation

CONTENT:
Int Immunopharmacol. 2021 Mar 23;95:107576. doi: 10.1016/j.intimp.2021.107576. Online ahead of print.

ABSTRACT

Inflammation is involved in noise-induced hearing loss (NIHL), but the mechanism is still unknown. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which triggers the inflammatory cascade, has been implicated in several inflammatory diseases in response to oxidative stress. However, whether the NLRP3 inflammasome is a key factor for permanent NIHL is still unknown. In this study, quantitative real-time polymerase chain reaction (qPCR), western blot, and enzyme-linked immunosorbent assays (ELISAs) demonstrated that the expression levels of activated caspase-1, interleukin (IL)-1β, IL-18, and NLRP3 were significantly increased in the cochleae of mice exposed to broadband noise (120 dB) for 4 h, compared with the control group. These results indicate that the activation of inflammasomes in the cochleae of mice during the pathological process of NIHL as well as NLRP3, a sensor protein of reactive oxygen species (ROS), may be key factors for inflammasome assembly and subsequent inflammation in cochleae. Moreover, many recent studies have revealed that NEK7 is an important component and regulator of NLRP3 inflammasomes by interacting with NLRP3 directly and that these interactions can be interrupted by oridonin. Here, we further determined that treatment with oridonin could indeed interrupt the interaction between NLRP3 and NEK7 as well as inhibit the downstream inflammasome activation in mouse cochleae after noise exposure. Furthermore, we tested anakinra, another inflammatory inhibitor, and it was shown to partially alleviate the degree of hearing impairment in some frequencies in an NIHL mouse model. These discoveries suggest that inhibiting NLRP3 inflammasomes and the downstream signaling pathway may provide a new strategy for the clinical treatment of NIHL.

PMID:33770730 | DOI:10.1016/j.intimp.2021.107576

SOURCE:
International immunopharmacology

PUBLISHER:

PMID:
pubmed:33770730

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33770730

DOI:
10.1016/j.intimp.2021.107576

DATE – PUBLISHED:
Fri, 26 Mar 2021 06:00:00 -0400

DATE – DOI:
2021-03-23T12:47:43Z

DATE – ADDED:
03/27/21 10:05AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33770730/

LINK – DOI:
https://doi.org/10.1016/j.intimp.2021.107576

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S1567576921002125?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-27T14:05:04+00:00, https://www.hearinglosstreatmentreport.com.

Frequency Therapeutics Releases New Data from Two FX-322 Clinical Studies

https://www.businesswire.com/news/home/20210323005208/en/Frequency-Therapeutics-Releases-New-Data-from-Two-FX-322-Clinical-Studies-Plans-to-Advance-Single-Dose-Regimen

Frequency Therapeutics Releases New Data from Two FX-322 Clinical Studies; Plans to Advance Single-Dose Regimen
Interim FX-322 Phase 2a Results Show Four Injection Schedule Had No Discernible Hearing Benefit

Separate FX-322 Phase 1b Study Confirms Hearing Improvement from Single Injection

Conference call at 8:30am ET today

Prevention of acquired sensorineural hearing loss by in vivo Htra2 gene editing

CATEGORY:
Research

SCREENSHOT:
Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing

TITLE:
Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing

CONTENT:
Genome Biol. 2021 Mar 22;22(1):86. doi: 10.1186/s13059-021-02311-4.

ABSTRACT

BACKGROUND: Aging, noise, infection, and ototoxic drugs are the major causes of human acquired sensorineural hearing loss, but treatment options are limited. CRISPR/Cas9 technology has tremendous potential to become a new therapeutic modality for acquired non-inherited sensorineural hearing loss. Here, we develop CRISPR/Cas9 strategies to prevent aminoglycoside-induced deafness, a common type of acquired non-inherited sensorineural hearing loss, via disrupting the Htra2 gene in the inner ear which is involved in apoptosis but has not been investigated in cochlear hair cell protection.

RESULTS: The results indicate that adeno-associated virus (AAV)-mediated delivery of CRISPR/SpCas9 system ameliorates neomycin-induced apoptosis, promotes hair cell survival, and significantly improves hearing function in neomycin-treated mice. The protective effect of the AAV-CRISPR/Cas9 system in vivo is sustained up to 8 weeks after neomycin exposure. For more efficient delivery of the whole CRISPR/Cas9 system, we also explore the AAV-CRISPR/SaCas9 system to prevent neomycin-induced deafness. The in vivo editing efficiency of the SaCas9 system is 1.73% on average. We observed significant improvement in auditory brainstem response thresholds in the injected ears compared with the non-injected ears. At 4 weeks after neomycin exposure, the protective effect of the AAV-CRISPR/SaCas9 system is still obvious, with the improvement in auditory brainstem response threshold up to 50 dB at 8 kHz.

CONCLUSIONS: These findings demonstrate the safe and effective prevention of aminoglycoside-induced deafness via Htra2 gene editing and support further development of the CRISPR/Cas9 technology in the treatment of non-inherited hearing loss as well as other non-inherited diseases.

PMID:33752742 | DOI:10.1186/s13059-021-02311-4

SOURCE:
Genome biology

PUBLISHER:

PMID:
pubmed:33752742

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33752742

DOI:
10.1186/s13059-021-02311-4

DATE – PUBLISHED:
Tue, 23 Mar 2021 06:00:00 -0400

DATE – DOI:
2021-03-22T09:13:12Z

DATE – ADDED:
03/23/21 07:24AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33752742/

LINK – DOI:
https://doi.org/10.1186/s13059-021-02311-4

LINK – PUBLISHER:
https://genomebiology.biomedcentral.com/articles/10.1186/s13059-021-02311-4?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-23T11:24:13+00:00, https://www.hearinglosstreatmentreport.com.

SCN11A gene deletion causes sensorineural hearing loss by impairing the ribbon synapses and auditory nerves

CATEGORY:
Research

SCREENSHOT:
SCN11A gene deletion causes sensorineural hearing loss by impairing the ribbon synapses and auditory nerves

TITLE:
SCN11A gene deletion causes sensorineural hearing loss by impairing the ribbon synapses and auditory nerves

CONTENT:
BMC Neurosci. 2021 Mar 22;22(1):18. doi: 10.1186/s12868-021-00613-8.

ABSTRACT

BACKGROUND: The SCN11A gene, encoded Nav1.9 TTX resistant sodium channels, is a main effector in peripheral inflammation related pain in nociceptive neurons. The role of SCN11A gene in the auditory system has not been well characterized. We therefore examined the expression of SCN11A in the murine cochlea, the morphological and physiological features of Nav1.9 knockout (KO) ICR mice.

RESULTS: Nav1.9 expression was found in the primary afferent endings beneath the inner hair cells (IHCs). The relative quantitative expression of Nav1.9 mRNA in modiolus of wild-type (WT) mice remains unchanged from P0 to P60. The number of presynaptic CtBP2 puncta in Nav1.9 KO mice was significantly lower than WT. In addition, the number of SGNs in Nav1.9 KO mice was also less than WT in the basal turn, but not in the apical and middle turns. There was no lesion in the somas and stereocilia of hair cells in Nav1.9 KO mice. Furthermore, Nav1.9 KO mice showed higher and progressive elevated ABR threshold at 16 kHz, and a significant increase in CAP thresholds.

CONCLUSIONS: These data suggest a role of Nav1.9 in regulating the function of ribbon synapses and the auditory nerves. The impairment induced by Nav1.9 gene deletion mimics the characters of cochlear synaptopathy.

PMID:33752606 | DOI:10.1186/s12868-021-00613-8

SOURCE:
BMC neuroscience

PUBLISHER:

PMID:
pubmed:33752606

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33752606

DOI:
10.1186/s12868-021-00613-8

DATE – PUBLISHED:
Tue, 23 Mar 2021 06:00:00 -0400

DATE – DOI:
2021-03-22T13:05:35Z

DATE – ADDED:
03/23/21 08:24AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33752606/

LINK – DOI:
https://doi.org/10.1186/s12868-021-00613-8

LINK – PUBLISHER:
https://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-021-00613-8?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-23T12:24:36+00:00, https://www.hearinglosstreatmentreport.com.

Endogenous Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Plays a Protective Effect Against Noise-Induced Hearing Loss

CATEGORY:
Research

SCREENSHOT:
Endogenous Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Plays a Protective Effect Against Noise-Induced Hearing Loss

TITLE:
Endogenous Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Plays a Protective Effect Against Noise-Induced Hearing Loss

CONTENT:
Front Cell Neurosci. 2021 Mar 22;15:658990. doi: 10.3389/fncel.2021.658990. eCollection 2021.

ABSTRACT

Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal polypeptide (VIP)-the secretin-glucagon family of neuropeptides. They act through two classes of receptors: PACAP type 1 (PAC1) and type 2 (VPAC1 and VPAC2). Among their pleiotropic effects throughout the body, PACAP functions as neuromodulators and neuroprotectors, rescuing neurons from apoptosis, mostly through the PAC1 receptor. To explore the potential protective effect of endogenous PACAP against Noise-induced hearing loss (NIHL), we used a knockout mouse model lacking PAC1 receptor expression (PACR1-/- ) and a transgenic humanized mouse model expressing the human PAC1 receptor (TgHPAC1R). Based on complementary approaches combining electrophysiological, histochemical, and molecular biological evaluations, we show PAC1R expression in spiral ganglion neurons and in cochlear apical cells of the organ of Corti. Wild-type (WT), PAC1R-/- , and TgHPAC1R mice exhibit similar auditory thresholds. For most of the frequencies tested after acute noise damage, however, PAC1R-/- mice showed a larger elevation of the auditory threshold than did their WT counterparts. By contrast, in a transgene copy number-dependent fashion, TgHPAC1R mice showed smaller noise-induced elevations of auditory thresholds compared to their WT counterparts. Together, these findings suggest that PACAP could be a candidate for endogenous protection against noise-induced hearing loss.

PMID:33828461 | PMC:PMC8019930 | DOI:10.3389/fncel.2021.658990

SOURCE:
Frontiers in cellular neuroscience

PUBLISHER:

PMID:
pubmed:33828461

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33828461

DOI:
10.3389/fncel.2021.658990

DATE – PUBLISHED:
Thu, 08 Apr 2021 06:00:00 -0400

DATE – DOI:
2021-03-22T06:42:56Z

DATE – ADDED:
04/08/21 01:18PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33828461/

LINK – DOI:
https://doi.org/10.3389/fncel.2021.658990

LINK – PUBLISHER:
https://www.frontiersin.org/articles/10.3389/fncel.2021.658990/full?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-04-08T17:18:29+00:00, https://www.hearinglosstreatmentreport.com.

Expression of serum proteins in noise induced hearing loss: insights into potential role in NIHL progression

CATEGORY:
Research

SCREENSHOT:
Expression of serum proteins in noise induced hearing loss workers of mining based industry

TITLE:
Expression of serum proteins in noise induced hearing loss workers of mining based industry

CONTENT:
J Proteomics. 2021 Mar 15:104185. doi: 10.1016/j.jprot.2021.104185. Online ahead of print.

ABSTRACT

Noise Induced Hearing Loss (NIHL) is caused by excessive noise exposure due to occupational activities thus affects communication and quality of life. Prolonged occupational and environmental exposure to loud noise damages key molecules present in the micro-machinery of the ear which are required for the mechano-electrical transduction of sound waves in cochlea. Specific proteins are known to be associated with hearing loss and related structural and functional disabilities in the human inner, outer hair cells and cochlea. Rationale of this study was to identify the cochlear proteins associated with the pathophysiology of NIHL using proteomic approaches in mining based industrial workers. Total (n = 210) samples were collected from mining based industrial workers of central India. Subjects were categorized based on audiometric analysis. Proteome changes of the host serum were investigated using one and two-dimensional electrophoresis in combination with LC-MS/MS and MALDI-TOF MS. Up-regulated 46 cochlear proteins among confirmed NIHL cases were identified by MASCOT. Shrinkage discriminant analysis provided top 25 discriminating feature proteins namely myosin, transthyretin, SERPIN, CCDC50, enkurin, transferin etc. The identified potential proteins may be used as biomarkers for early detection and to understand the pathogenic mechanism of NIHL. Evaluation of these biomarkers in follow-up cases may further aid in improving NIHL diagnosis. SIGNIFICANCE: Human proteome study in Noise Induced Hearing Loss (NIHL) cases has not been published till date. This study represents most comprehensive proteomic analysis in NIHL cases taken from Indian mine workers. The identified key twenty-five discriminating feature proteins which are upregulated when an individual develops (or is in stage of development of) NIHL, provides insights into the potential roles of these varied proteins in disease progression. The proteins thus identified by proteomic approach may be used as early diagnostic biomarker to predict the occurrence of disease at very early stage.

PMID:33737237 | DOI:10.1016/j.jprot.2021.104185

SOURCE:
Journal of proteomics

PUBLISHER:

PMID:
pubmed:33737237

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33737237

DOI:
10.1016/j.jprot.2021.104185

DATE – PUBLISHED:
Fri, 19 Mar 2021 06:00:00 -0400

DATE – DOI:
2021-03-18T20:32:33Z

DATE – ADDED:
03/19/21 03:00PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33737237/

LINK – DOI:
https://doi.org/10.1016/j.jprot.2021.104185

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S1874391921000841?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-19T19:00:02+00:00, https://www.hearinglosstreatmentreport.com.

The DNA methylation inhibitor RG108 protects against noise-induced hearing loss

CATEGORY:
Research

SCREENSHOT:
The DNA methylation inhibitor RG108 protects against noise-induced hearing loss

TITLE:
The DNA methylation inhibitor RG108 protects against noise-induced hearing loss

CONTENT:
Cell Biol Toxicol. 2021 Mar 15. doi: 10.1007/s10565-021-09596-y. Online ahead of print.

ABSTRACT

BACKGROUND: Noise-induced hearing loss represents a commonly diagnosed type of hearing disability, severely impacting the quality of life of individuals. The current work is aimed at assessing the effects of DNA methylation on noise-induced hearing loss.

METHODS: Blocking DNA methyltransferase 1 (DNMT1) activity with a selective inhibitor RG108 or silencing DNMT1 with siRNA was used in this study. Auditory brainstem responses were measured at baseline and 2 days after trauma in mice to assess auditory functions. Whole-mount immunofluorescent staining and confocal microcopy of mouse inner ear specimens were performed to analyze noise-induced damage in cochleae and the auditory nerve at 2 days after noise exposure.

RESULTS: The results showed that noise exposure caused threshold elevation of auditory brainstem responses and cochlear hair cell loss. Whole-mount cochlea staining revealed a reduction in the density of auditory ribbon synapses between inner hair cells and spiral ganglion neurons. Inhibition of DNA methyltransferase activity via a non-nucleoside specific pharmacological inhibitor, RG108, or silencing of DNA methyltransferase-1 with siRNA significantly attenuated ABR threshold elevation, hair cell damage, and the loss of auditory synapses.

CONCLUSIONS: This study suggests that inhibition of DNMT1 ameliorates noise-induced hearing loss and indicates that DNMT1 may be a promising therapeutic target. Graphical Headlights • RG108 protected against noise-induced hearing loss • RG108 administration protected against noise-induced hair cell loss and auditory neural damage. • RG108 administration attenuated oxidative stress-induced DNA damage and subsequent apoptosis-mediated cell loss in the cochlea after noise exposure.

PMID:33723744 | DOI:10.1007/s10565-021-09596-y

SOURCE:
Cell biology and toxicology

PUBLISHER:

PMID:
pubmed:33723744

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33723744

DOI:
10.1007/s10565-021-09596-y

DATE – PUBLISHED:
Tue, 16 Mar 2021 06:00:00 -0400

DATE – DOI:
2021-03-15T18:03:14Z

DATE – ADDED:
03/16/21 02:49PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33723744/

LINK – DOI:
https://doi.org/10.1007/s10565-021-09596-y

LINK – PUBLISHER:
http://link.springer.com/10.1007/s10565-021-09596-y?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-16T18:49:43+00:00, https://www.hearinglosstreatmentreport.com.

Treatment With Calcineurin Inhibitor FK506 Attenuates Noise-Induced Hearing Loss

CATEGORY:
Research

SCREENSHOT:
Treatment With Calcineurin Inhibitor FK506 Attenuates Noise-Induced Hearing Loss

TITLE:
Treatment With Calcineurin Inhibitor FK506 Attenuates Noise-Induced Hearing Loss

CONTENT:
Front Cell Dev Biol. 2021 Mar 12;9:648461. doi: 10.3389/fcell.2021.648461. eCollection 2021.

ABSTRACT

Attenuation of noise-induced hair cell loss and noise-induced hearing loss (NIHL) by treatment with FK506 (tacrolimus), a calcineurin (CaN/PP2B) inhibitor used clinically as an immunosuppressant, has been previously reported, but the downstream mechanisms of FK506-attenuated NIHL remain unknown. Here we showed that CaN immunolabeling in outer hair cells (OHCs) and nuclear factor of activated T-cells isoform c4 (NFATc4/NFAT3) in OHC nuclei are significantly increased after moderate noise exposure in adult CBA/J mice. Consequently, treatment with FK506 significantly reduces moderate-noise-induced loss of OHCs and NIHL. Furthermore, induction of reactive oxygen species (ROS) by moderate noise was significantly diminished by treatment with FK506. In agreement with our previous finding that autophagy marker microtubule-associated protein light chain 3B (LC3B) does not change in OHCs under conditions of moderate-noise-induced permanent threshold shifts, treatment with FK506 increases LC3B immunolabeling in OHCs after exposure to moderate noise. Additionally, prevention of NIHL by treatment with FK506 was partially abolished by pretreatment with LC3B small interfering RNA. Taken together, these results indicate that attenuation of moderate-noise-induced OHC loss and hearing loss by FK506 treatment occurs not only via inhibition of CaN activity but also through inhibition of ROS and activation of autophagy.

PMID:33777956 | PMC:PMC7994600 | DOI:10.3389/fcell.2021.648461

SOURCE:
Frontiers in cell and developmental biology

PUBLISHER:

PMID:
pubmed:33777956

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33777956

DOI:
10.3389/fcell.2021.648461

DATE – PUBLISHED:
Mon, 29 Mar 2021 06:00:00 -0400

DATE – DOI:
2021-03-12T06:50:17Z

DATE – ADDED:
03/29/21 01:57PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33777956/

LINK – DOI:
https://doi.org/10.3389/fcell.2021.648461

LINK – PUBLISHER:
https://www.frontiersin.org/articles/10.3389/fcell.2021.648461/full?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-29T17:57:07+00:00, https://www.hearinglosstreatmentreport.com.

Hidden hearing loss is associated with loss of ribbon synapses of cochlea inner hair cells

CATEGORY:6
Research

SCREENSHOT:
Hidden hearing loss is associated with loss of ribbon synapses of cochlea inner hair cells

TITLE:
Hidden hearing loss is associated with loss of ribbon synapses of cochlea inner hair cells

CONTENT:
Biosci Rep. 2021 Mar 18:BSR20201637. doi: 10.1042/BSR20201637. Online ahead of print.

ABSTRACT

This study aimed to observe the changes in the cochlea ribbon synapses after repeated exposure to moderate-to-high intensity noise. Guinea pigs received 95 dB SPL white noise exposure 4 hours a day for consecutive 7 days (we regarded it a medium-term and moderate-intensity noise, or MTMI noise). Animals were divided into 4 groups: Control, 1DPN (1-day post noise), 1WPN (1-week post noise), and 1MPN (1-month post noise). Auditory function analysis by ABR and CAP recordings, as well as ribbon synapse morphological analyses by immunohistochemistry (Ctbp2 and PSD95 staining) were performed one day, one week, and one month after noise exposure. After MTMI noise exposure, the amplitudes of auditory brainstem response (ABR) I and III waves were suppressed. The compound action potential (CAP) threshold was elevated, and CAP amplitude was reduced in the 1DPN group. No apparent changes in hair cell shape, arrangement or number were observed, but the number of ribbon synapse was reduced. The 1WPN and 1MPN groups showed that part of ABR and CAP changes recovered, as well as the synapse number. The defects in cochlea auditory function and synapse changes were observed mainly in the high-frequency region. Together, repeated exposure in MTMI noise can cause hidden hearing loss, which is partially reversible after leaving the noise environment; and MTMI noise induced hidden hearing loss is associated with inner hair cell ribbon synapses.

PMID:33734328 | DOI:10.1042/BSR20201637

SOURCE:
Bioscience reports

PUBLISHER:

PMID:
pubmed:33734328

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33734328

DOI:
10.1042/BSR20201637

DATE – PUBLISHED:
Thu, 18 Mar 2021 06:00:00 -0400

DATE – DOI:
2021-03-18T15:54:01Z

DATE – ADDED:
03/18/21 07:41PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33734328/

LINK – DOI:
https://doi.org/10.1042/BSR20201637

LINK – PUBLISHER:
https://portlandpress.com/bioscirep/article/doi/10.1042/BSR20201637/228102/Hidden-hearing-loss-is-associated-with-loss-of?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-18T23:41:43+00:00, https://www.hearinglosstreatmentreport.com.

VEGF-A165 restores vascular function to the inner ear and could potentially reverse common forms of hearing loss…

Could improving poor blood supply to the damaged inner ear reverse noise-induced and/or age-related hearing loss?

Yes, according to some fascinating new research from Zhang et al, published yesterday on March 9, 2021, that describes a unique approach to hearing restoration that is backed by “clear-cut evidence”…

VEGF-A165 article screenshot
This VEGF-A165 research paper is hot off the press!!!

Here is a link to a full-text PDF copy of the paper (and all the science-y details):

VEGF-A165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss [PDF]

Sneak preview of the abstract:

When hearing loss is caused by noise or aging, it is often associated with breakdown of the barrier between the cochlea and its blood vessels. Pericytes populate many small vessels in the adult inner ear, however, their role in different forms of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model, we show that loss of pericytes leads to marked changes in vascular structure, resulting in poor blood circulation and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models in combination with exogenous donor pericytes, we show pericytes, signaled by endothelial growth factor isoform A165 (VEGF-A165), vigorously drives new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1 (AAV1)-mediated VEGF-A165 viral vector to pericyte depleted animals regenerated lost pericytes, improved blood supply, reduced loss of sensory hair cells, and attenuated hearing loss. These studies provide the first clear-cut evidence that pericytes are critical for adult hearing and can regenerate cochlear vasculature. The restoration of vascular function in the damaged inner ear with AAV1-mediated VEGF-A165 gene therapy is a new strategy for ameliorating vascular associated hearing disorders, including common forms of age-related hearing loss.

SOURCE: Zhang et al. Published March 9, 2021. JCI Insight 2021. https://doi.org/10.1172/jci.insight.143285.

That’s all for now.

The Hearing Loss Treatment Report system will be monitoring the scientific literature and news for any further mentions of VEGF-A165… including any progress it makes toward that first big milestone: human clinical trials.

We don’t have a timeline for you (yet)… but you can expect some follow-up coverage in the coming weeks/months.

Stay tuned.

RE: how to get VEGF-A165 updates

To follow what’s happening with VEGF-A165 (as well as other treatments such as FX-322, OTO-413, PIPE-505), I encourage you to sign up for Hearing Loss Treatment Report email updates. These updates are 100% free… your information is kept private, and… you won’t get any spammy marketing emails or promotional emails. That’s a promise. Instead, you will only receive important (and often exclusive) updates related to up-and-coming hearing loss treatments and scientific breakthroughs.

Questions? Comments? Feedback?

Send an email to michael@urgentresearch.com and speak your mind.

I read every email and try my best to reply (thoughtfully) within 1-2 days.

P.S. Do you like these “exclusive” update posts?
Kindly share them with people you know who might find them interesting.

Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss

CATEGORY:
Research

SCREENSHOT:
Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss

TITLE:
Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss

CONTENT:
Mol Ther Methods Clin Dev. 2021 Mar 10;21:209-236. doi: 10.1016/j.omtm.2021.03.005. eCollection 2021 Jun 11.

ABSTRACT

There is growing attention and effort focused on treating the root cause of sensorineural hearing loss rather than managing associated secondary characteristic features. With recent substantial advances in understanding sensorineural hearing-loss mechanisms, gene delivery has emerged as a promising strategy for the biological treatment of hearing loss associated with genetic dysfunction. There are several successful and promising proof-of-principle examples of transgene deliveries in animal models; however, there remains substantial further progress to be made in these avenues before realizing their clinical application in humans. Herein, we review different aspects of development, ongoing preclinical studies, and challenges to the clinical transition of transgene delivery of the inner ear toward the restoration of lost auditory and vestibular function.

PMID:33850952 | PMC:PMC8010215 | DOI:10.1016/j.omtm.2021.03.005

SOURCE:
Molecular therapy. Methods & clinical development

PUBLISHER:

PMID:
pubmed:33850952

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33850952

DOI:
10.1016/j.omtm.2021.03.005

DATE – PUBLISHED:
Wed, 14 Apr 2021 06:00:00 -0400

DATE – DOI:
2021-03-11T08:48:48Z

DATE – ADDED:
04/14/21 04:52PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33850952/

LINK – DOI:
https://doi.org/10.1016/j.omtm.2021.03.005

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S2329050121000450?utm_source=hearinglosstreatmentreport.com

https://www.cell.com/molecular-therapy-family/methods/fulltext/S2329-0501(21)00045-0

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-04-14T20:52:40+00:00, https://www.hearinglosstreatmentreport.com.

High Dose Oral Steroids in Sudden Sensorineural Hearing Loss

CATEGORY:
Clinical Trials

TITLE:
High Dose Oral Steroids in Sudden Sensorineural Hearing Loss

INTERVENTION/TREATMENT:

PHASE:

DESCRIPTION:
Condition :   Sudden Sensorineural Hearing Loss (SSNHL)

Interventions :   Drug: Dexamethasone;   Drug: Prednisone

Sponsor :   University of Colorado, Denver

Recruiting

ID:
NCT03255473

STATUS:

DATE – FIRST POSTED:
Mon, 21 Aug 2017 12:00:00 EDT

DATE – LAST UPDATE POSTED:
03/10/21 06:35AM

DATE – RETRIEVED:
03/10/21 06:35AM

LINK – STUDY HISTORY:
https://clinicaltrials.gov/ct2/history/NCT03255473

LINK – STUDY RECORD:
https://clinicaltrials.gov/ct2/show/NCT03255473

VEGF-A165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss

CATEGORY:
Research

SCREENSHOT:
VEGF-A165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss

TITLE:
VEGF-A165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss

CONTENT:
JCI Insight. 2021 Mar 9:143285. doi: 10.1172/jci.insight.143285. Online ahead of print.

ABSTRACT

AbstractMillions of people are affected by hearing loss. When hearing loss is caused by noise or aging, it is often associated with breakdown of the barrier between the cochlea and its blood vessels. Pericytes populate many small vessels in the adult inner ear, however, their role in different forms of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model, we show that loss of pericytes leads to marked changes in vascular structure, resulting in poor blood circulation and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models in combination with exogenous donor pericytes, we show pericytes, signaled by endothelial growth factor isoform A165 (VEGF-A165), vigorously drives new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1 (AAV1)-mediated VEGF-A165 viral vector to pericyte depleted animals regenerated lost pericytes, improved blood supply, reduced loss of sensory hair cells, and attenuated hearing loss. These studies provide the first clear-cut evidence that pericytes are critical for adult hearing and can regenerate cochlear vasculature. The restoration of vascular function in the damaged inner ear with AAV1-mediated VEGF-A165 gene therapy is a new strategy for ameliorating vascular associated hearing disorders, including common forms of age-related hearing loss.

PMID:33690221 | DOI:10.1172/jci.insight.143285

SOURCE:
JCI insight

PUBLISHER:

PMID:
pubmed:33690221

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33690221

DOI:
10.1172/jci.insight.143285

DATE – PUBLISHED:
Wed, 10 Mar 2021 06:00:00 -0500

DATE – DOI:
2021-03-09T17:03:21Z

DATE – ADDED:
03/10/21 10:18PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33690221/

LINK – DOI:
https://doi.org/10.1172/jci.insight.143285

LINK – PUBLISHER:
http://insight.jci.org/articles/view/143285?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-11T03:18:27+00:00, https://www.hearinglosstreatmentreport.com.

Contribution of Macrophages and Fractalkine Towards Degeneration and Repair of Cochlear Synapses

Parent Project Number
1P20GM139762-01

Sub-Project ID
5859

Contact PI/Project Leader
KAUR, TEJBEER

Awardee Organization
CREIGHTON UNIVERSITY

Abstract

Project Summary/Abstract: Noise trauma can primarily damage the synaptic connections between the inner hair cells and the peripheral axons of the spiral ganglion neurons. Noise-induced synaptopathy is attributed to glutamate excitotoxicity and leads to gradual axonal degeneration and ultimately death of the spiral ganglion neurons. The consequences of loss of synapses and neurons include auditory perceptual dysfunctions leading to difficulty in speech recognition and listening in noisy environments. This type of auditory dysfunction is known as “hidden hearing loss” because it is not readily diagnosed through standard hearing tests. Moreover, absence of spiral ganglion neurons limits the performance of primary therapies for hearing loss such as cochlear implants and future hair cell regeneration strategies. Currently, there are no approved drugs that promote neuron survival or elicit regeneration of lost auditory nerves and replenish their synaptic connections with surviving hair cells. Therefore, it is of great interest to understand the mechanisms for synaptic and neuron degeneration and regeneration for the development of better ototherapeutics.

We recently demonstrated that synaptopathic noise trauma is sufficient to recruit macrophages (innate-immune cells) towards the damaged inner hair cell-synaptic region. While the damaged synapses can undergo spontaneous repair however, disruption of fractalkine signaling (by genetic deletion of fractalkine (FKN) receptor CX3CR1 on macrophages) impairs such spontaneous synaptic repair and increases spiral ganglion neuron loss after trauma. These data imply that intact fractalkine signaling is necessary for synaptic repair and neuron survival in the damaged cochlea.

Here, we propose to investigate the effect of activation of fractalkine signaling on prevention and repair of loss of synapses and neuron survival following cochlear trauma.

  • Aim 1 will determine whether FKN treatment repairs damaged synapses after noise trauma or excitotoxic insult in mammalian mouse cochlea. Specifically, FKN peptide will be injected either (transtympanically) after synaptopathic noise trauma in vivo or after glutamate- induced excitotoxicity in cochlear explants. The precise contribution of FKN membrane or soluble isoforms towards synaptic repair will be examined.
  • Aim 2 will determine whether FKN treatment reduces degeneration of synapses following noise trauma or glutamate excitotoxicity. We will treat with FKN membrane or soluble isoforms prior to glutamate treatment in ex vivo cochlear explants or prior to noise trauma in vivo (transtympanically).
  • In Aim 3, we will eliminate cochlear macrophages and examine the influence of this intervention on the degree of synaptic degeneration and repair after synaptopathic noise trauma. For each aim, auditory function along with morphometric analyses of hair cell, macrophage, synapse and spiral ganglion neuron counts will be performed.

Together, the study design will aid in investigating the effect of macrophages and fractalkine treatment on cochlear synapse degeneration and repair and hearing restoration and may lead to identification of novel fractalkine-based therapeutics for “hidden-hearing loss”.

Project Funding for FY 2021
$288,481

Treatment of Long-term Sudden Sensorineural Hearing Loss as an Otologic Migraine Phenomenon

CATEGORY:
Research

SCREENSHOT:
Treatment of Long-term Sudden Sensorineural Hearing Loss as an Otologic Migraine Phenomenon

TITLE:
Treatment of Long-term Sudden Sensorineural Hearing Loss as an Otologic Migraine Phenomenon

CONTENT:
Otol Neurotol. 2021 Mar 5. doi: 10.1097/MAO.0000000000003111. Online ahead of print.

ABSTRACT

OBJECTIVES: To describe a cohort of patients presenting with long-term sudden sensorineural hearing loss (SSNHL) treated with prophylactic migraine and intratympanic steroid therapy.

METHODS: Patients presenting to a neurotology clinic at least 6 weeks from SSNHL onset were included. All patients received migraine prophylactic medication (nortriptyline, topiramate, and/or verapamil) and lifestyle changes for at least 6 weeks, as well as intratympanic steroid injections, if appropriate.

RESULTS: Twenty-one patients (43% female) with a mean age of 64 ± 11 years who presented 9 ± 8 months (median = 5) from symptom onset were included. Posttreatment hearing thresholds were significantly improved compared with pretreatment thresholds at 500 Hz (49 ± 19 dB versus 55 ± 20 dB, p = 0.01), 1000 Hz (52 ± 19 dB versus 57 ± 21 dB, p = 0.03), low-frequency pure-tone average (53 ± 15 dB versus 57 ± 17 dB, p = 0.01), and speech-frequency pure-tone average (57 ± 13 dB versus 60 ± 15 dB, p = 0.02). Posttreatment word-recognition-score (WRS) and speech-recognition-threshold (SRT) were also significantly improved (45 ± 28% versus 70 ± 28% and 57 ± 18 dB versus 50 ± 16 dB, respectively, both p < 0.01). Notably, ≥15% improvement in WRS and ≥10 dB improvement in SRT was observed in 13 (68%) and 8 (40%) patients, respectively. Of the 11 patients who presented with initial < 50% WRS, 8 (73%) had improved posttreatment >50% WRS with an average improvement of 39 ± 9%.

CONCLUSIONS: Migraine medications in addition to intratympanic steroid injections significantly improved SRT and hearing frequencies in 40% and 29% of SSNHL patients, respectively, while significant WRS recovery was observed in most (68%) patients. This suggests SSNHL may be an otologic migraine phenomenon, which may be at least partially reversible even after the traditional 30-day postonset window.

PMID:33710150 | DOI:10.1097/MAO.0000000000003111

SOURCE:
Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology

PUBLISHER:

PMID:
pubmed:33710150

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33710150

DOI:
10.1097/MAO.0000000000003111

DATE – PUBLISHED:
Fri, 12 Mar 2021 06:00:00 -0500

DATE – DOI:
2021-03-12T14:03:36Z

DATE – ADDED:
03/12/21 01:58PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33710150/

LINK – DOI:
https://doi.org/10.1097/MAO.0000000000003111

LINK – PUBLISHER:
https://journals.lww.com/10.1097/MAO.0000000000003111?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-03-12T18:58:06+00:00, https://www.hearinglosstreatmentreport.com.

Research center at Creighton University awarded $10.8 million NIH grant to help researchers discover new drugs for hearing loss

https://www.newswise.com/articles/translational-hearing-center-awarded-largest-nih-grant-in-creighton-university-history

Translational Hearing Center awarded largest NIH grant in Creighton University history
NIH grant to help researchers translate basic hearing loss research into practical therapies

Research center at Creighton University awarded $10.8 million NIH grant to help researchers discover new drugs for hearing loss

Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss

CATEGORY:
Clinical Trials

TITLE:
Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss

INTERVENTION/TREATMENT:

PHASE:

DESCRIPTION:
Condition :   Sensorineural Hearing Loss

Interventions :   Drug: PIPE-505;   Drug: Diluent alone

Sponsor :   Pipeline Therapeutics, Inc.

Recruiting

ID:
NCT04462198

STATUS:

DATE – FIRST POSTED:
Wed, 08 Jul 2020 12:00:00 EDT

DATE – LAST UPDATE POSTED:
10/14/20 08:47PM

DATE – RETRIEVED:
10/14/20 08:47PM

LINK – STUDY HISTORY:
https://clinicaltrials.gov/ct2/history/NCT04462198

LINK – STUDY RECORD:
https://clinicaltrials.gov/ct2/show/NCT04462198

Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

CATEGORY:
Research

SCREENSHOT:
Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

TITLE:
Activation of KCNQ4 as a Therapeutic Strategy to Treat Hearing Loss

CONTENT:
Int J Mol Sci. 2021 Mar 2;22(5):2510. doi: 10.3390/ijms22052510.

ABSTRACT

Potassium voltage-gated channel subfamily q member 4 (KCNQ4) is a voltage-gated potassium channel that plays essential roles in maintaining ion homeostasis and regulating hair cell membrane potential. Reduction of the activity of the KCNQ4 channel owing to genetic mutations is responsible for nonsyndromic hearing loss, a typically late-onset, initially high-frequency loss progressing over time. In addition, variants of KCNQ4 have also been associated with noise-induced hearing loss and age-related hearing loss. Therefore, the discovery of small compounds activating or potentiating KCNQ4 is an important strategy for the curative treatment of hearing loss. In this review, we updated the current concept of the physiological role of KCNQ4 in the inner ear and the pathologic mechanism underlying the role of KCNQ4 variants with regard to hearing loss. Finally, we focused on currently developed KCNQ4 activators and their pros and cons, paving the way for the future development of specific KCNQ4 activators as a remedy for hearing loss.

PMID:33801540 | DOI:10.3390/ijms22052510

SOURCE:
International journal of molecular sciences

PUBLISHER:

PMID:
pubmed:33801540

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33801540

DOI:
10.3390/ijms22052510

DATE – PUBLISHED:
Sat, 03 Apr 2021 06:00:00 -0400

DATE – DOI:
2021-03-03T02:30:13Z

DATE – ADDED:
04/03/21 05:12PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33801540/

LINK – DOI:
https://doi.org/10.3390/ijms22052510

LINK – PUBLISHER:
https://www.mdpi.com/1422-0067/22/5/2510/htm
https://www.mdpi.com/1422-0067/22/5/2510?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-04-03T21:12:02+00:00, https://www.hearinglosstreatmentreport.com.

Verification of the Efficacy/Safety of the Dual Drug Delivery for Hearing Loss

https://clinicaltrials.gov/ct2/show/NCT04766853

Verification of the Efficacy/Safety of the Dual Drug Delivery for Hearing Loss

Brief Summary:
This study is a prospective, randomized pilot study. To verify an efficacy and safety of the dual drug injectable delivery vehicle, patients who have not responded to the existing standard treatment will be enrolled. Hearing test and endoscopy of tympanic membrane will be conducted after intratympanic treatment for evaluation.

Condition or disease Intervention/treatment Phase
Hearing Loss, Sudden
Hearing Loss Ototoxic
Hearing Loss, Noise-Induced
Meniere Disease
Drug: Dexamethasone
Drug: Hyaluronic acid
Phase 1
Phase 2

Study Design
Go to sections
Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Verification of the Efficacy / Safety of the Dual Drug Injectable Delivery Vehicle for Treating Intractable Hearing Loss (Pilot Study)
Estimated Study Start Date : March 2021
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2022

Promise of Optogenetics ‘Sheds Light’ on Hearing Restoration

https://journals.lww.com/thehearingjournal/Fulltext/2021/03000/Promise_of_Optogenetics__Sheds_Light__on_Hearing.1.aspx

Promise of Optogenetics ‘Sheds Light’ on Hearing Restoration
Glantz, Gordon

The Hearing Journal: March 2021 – Volume 74 – Issue 3 – p 20,22,23
doi: 10.1097/01.HJ.0000737552.03771.a4

Molecular Behavior of HMGB1 in the Cochlea Following Noise Exposure and in vitro

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959764/

https://www.frontiersin.org/articles/10.3389/fcell.2021.642946/full

Molecular Behavior of HMGB1 in the Cochlea Following Noise Exposure and in vitro

Abstract
Noise-induced hearing loss (NIHL) is characterized by cellular damage to the inner ear, which is exacerbated by inflammation. High-mobility group box 1 (HMGB1), a representative damage-associated molecular pattern (DAMP), acts as a mediator of inflammation or an intercellular messenger according to its cellular localization. Blocking or regulating HMGB1 offers an attractive approach in ameliorating NIHL. However, the precise therapeutic intervention must be based on a deeper understanding of its dynamic molecular distribution and function in cochlear pathogenesis after acoustic trauma. Here, we have presented the spatiotemporal dynamics of the expression of HMGB1, exhibiting distribution variability in specific cochlear regions and cells following noise exposure. After gene manipulation, we further investigated the characteristics of cellular HMGB1 in HEI-OC1 cells. The higher cell viability observed in the HMGB1 knocked-down group after stimulation with H2O2 indicated the possible negative effect of HMGB1 on cellular lifespan. In conclusion, this study demonstrated that HMGB1 is involved in NIHL pathogenesis and its molecular biology has essential and subtle influences, preserving a translational potential for pharmacological intervention.

Frequency Therapeutics Announces Publication of FX-322 Phase 1/2 Data Showing Hearing Improvements in Sensorineural Hearing Loss Patients

https://www.businesswire.com/news/home/20210222005818/en/Frequency-Therapeutics-Announces-Publication-of-Phase-12-Data-Showing-Hearing-Improvements-in-Acquired-Sensorineural-Hearing-Loss-Patients-Receiving-FX-322

Frequency Therapeutics Announces Publication of Phase 1/2 Data Showing Hearing Improvements in Acquired Sensorineural Hearing Loss Patients Receiving FX-322
Results Published in Leading Peer-Reviewed Otolaryngology Journal, Otology & Neurotology

Statistically Significant Improvements Observed in Word Recognition Tests in Quiet and in Noise; Suggests Potential to Improve Speech Intelligibility, a Major Unmet Need for Individuals with Hearing Loss

Company Expects Interim FX-322 Phase 2a Study Data Later this Quarter

https://journals.lww.com/otology-neurotology/Abstract/9000/Improved_Speech_Intelligibility_in_Subjects_With.95768.aspx

T2 relaxation time shortening in the cochlea of patients with sudden sensory neuronal hearing loss: changes in inner ear fluid composition implicated in idiopathic SSNHL development

CATEGORY:
Research

SCREENSHOT:
T2 relaxation time shortening in the cochlea of patients with sudden sensory neuronal hearing loss: a retrospective study using quantitative synthetic magnetic resonance imaging Screenshot

TITLE:
T2 relaxation time shortening in the cochlea of patients with sudden sensory neuronal hearing loss: a retrospective study using quantitative synthetic magnetic resonance imaging

CONTENT:
Eur Radiol. 2021 Feb 20. doi: 10.1007/s00330-021-07749-5. Online ahead of print.

ABSTRACT

OBJECTIVES: High cochlear signal intensity on three-dimensional (3D) T2 fluid-attenuated inversion recovery (FLAIR) sequences in patients with sudden sensorineural hearing loss (SSNHL) has been reported. Here, we evaluated the cochlear T2 relaxation time differences in patients with idiopathic SSNHL using quantitative synthetic MRI (SyMRI).

METHODS: Twenty-four patients with unilateral SSNHL who underwent precontrast conventional 3D FLAIR and SyMRI were retrospectively included. T1 and T2 relaxation times and the proton density (PD) of the bilateral ears were measured by manually drawn regions of interest. Wilcoxon signed-rank tests and intra- and interobserver correlation analyses were performed. Qualitative analysis was also performed to determine the presence and laterality of the asymmetric high signal intensity on synthetic FLAIR (SyFLAIR) images.

RESULTS: The T2 relaxation time was significantly lower in the affected (basal and apico-middle turns) than in the unaffected cochlea (basal turn: 519 ± 181.3 vs. 608.8 ± 203.6, p = 0.042; apico-middle turn: 410.8 ± 163.8 vs. 514.5 ± 186.3, p = 0.037). There were no significant differences in the T1 relaxation time and PD between the affected and unaffected ears (p > 0.05). Additionally, three patients without asymmetric signal intensity on conventional MRI showed asymmetric increased signal intensity in the affected ear on SyFLAIR.

CONCLUSIONS: The T2 relaxation time was significantly shorter in the affected than in the unaffected cochlea of patients with idiopathic SSNHL. The SyMRI-derived T2 relaxation time may be a promising imaging marker, suggesting that the changes in inner ear fluid composition are implicated in the idiopathic SSNHL development.

KEY POINTS: • T2 relaxation time was significantly lower in the affected than in the unaffected cochlea. • SyFLAIR showed increased lesion conspicuity compared to conventional 3D-FLAIR in detecting asymmetric high signal intensity of the affected side. • SyMRI-derived T2 relaxation time may be a promising imaging marker of the affected ear in patients with idiopathic SSNHL.

PMID:33609144 | DOI:10.1007/s00330-021-07749-5

SOURCE:
European radiology

PUBLISHER:

PMID:
pubmed:33609144

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33609144

DOI:
10.1007/s00330-021-07749-5

DATE – PUBLISHED:
Sat, 20 Feb 2021 06:00:00 -0500

DATE – DOI:
2021-02-20T17:19:51Z

DATE – ADDED:
02/21/21 01:27AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33609144/

LINK – DOI:
https://doi.org/10.1007/s00330-021-07749-5

LINK – PUBLISHER:
http://link.springer.com/10.1007/s00330-021-07749-5

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-02-21T06:27:26+00:00, https://www.hearinglosstreatmentreport.com.

Sensorion Presents New Preclinical Data on SENS-401 at ARO 2021: significant treatment benefits in rats with severe hearing loss when initiated within 7 days of acoustic trauma

https://www.businesswire.com/news/home/20210218006082/en/Sensorion-Presents-New-Preclinical-Data-on-SENS-401-at-ARO-2021

Sensorion Presents New Preclinical Data on SENS-401 at ARO 2021
SENS-401 yields significant treatment benefits in rats with severe hearing loss when initiated with a delay up to 7 days after the initial acoustic trauma
Sensorion presenting three posters at Association for Research in Otolaryngology (ARO) meeting
ARO will be hosted virtually on February 20-24, 2021

Reduction of α2-Na/K-ATPase might play an important role in the pathogenesis of age-related hearing loss

CATEGORY:
Research

SCREENSHOT:
Expression of alpha2-Na/K-ATPase in C57BL/6J Mice Inner Ear and Its Relationship with Age-related Hearing Loss Screenshot

TITLE:
Expression of alpha2-Na/K-ATPase in C57BL/6J Mice Inner Ear and Its Relationship with Age-related Hearing Loss

CONTENT:
Curr Med Sci. 2021 Feb;41(1):153-157. doi: 10.1007/s11596-021-2330-5. Epub 2021 Feb 13.

ABSTRACT

K+ cycling in the cochlea is critical to maintain hearing. Many sodium-potassium pumps are proved to participate in K+ cycling, such as Na/K-ATPase. The α2-Na/K-ATPase is an important isoform of Na/K-ATPase. The expression of α2-Na/K-ATPase in the cochlea is not clear. In this study, we used C57BL/6 mice as a model of presbycusis and implemented immunohistochemistry staining and quantitative real time-PCR, and the α2-Na/K-ATPase expression pattern was confirmed in the inner ear. It was found α2-Na/K-ATPase was expressed widely in cochlea and its mRNA and protein expression was gradually reduced with aging (4-, 14-, 26- and 48-weeks old mice). We suspected that, the down-regulation of α2-Na/K-ATPase expression might be associated with the remodeling of K+ cycling, degeneration of morphological structure and decrease of hearing function in aging C57 mice. In conclusion, we speculated that the reduction of α2-Na/K-ATPase might play an important role in the pathogenesis of age-related hearing loss.

PMID:33582920 | DOI:10.1007/s11596-021-2330-5

SOURCE:
Current medical science

PUBLISHER:

PMID:
pubmed:33582920

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33582920

DOI:
10.1007/s11596-021-2330-5

DATE – PUBLISHED:
Sun, 14 Feb 2021 06:00:00 -0500

DATE – DOI:
2021-02-14T09:43:18Z

DATE – ADDED:
02/15/21 01:12AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33582920/

LINK – DOI:
https://doi.org/10.1007/s11596-021-2330-5

LINK – PUBLISHER:
http://link.springer.com/10.1007/s11596-021-2330-5

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-02-15T06:12:41+00:00, https://www.hearinglosstreatmentreport.com.

OTO-413 Phase 1/2 trial expansion in hearing loss expected to start in Q2 2021 with results anticipated in mid-2022

https://www.globenewswire.com/news-release/2021/02/11/2174562/0/en/Otonomy-Reports-Fourth-Quarter-and-Full-Year-2020-Financial-Results-and-Provides-Corporate-Update.html

Otonomy Reports Fourth Quarter and Full Year 2020 Financial Results and Provides Corporate Update

February 11, 2021 16:17 ET | Source: Otonomy, Inc.
OTIVIDEX® Phase 3 trial results in Ménière’s disease expected by end of February
OTO-313 Phase 2 trial in tinnitus planned to start in first quarter of 2021 with top-line results expected in mid-2022
OTO-413 Phase 1/2 trial expansion in hearing loss expected to start in second quarter of 2021 with results anticipated in mid-2022

Frequency Therapeutics Appoints Kevin Franck, Ph.D., as Senior Vice President, Strategic Marketing and New Product Planning… to help lead pre-commercial strategy and launch planning for FX-322 (and its potential commercialization both in the US and internationally)…

https://www.businesswire.com/news/home/20210208005168/en/Frequency-Therapeutics-Appoints-Kevin-Franck-Ph.D.-as-Senior-Vice-President-Strategic-Marketing-and-New-Product-Planning

Frequency Therapeutics Appoints Kevin Franck, Ph.D., as Senior Vice President, Strategic Marketing and New Product Planning… to help lead pre-commercial strategy and launch planning for FX-322 and for potential commercialization in the US…

Frequency Therapeutics Appoints Kevin Franck, Ph.D., as Senior Vice President, Strategic Marketing and New Product Planning
Dr. Franck joins from Massachusetts Eye and Ear, where he was Director of Audiology and Harvard Medical School Faculty in the Department of Otolaryngology-Head and Neck Surgery

February 08, 2021 07:00 AM Eastern Standard 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 the appointment of Kevin Franck, Ph.D., as Senior Vice President of Strategic Marketing and New Product Planning. Dr. Franck will lead pre-commercial strategy and launch planning for Frequency’s clinical pipeline, including its lead program aimed at developing a restorative treatment for sensorineural hearing loss (SNHL), the most common form of hearing loss.

New pill [SPI-1005] that may help improve age-related hearing loss by protecting delicate hair cells in the inner ear

https://www.dailymail.co.uk/health/article-9238361/New-pill-help-hear-clearly-protecting-delicate-hair-cells-inner-ear.html

New pill that may help improve age-related hearing loss by protecting delicate hair cells in the inner ear
A new drug, SPI-1005, aids hearing by protecting delicate hair cells in inner ear
It is also being tested in U.S. as a potential treatment for patients with Covid-19
The number of auditory hair cells declines due to age, disease and loud noise

PREVIEW: “Preclinical/Clinical Translational Evidence for a Potential Hearing Restoration Therapeutic, FX-322” [ARO 2021 Podium Presentation]

Here is a sneak preview of an upcoming podium presentation from Will McLean (Frequency Therapeutics) about hearing restoration and FX-322:

FX-322 podium abstract for ARO February 2021

What’s happening:

In less than two weeks from today, the 44th Annual ARO MidWinter Meeting will begin.

It is a virtual conference.

On Monday, February 22, 2021, Will McLean (Frequency Therapeutics) will give a podium presentation at this virtual conference.

Topic? FX-322…

Here is a copy of McLean’s podium abstract:

Preclinical/Clinical Translational Evidence for a Potential Hearing Restoration Therapeutic, FX-322

Background: Cochlear hair cell loss in mammals is permanent because progenitor cells fail to divide and differentiate on their own. Previous work has shown that the two compounds in FX-322 enhance the regenerative potential of mouse and human progenitor cells in vitro. This multi-group collaboration assessed the pharmacodynamic (PD) and restorative potential of FX-322 in a mouse noise-induced hearing loss (NIHL) model, cochlear pharmacokinetics (PK) of intratympanically injected FX-322 in guinea pigs, perilymph concentrations in patients undergoing cochlear implantation, and a safety study of FX-322 in patients with permanent sensorineural hearing loss (SNHL).

Methods: PD effects were first assessed in a NIHL mouse model to assess the therapeutic potential of FX-322. PK studies with FX-322 were performed in guinea pigs to calibrate a well-established computer model predicting drug distribution over the length of the cochlea with time. The animal PK model was extended to humans by analysis of perilymph samples collected from subjects undergoing cochlear implant surgery. A double-blinded, placebo-controlled, safety trial in patients with permanent/stable SNHL was conducted to assess the systemic safety, plasma PK, and effects on otoscopy, audiometry, and word testing (WR, WIN). The trial enrolled 23 patients with medical histories consistent with either NIHL or sudden SNHL. Treatment was a single unilateral intratympanic dose and patients were monitored overnight for safety, PK and PD over a 90-day period.

Results: Animal PD – A single intratympanic injection of FX322 was associated with increased hair cell counts and improved auditory function compared to placebo in mice with NIHL within one month after treatment. Guinea Pig PK – FX-322 concentrations in samples taken from the RW niche were found to decrease with time, with elimination half-times under 1 hour. The highest drug concentration was observed in the basal regions. Human PK – Intraoperative middle ear contents and perilymph were analyzed for FX-322 approximately 1 hour into surgery for cochlear implant subjects (n=7). While some subjects had anatomical features that have been speculated to impair drug entry, such as mucosal folds or bony overhangs, FX-322 was quantified in all samples analyzed. Human Safety and PD – FX-322 was associated with a favorable safety profile. In FX-322-treated subject ears WR and WIN improved over the duration of the study while placebo-treated subject ears did not.

Conclusions: Both preclinical and clinical PK analyses suggest that FX-322 was able to achieve therapeutically active levels in the extended high frequency region of the cochlea. Preclinically, this was associated with an increase in hair cell counts and auditory brainstem response thresholds. The present work provides the first evidence that a novel potential therapeutic, FX-322, is associated with clinically meaningful improvements in speech recognition in subjects with permanent and stable SNHL, and larger clinical studies are underway.

The source of this “podium abstract” is the Association for Research in Otolaryngology (ARO)’s 44th Annual Mid-Winter Meeting event website.

Here is a link to the official PDF copy of the February 22, 2021 FX-322 podium presentation [EDIT #1: the link does not work, removed] (uploaded online by ARO’s event organizers… who have once again done a superb job organizing all of the presentations, speakers, podiums, posters, and more, into a friendly and searchable format *even when some links don’t work!).

What’s “new” here?

For readers who have been closely following FX-322 updates… there is nothing truly “new” in this presentation preview. However, we do not know what other data or information or announcements will be shared alongside this presentation. Perhaps we will also get a press release on Monday, February 22 which gives us more substantial “news” *fingers crossed*…

RE: FX-322 updates…

If you’re interested in news updates RE: the very latest hearing loss treatments and recent progress toward potential cures… remember to sign up for the HearingLossTreatmentReport.com email newsletter. It’s 100% free and the goal is to give you an easy (and fast) way to get updates about FX-322 and other promising hearing restoration therapeutics – earlier… often days (and sometimes weeks) ahead of “mainstream” sources.

Questions? Comments? Feedback? Send an email to michael@urgentresearch.com and say hello.

An antibody to RGMa promotes regeneration of cochlear synapses after noise exposure

https://www.nature.com/articles/s41598-021-81294-5

An antibody to RGMa promotes regeneration of cochlear synapses after noise exposure

Treatment of noise-exposed animals with an anti-RGMa blocking antibody regenerated inner hair cell synapses and resulted in recovery of wave-I amplitude of the auditory brainstem response, indicating effective reversal of synaptopathy.

COMMENT: see preprint from July 2, 2020
https://www.biorxiv.org/content/10.1101/2020.07.01.183269v1.full

Stem Cells and Gene Therapy in Progressive Hearing Loss: the State of the Art

CATEGORY:
Research

SCREENSHOT:
Stem Cells and Gene Therapy in Progressive Hearing Loss: the State of the Art Screenshot

TITLE:
Stem Cells and Gene Therapy in Progressive Hearing Loss: the State of the Art

CONTENT:
J Assoc Res Otolaryngol. 2021 Jan 28. doi: 10.1007/s10162-020-00781-0. Online ahead of print.

ABSTRACT

Progressive non-syndromic sensorineural hearing loss (PNSHL) is the most common cause of sensory impairment, affecting more than a third of individuals over the age of 65. PNSHL includes noise-induced hearing loss (NIHL) and inherited forms of deafness, among which is delayed-onset autosomal dominant hearing loss (AD PNSHL). PNSHL is a prime candidate for genetic therapies due to the fact that PNSHL has been studied extensively, and there is a potentially wide window between identification of the disorder and the onset of hearing loss. Several gene therapy strategies exist that show potential for targeting PNSHL, including viral and non-viral approaches, and gene editing versus gene-modulating approaches. To fully explore the potential of these therapy strategies, a faithful in vitro model of the human inner ear is needed. Such models may come from induced pluripotent stem cells (iPSCs). The development of new treatment modalities by combining iPSC modeling with novel and innovative gene therapy approaches will pave the way for future applications leading to improved quality of life for many affected individuals and their families.

PMID:33507440 | DOI:10.1007/s10162-020-00781-0

SOURCE:
Journal of the Association for Research in Otolaryngology : JARO

PUBLISHER:

PMID:
pubmed:33507440

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:33507440

DOI:
10.1007/s10162-020-00781-0

DATE – PUBLISHED:
Thu, 28 Jan 2021 06:00:00 -0500

DATE – DOI:
2021-01-28T16:56:11Z

DATE – ADDED:
01/28/21 11:57PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33507440/

LINK – DOI:
https://doi.org/10.1007/s10162-020-00781-0

LINK – PUBLISHER:
http://link.springer.com/10.1007/s10162-020-00781-0

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2021-01-29T04:57:19+00:00, https://www.hearinglosstreatmentreport.com.

Frequency Therapeutics appoints Chief Manufacturing Officer as it prepares for larger studies in support of lead FX-322 program

https://investors.frequencytx.com/news-releases/news-release-details/frequency-therapeutics-appoints-quentin-mccubbin-phd-chief

Frequency Therapeutics Appoints Quentin McCubbin, Ph.D., as Chief Manufacturing Officer
WOBURN, Mass.–(BUSINESS WIRE)–Jan. 19, 2021– 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 the appointment of Quentin McCubbin, Ph.D., as chief manufacturing officer. Dr. McCubbin will oversee Company technical operations, leading drug product formulation, chemistry manufacturing and controls (CMC) and supply chain, to support the development of Frequency’s pipeline of product candidates.

Dr. McCubbin joins Frequency from Cerevel Therapeutics, a clinical-stage biotechnology company where he served as head of technical operations. Prior to Cerevel, he spent 19 years at Takeda/Millennium Pharmaceuticals in various roles progressing in responsibility, including six years as vice president of pharmaceutical sciences and global head of process chemistry.

“Quentin’s background and leadership in technical operations will be critical as we prepare for larger studies in support of our lead FX-322 program that aims to treat the most common form of hearing loss, and as we look to diversify and expand our clinical pipeline with a program for remyelination in multiple sclerosis,” sa

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