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FX-322 in Adults With Age-Related Sensorineural Hearing Loss

CATEGORY:
Clinical Trials

TITLE:
FX-322 in Adults With Age-Related Sensorineural Hearing Loss

INTERVENTION/TREATMENT:

PHASE:

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

Interventions :   Drug: FX-322;   Other: placebo

Sponsor :   Frequency Therapeutics

Recruiting

ID:
NCT04601909

STATUS:

DATE – FIRST POSTED:
Mon, 26 Oct 2020 12:00:00 EDT

DATE – LAST UPDATE POSTED:
10/26/20 07:11AM

DATE – RETRIEVED:
10/26/20 07:11AM

LINK – STUDY HISTORY:
https://clinicaltrials.gov/ct2/history/NCT04601909

LINK – STUDY RECORD:
https://clinicaltrials.gov/ct2/show/NCT04601909

SENS-401 Phase 2 trial results expected in mid-2021, prelinical data expected by end of 2020

https://www.businesswire.com/news/home/20201020006234/en/Sensorion-reports-2020-first-half-results

Preclinical data from these studies are expected by the end of 2020.

Sensorion reports 2020 first half results
Financial position strengthened with €31m (US$36.5m) capital raise in September 2020

Gene therapy agreement expands pipeline and preclinical data
SENS-401 Phase II trial progressing with results expected in mid-2021
Cash position of €30.7m as of June 30, 2020, further reinforced by September capital raise
Cash runway now extended to H2 2022

Perspectives on Human Hearing Loss, Cochlear Regeneration, and the Potential for Hearing Restoration Therapies

CATEGORY:
Research

TITLE:
Perspectives on Human Hearing Loss, Cochlear Regeneration, and the Potential for Hearing Restoration Therapies

DESCRIPTION:
Most adults who acquire hearing loss find it to be a disability that is poorly corrected by current prosthetics. This gap drives current research in cochlear mechanosensory hair cell regeneration and in hearing restoration. Birds and fish can spontaneously regenerate lost hair cells through a process that has become better defined in the last few years. Findings from these studies have informed new research on hair cell regeneration in the mammalian cochlea. Hair cell regeneration is one part of…

CONTENT:
Brain Sci. 2020 Oct 20;10(10):E756. doi: 10.3390/brainsci10100756.

ABSTRACT

Most adults who acquire hearing loss find it to be a disability that is poorly corrected by current prosthetics. This gap drives current research in cochlear mechanosensory hair cell regeneration and in hearing restoration. Birds and fish can spontaneously regenerate lost hair cells through a process that has become better defined in the last few years. Findings from these studies have informed new research on hair cell regeneration in the mammalian cochlea. Hair cell regeneration is one part of the greater problem of hearing restoration, as hearing loss can stem from a myriad of causes. This review discusses these issues and recent findings, and places them in the greater social context of need and community.

PMID:33092183 | DOI:10.3390/brainsci10100756

SOURCE:
Brain sciences

DATE – PUBLISHED:
20 Oct 2020

DATE – ADDED:
Fri, 23 Oct 2020 06:00:00 -0400

DATE – FOUND:
10/23/20 07:18AM

PUBMED ID:
pubmed:33092183

DOI:
10.3390/brainsci10100756

PUBMED LINK:
https://pubmed.ncbi.nlm.nih.gov/33092183/

DOI LINK:
https://doi.org/10.3390/brainsci10100756

PUBLISHER LINK:
https://www.mdpi.com/2076-3425/10/10/756

Efficacy of SENS 401 in Subjects With Severe or Profound Sudden Sensorineural Hearing Loss

CATEGORY:
Clinical Trials

TITLE:
Efficacy of SENS 401 in Subjects With Severe or Profound Sudden Sensorineural Hearing Loss

INTERVENTION/TREATMENT:

PHASE:

DESCRIPTION:
Condition :   Severe Sudden Sensorineural Hearing Loss

Interventions :   Drug: SENS-401;   Other: Placebo Oral Tablet

Sponsor :   Sensorion

Recruiting

ID:
NCT03603314

STATUS:

DATE – FIRST POSTED:
Fri, 27 Jul 2018 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/NCT03603314

LINK – STUDY RECORD:
https://clinicaltrials.gov/ct2/show/NCT03603314

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

Progenitor cell therapy for acquired pediatric nervous system injury: Traumatic brain injury and acquired sensorineural hearing loss

CATEGORY:
Research

TITLE:
Progenitor cell therapy for acquired pediatric nervous system injury: Traumatic brain injury and acquired sensorineural hearing loss

DESCRIPTION:
While cell therapies hold remarkable promise for replacing injured cells and repairing damaged tissues, cell replacement is not the only means by which these therapies can achieve therapeutic effect. For example, recent publications show that treatment with varieties of adult, multipotent stem cells can improve outcomes in patients with neurological conditions such as traumatic brain injury and hearing loss without directly replacing damaged or lost cells. As the immune system plays a central…

CONTENT:
Stem Cells Transl Med. 2020 Oct 9. doi: 10.1002/sctm.20-0026. Online ahead of print.

ABSTRACT

While cell therapies hold remarkable promise for replacing injured cells and repairing damaged tissues, cell replacement is not the only means by which these therapies can achieve therapeutic effect. For example, recent publications show that treatment with varieties of adult, multipotent stem cells can improve outcomes in patients with neurological conditions such as traumatic brain injury and hearing loss without directly replacing damaged or lost cells. As the immune system plays a central role in injury response and tissue repair, we here suggest that multipotent stem cell therapies achieve therapeutic effect by altering the immune response to injury, thereby limiting damage due to inflammation and possibly promoting repair. These findings argue for a broader understanding of the mechanisms by which cell therapies can benefit patients.

PMID:33034162 | DOI:10.1002/sctm.20-0026

SOURCE:
Stem cells translational medicine

DATE – PUBLISHED:
9 Oct 2020

DATE – ADDED:
Fri, 09 Oct 2020 06:00:00 -0400

DATE – FOUND:
10/09/20 07:09AM

PUBMED ID:
pubmed:33034162

DOI:
10.1002/sctm.20-0026

PUBMED LINK:
https://pubmed.ncbi.nlm.nih.gov/33034162/

DOI LINK:
https://doi.org/10.1002/sctm.20-0026

PUBLISHER LINK:
https://onlinelibrary.wiley.com/doi/10.1002/sctm.20-0026

Estimated FX-322 Phase 2a Study Completion Date: May 21, 2021

Very quick update:

The FX-322 Phase 2a clinical trial is now *officially* active and we now have an updated estimated completion date for the study: May 21, 2021.

Details below:

  • The FX-322 study record was updated on October 8, 2020
  • The study status was changed from “Recruiting” to “Active, not recruiting”
  • The study completion date was changed from September 30, 2020 [Anticipated] to May 21, 2021 [Anticipated].

FX-322 trial update October 8, 2020 now active

Source: History of Changes for Study: NCT04120116 (FX-322 in Adults With Stable Sensorineural Hearing Loss)

That’s all for now.

For the latest FX-322 updates and news of other hearing loss treatments, sign up for the free once-weekly email newsletter.

Email michael@urgentresearch.com and say hello. Let me know what type of hearing loss treatment updates you like best. Feedback encouraged.

Also, remember to check out TinnitusTreatmentReport.com if you don’t already know about it.

FX-322 in Adults With Stable Sensorineural Hearing Loss

New item in Clinical Trial category found.

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

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

Interventions :   Drug: FX-322;   Drug: Placebo

Sponsor :   Frequency Therapeutics

Active, not recruiting

ID:
NCT04120116

FIRST POSTED:
Wed, 09 Oct 2019 12:00:00 EDT

LAST UPDATE POSTED:
10/08/20 07:05AM

RECRUITMENT STATUS:
recruiting

INTERVENTION/DRUG:
FX-322

SOURCE LINK:
https://clinicaltrials.gov/ct2/show/NCT04120116?type=Intr&cond=Sensorineural+Hearing+Loss&phase=0124&lupd_s=10%2F07%2F2020&lupd_d=1&sort=nwst

LINK:
https://clinicaltrials.gov/ct2/show/NCT04120116

Inhibition of SRp30c may act as a new treatment way of glucocorticoid-resistant sudden sensorineural hearing loss

CATEGORY:
Research

TITLE:
GRβ Regulates Glucocorticoid Resistance in Sudden Sensorineural Hearing Loss

DESCRIPTION:
CONCLUSION: We clarified the mechanisms of high expression of GRβ in glucocorticoid-resistant sudden sensorineural hearing loss, and proved that the inhibition of SRp30c may act as a new treatment way of glucocorticoid-resistant sudden sensorineural hearing loss.

CONTENT:
Curr Pharm Biotechnol. 2020 Oct 8. doi: 10.2174/1389201021666201008163534. Online ahead of print.

ABSTRACT

BACKGROUND: In recent years, the incidence of sudden deafness has gradually increased, with a very limited understanding of the etiology and the pathogenesis. Glucocorticoids are the first choice for the treatment, but some hormoneresistant patients are not sensitive to glucocorticoid therapy. The pathogenesis is not yet known. In this study, we aim to construct HEI-OC1 cell line stably overexpressing glucocorticoid receptor beta (GRβ), and identify its exact role in the cases of glucocorticoid-resistant sudden deafness.

METHOD: We used the endotoxin lipopolysaccharide-stimulated cochlear hair cells (HEI-OC1) to investigate the relationship of inflammation factor IL-2, TNF alpha, and SRp30c with the high expression GRβ. We build a stable GRβ high expression HEI-OC1 cell line and clarified its effects on the therapeutic effect from Dexamethasone. MTT assay, colony formation assay, CCK-8 assay, Western blot, and RT-qPCR were utilized for the characterizations.

RESULTS: Dexamethasone reduced LPS-induced inflammatory response in HEI-OC1 cells (p<0.05), detected by MTT assay. Dexamethasone could protect HEI-OC1 cells, but its protective effect was weakened due to the transfection of SRp30c overexpression plasmid (p<0.05). The transfection of SRp30c over-expression plasmid in HEI-OC1 cells could elevate the expressions of GRβ (p<0.05). CONCLUSION: We clarified the mechanisms of high expression of GRβ in glucocorticoid-resistant sudden sensorineural hearing loss, and proved that the inhibition of SRp30c may act as a new treatment way of glucocorticoid-resistant sudden sensorineural hearing loss. PMID:33032506 | DOI:10.2174/1389201021666201008163534 SOURCE: Current pharmaceutical biotechnology DATE - PUBLISHED: 8 Oct 2020 DATE - ADDED: Fri, 09 Oct 2020 06:00:00 -0400 DATE - FOUND: 10/09/20 07:09AM PUBMED ID: pubmed:33032506 DOI: 10.2174/1389201021666201008163534 PUBMED LINK: https://pubmed.ncbi.nlm.nih.gov/33032506/ DOI LINK: https://doi.org/10.2174/1389201021666201008163534 PUBLISHER LINK: https://www.eurekaselect.com/186752/article

Altered outer hair cell mitochondrial and subsurface cisternae connectomics are candidate mechanisms for hearing-loss in mice

CATEGORY:
Research

TITLE:
Altered outer hair cell mitochondrial and subsurface cisternae connectomics are candidate mechanisms for hearing-loss in mice

DESCRIPTION:
Organelle crosstalk is vital for cellular functions. The propinquity of mitochondria, endoplasmic reticulum (ER), and plasma membrane promote regulation of multiple functions, which include intracellular Ca^(2+) flux, and cellular biogenesis. Although the purposes of apposing mitochondria and ER have been described, an understanding of altered organelle connectomics related to disease states is emerging. Since inner ear outer hair cell (OHC) degeneration is a common trait of age-related hearing…

CONTENT:
J Neurosci. 2020 Oct 5:JN-RM-2901-19. doi: 10.1523/JNEUROSCI.2901-19.2020. Online ahead of print.

ABSTRACT

Organelle crosstalk is vital for cellular functions. The propinquity of mitochondria, endoplasmic reticulum (ER), and plasma membrane promote regulation of multiple functions, which include intracellular Ca2+ flux, and cellular biogenesis. Although the purposes of apposing mitochondria and ER have been described, an understanding of altered organelle connectomics related to disease states is emerging. Since inner ear outer hair cell (OHC) degeneration is a common trait of age-related hearing loss, the objective of this study was to investigate whether the structural and functional coupling of mitochondria with subsurface cisternae (SSC), was affected by aging. We applied functional and structural probes to equal numbers of male and female mice with a hearing phenotype akin to human aging. We discovered the polarization of cristae and crista junctions in mitochondria tethered to the SSC in OHCs. Aging was associated with SSC stress and decoupling of mitochondria with the SSC, mitochondrial fission/fusion imbalance, a remarkable reduction in mitochondrial and cytoplasmic Ca2+ levels, reduced K+ -induced Ca2+ uptake, and marked plasticity of cristae membranes. A model of structure-based ATP production predicts profound energy stress in older OHCs. This report provides data suggesting that altered membrane organelle connectomics may result in progressive hearing loss.SIGNIFICANCE STATEMENT We address the question, “Do aged OHCs exhibit detectable changes in organelle connectomics that would help us better understand human hearing loss in a relevant mouse model?” Because of the close association of mitochondria SSC over much of the OHC inner surface, mitochondria-SSC connectomics appears to play a central role in hearing. In polarized cells such as OHCs, where there is functional segregation of apical versus basal regions, the relationship between altered organelle connectomics and hearing loss is unknown. We propose a mechanism of mitochondria-SSC dysregulation related to aging and OHC degeneration, showing distinct altered mitochondrial and cytoplasmic Ca2+ regulation, mitochondrial polarization, and fission/fusion imbalance, mitochondrial-SSC decoupling, and SSC and cellular energy stress.

PMID:33020216 | DOI:10.1523/JNEUROSCI.2901-19.2020

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

DATE – PUBLISHED:
5 Oct 2020

DATE – ADDED:
Tue, 06 Oct 2020 06:00:00 -0400

DATE – FOUND:
10/06/20 07:06AM

PUBMED ID:
pubmed:33020216

DOI:
10.1523/JNEUROSCI.2901-19.2020

PUBMED LINK:
https://pubmed.ncbi.nlm.nih.gov/33020216/

DOI LINK:
https://doi.org/10.1523/JNEUROSCI.2901-19.2020

PUBLISHER LINK:
http://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.2901-19.2020

Biomarkers Suggesting Favorable Prognostic Outcomes in Sudden Sensorineural Hearing Loss

CATEGORY:
Research

TITLE:
Biomarkers Suggesting Favorable Prognostic Outcomes in Sudden Sensorineural Hearing Loss

DESCRIPTION:
Sudden sensorineural hearing loss (SSNHL) is a medical emergency, making detailed examination to determine possible causes and early treatment important. However, etiological examinations in SSNHL do not always reveal a cause, and several factors have been found to affect treatment outcomes. Various studies are being performed to determine the prognosis and effects of treatment in patients who experience sudden hearing loss, and to identify biomarkers associated with this condition. Embase,…

CONTENT:
Int J Mol Sci. 2020 Sep 30;21(19):E7248. doi: 10.3390/ijms21197248.

ABSTRACT

Sudden sensorineural hearing loss (SSNHL) is a medical emergency, making detailed examination to determine possible causes and early treatment important. However, etiological examinations in SSNHL do not always reveal a cause, and several factors have been found to affect treatment outcomes. Various studies are being performed to determine the prognosis and effects of treatment in patients who experience sudden hearing loss, and to identify biomarkers associated with this condition. Embase, PubMed, and the Cochrane database were searched using the key words SSNHL, prognostic, and biomarker. This search identified 4 articles in Embase, 28 articles in PubMed, and 36 in the Cochrane database. Of these 68 articles, 3 were duplicates and 37 were unrelated to the research topic. After excluding these articles, the remaining 28 articles were reviewed. Factors associated with SSNHL were divided into six categories: metabolic, hemostatic, inflammatory, immunologic, oxidative, and other factors. The associations between these factors with the occurrence of SSNHL and with patient prognosis were analyzed. Low monocyte counts, low neutrophil/lymphocyte ratio (NLR) and monocyte/high-density lipoproteins (HDL) cholesterol ratio (MHR), and low concentrations of fibrinogen, platelet glycoprotein (GP) IIIa, and TNF-α were found to be associated with good prognosis. However, these factors alone could not completely determine the onset of and recovery from SSNHL, suggesting the need for future basic and clinical studies.

PMID:33008090 | DOI:10.3390/ijms21197248

SOURCE:
International journal of molecular sciences

DATE – PUBLISHED:
30 Sep 2020

DATE – ADDED:
Sat, 03 Oct 2020 06:00:00 -0400

DATE – FOUND:
10/04/20 02:17AM

PUBMED ID:
pubmed:33008090

DOI:
10.3390/ijms21197248

PUBMED LINK:
https://pubmed.ncbi.nlm.nih.gov/33008090/

DOI LINK:
https://doi.org/10.3390/ijms21197248

PUBLISHER LINK:
https://www.mdpi.com/1422-0067/21/19/7248
https://www.mdpi.com/1422-0067/21/19/7248/htm

How much will FX-322 cost? David Lucchino, Frequency Therapeutics CEO, talks pricing and value…

How much will FX-322 cost?

David Lucchino, CEO of Frequency Therapeutics, was recently asked for some “rough ideas around [the] pricing and reimbursement” of FX-322.

Here is a lightly edited* almost-word-for-word transcript of David’s response**:

*EDITED HOW? Disconnected parts of speech and filler words such as umm, well, you know, etc., have been removed for sake of clarity.

**SPOILER ALERT: David, understandably, does NOT give us a specific number. He gives us the answer we all expected, that of a responsible CEO. As he says, “specifics around pricing and regulatory ‘really need to be managed and played out appropriately'” (in other words, NOT eagerly telling us “FX-322 WILL COST EXACTLY THESE MANY DOLLARS” while the drug is still in phase 2a clinical trials).

Alas.

Specifics? Best I can do is this:

HOST: […] walk us through your thinking around the target patient population and maybe some kind of rough ideas around pricing and reimbursement […]

DAVID LUCCHINO: I’m still evolving our understanding of this as we really work in partner with the FDA to understand exactly the true, we think, impact of our therapy. So it’s hard for me to speak in any absolutes. We know that the market is absolutely substantial and the unmet clinical need is very, very high. We think that hearing aids will continue to have a real role and be a good option for patients, though we think having a therapy that can truly start to heal someone’s hearing and create a healthy cochlea, if you will, is going to be a very strong value proposition both with or without hearing aids. I think that specifics around pricing and regulatory, those really need to be managed and played out appropriately. I think that we’re aware of what hearing aids are priced at, and we’re aware of what cochlear implants are priced at, and how hearing aids are handled from a regulatory standpoint and our goal is to deliver a highly effective therapy and do it in a way where we can continue to build out a very successful company that investors will recognize for years and years to come.

HOST: Excellent, super helpful.

SOURCE: Where is this from? These comments were made during a live Q&A at the Oppenheimer Virtual Fall Healthcare Life Sciences & MedTech Summit, which took place on Tuesday, September 22, 2020 at 10:00 am Eastern Time.

As David’s comments suggest, a lot of work goes into determining the price of a treatment such as FX-322. Meanwhile, the drug only recently completed enrollment for its Phase 2a study.

So don’t expect any “Hey it will cost THIS many dollars” answers yet…

For now, this recent commentary is the most recent and up-to-date information regarding FX-322’s price tag. Straight from the CEO’s mouth.

And let’s be honest, it is the reply we all expected… But with some interesting “price anchoring” thrown in with the mention of hearing aid costs (average price: $2372) and cochlear implant costs (average price: between $30,000-$100,000).***

Why would David mention those price points? How do drug companies calculate price? How do comparisons and price anchoring factor into that calculation?

Hmmmm…

Let the speculation begin!

Excellent Super Helpful vague troll face meme

LINK TO VIDEO: If you want to watch the interview, here is a link to the video recording of the Frequency Therapeutics virtual event webcast (the FX-322 pricing-related comments begin at around 39:00):

https://wsw.com/webcast/oppenheimer5/freq/2713518

And…

If you want an easy way to follow FX-322 including any future updates RE: cost of FX-322, join the weekly email update list. It’s a free, once-weekly email [starting soon] that lists all the new links that were added to this site’s front page during the previous 7 days. No spam, no nonsense.

***Reference: https://www.hearingtracker.com/how-much-do-hearing-aids-cost, https://www.hearingtracker.com/cochlear-implants#a-how-much-do-cochlear-implants-cost.

Altered Brain Activity and Functional Connectivity in Sudden Sensorineural Hearing Loss

CATEGORY:
Research

TITLE:
Altered Brain Activity and Functional Connectivity in Unilateral Sudden Sensorineural Hearing Loss

DESCRIPTION:
CONCLUSION: SSNHL causes functional alterations in brain regions, mainly in the striatum, auditory cortex, visual cortex, MTG, AG, precuneus, and limbic lobes within the acute period of hearing loss.

CONTENT:
Neural Plast. 2020 Sep 22;2020:9460364. doi: 10.1155/2020/9460364. eCollection 2020.

ABSTRACT

BACKGROUND: Sudden sensorineural hearing loss (SSNHL) is an otologic emergency and could lead to social difficulties and mental disorders in some patients. Although many studies have analyzed altered brain function in populations with hearing loss, little information is available about patients with idiopathic SSNHL. This study is aimed at investigating brain functional changes in SSNHL via functional magnetic resonance imaging (fMRI).

METHODS: Thirty-six patients with SSNHL and thirty well-matched normal hearing individuals underwent resting-state fMRI. Amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and functional connectivity (FC) values were calculated.

RESULTS: In the SSNHL patients, ALFF and fALFF were significantly increased in the bilateral putamen but decreased in the right calcarine cortex, right middle temporal gyrus (MTG), and right precentral gyrus. Widespread increases in FC were observed between brain regions, mainly including the bilateral auditory cortex, bilateral visual cortex, left striatum, left angular gyrus (AG), bilateral precuneus, and bilateral limbic lobes in patients with SSNHL. No decreased FC was observed.

CONCLUSION: SSNHL causes functional alterations in brain regions, mainly in the striatum, auditory cortex, visual cortex, MTG, AG, precuneus, and limbic lobes within the acute period of hearing loss.

PMID:33029130 | PMC:PMC7527900 | DOI:10.1155/2020/9460364

SOURCE:
Neural plasticity

DATE – PUBLISHED:
22 Sep 2020

DATE – ADDED:
Thu, 08 Oct 2020 06:00:00 -0400

DATE – FOUND:
10/08/20 06:42AM

PUBMED ID:
pubmed:33029130

DOI:
10.1155/2020/9460364

PUBMED LINK:
https://pubmed.ncbi.nlm.nih.gov/33029130/

DOI LINK:
https://doi.org/10.1155/2020/9460364

PUBLISHER LINK:
https://www.hindawi.com/journals/np/2020/9460364/

Hearing Loss – Reddit

https://www.reddit.com/r/HearingLoss/

Hearing Loss – Reddit
r/HearingLoss

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

https://clinicaltrials.gov/ct2/show/NCT04129775?type=Intr&cond=Hearing+Loss&lupd_s=10%2F03%2F2019&lupd_d=14&sort=nwst

Condition :   Sensorineural Hearing Loss

Interventions :   Drug: OTO-413;   Drug: Placebo

Sponsor :   Otonomy, Inc.

Recruiting

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

NCT04129775

Thu, 17 Oct 2019 12:00:00 EDT

Last Update Posted: 10/17/19 08:21AM

https://clinicaltrials.gov/ct2/show/NCT04129775

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

Updated: September 14, 2020
Active, not recruiting

Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled Phase 1/2 Study of OTO-413 Given as a Single Intratympanic Injection in Subjects With Speech-in-noise Hearing Impairment
Actual Study Start Date : October 1, 2019
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2020

Frequency Therapeutics Presents Results Demonstrating Sustained Improvement in Hearing Loss Patients Treated with FX-322

https://investors.frequencytx.com/news-releases/news-release-details/frequency-therapeutics-presents-results-demonstrating-sustained

Frequency Therapeutics Presents Results Demonstrating Sustained Improvement in Hearing Loss Patients Treated with FX-322

Evidence of Durable Hearing Improvements in Follow-Up with Patients from Phase 1/2 Study; Speech Intelligibility and Audibility Sustained for Up to 21 Months After Initial Dosing

Data Highlighted at the 2020 American Academy of Otolaryngology – Head and Neck Surgery (AAO-HNS) Annual Meeting

Role of protein in development of new hearing hair cells: Finding could lead to future treatments for hearing loss

https://www.sciencedaily.com/releases/2020/09/200911200012.htm

Role of protein in development of new hearing hair cells
Finding could lead to future treatments for hearing loss

Date:
September 11, 2020

Source:
University of Maryland School of Medicine

Summary:
Researchers have conducted a study that has determined the role that a critical protein plays in the development of hair cells. These hair cells are vital for hearing. Some of these cells amplify sounds that come into the ear, and others transform sound waves into electrical signals that travel to the brain.

Circulating microRNAs as potentially new diagnostic biomarkers of idiopathic sudden sensorineural hearing loss

https://www.tandfonline.com/doi/abs/10.1080/00016489.2020.1810859?journalCode=ioto20

https://www.ncbi.nlm.nih.gov/pubmed/32876518?dopt=Abstract

Related Articles

Circulating microRNAs as potentially new diagnostic biomarkers of idiopathic sudden sensorineural hearing loss.

Acta Otolaryngol. 2020 Sep 02;:1-8

Authors: Ha SM, Hwang KR, Park IH, Park S, Choi JS, Park DJ, Park JE, Lee SH, Lee HY, Seo YJ

Abstract

BACKGROUND: Early detection of inner ear cell damage can reduce the chances of permanent damage to hearing ability. However, current inner ear cell damage detection methods can detect damage only after the patient has lost hearing ability. MicroRNA expression levels in circulating systems are affected in diseases or conditions arising from the distant lesions. Therefore, detection of circulating microRNA expression levels could be one of the best ways to obtain information on inaccessible lesion sites.

AIMS/OBJECTIVES: This study aims to establish a method for monitoring idiopathic sudden sensorineural hearing loss (ISSNHL) by analyzing circulating microRNA expression levels. 21 ISSNHL patients and 24 healthy controls were enrolled.

MATERIAL AND METHODS: Real-time quantitative polymerase chain reaction was performed for detecting expression levels of circulating microRNAs.

RESULTS: Among eight circulating microRNAs, expression levels of five circulating microRNAs significantly differed between ISSNHL patients and healthy controls. circulating microRNA expression levels correlates with treatment outcomes and hearing ability.

CONCLUSIONS AND SIGNIFICANCE: Using methods combining the evaluation of miR-183, miR-210, miR-18b, and miR-23a cut-off values identified in ISSNHL patients and healthy controls during receiver operating characteristic curve analysis, sensitivity and specificity of 80.95% (17/21) and 87.50% (21/24) were obtained, respectively.

PMID: 32876518 [PubMed – as supplied by publisher]

Dextromethorphan Attenuates Sensorineural Hearing Loss in an Animal Model and Population-Based Cohort Study

https://www.mdpi.com/1660-4601/17/17/6336/htm

https://pubmed.ncbi.nlm.nih.gov/32878128/

Open Access
Article

Dextromethorphan Attenuates Sensorineural Hearing Loss in an Animal Model and Population-Based Cohort Study

Int. J. Environ. Res. Public Health 2020, 17(17), 6336; https://doi.org/10.3390/ijerph17176336

Received: 31 July 2020 / Revised: 27 August 2020 / Accepted: 28 August 2020 / Published: 31 August 2020

COMMENT: This link was added manually from a PubMed search (September 9, 2020), it has not (yet?) been retrieved by the system. Add this potentially missed link to error logbook, investigate cause.

The Role of Anti-Endothelial Cell Autoantibodies and Immune Response in Acute Low-Tone Hearing Loss

https://journals.sagepub.com/doi/10.1177/0145561320952501

https://www.ncbi.nlm.nih.gov/pubmed/32865463?dopt=Abstract

Related Articles

The Role of Anti-Endothelial Cell Autoantibodies and Immune Response in Acute Low-Tone Hearing Loss.

Ear Nose Throat J. 2020 Aug 31;:145561320952501

Authors: Chen D, Wang Z, Jia G, Mao H, Ni Y

Abstract

OBJECTIVE: Immunity is associated with acute low tone hearing loss. However, the exact pathophysiology of immunity-mediated acute low tone hearing loss remains unknown. In this study, we evaluated the presence, therapeutic effectiveness, and immunopathological mechanisms of anti-endothelial cell autoantibodies (AECEs) in patients with acute low-frequency hearing loss.

MATERIAL AND METHODS: Forty-nine patients who were treated as inpatients having acute low-frequency hearing loss and additional symptoms, such as ear fullness, tinnitus, dizziness, or hyperacusis, were enrolled in this study. Serum samples from these patients were collected for laboratory serum autoimmunity detection, including AECAs, antinuclear antibodies, immunoglobulin, and circular immune complex. Therapeutic responses to combination therapy in short-term outcome and serum cytokine levels were compared between AECA-positive and AECA-negative patients.

RESULTS: Anti-endothelial cell autoantibodies-positive patients tended to show significantly less response to standard therapy compared with AECAs controls (P < .05). Moreover, some serum cytokine levels elevated in both AECAs- and AECAs+ groups. Positive ratio of interleukin-8 and concentrations of macrophage inflammatory protein-1α were found higher in AECAs+ groups (P < .05). CONCLUSION: The results supported that AECAs might wield influence on the short-term outcome of acute low-tone hearing loss (ALHL) treatment. Furthermore, AECA-mediated acute low-frequency hearing loss possibly involved dysregulation of inflammation process and release of cytokines. PMID: 32865463 [PubMed - as supplied by publisher]

Protective Effects of EPI-743 on Noise-Induced Hearing Loss [Completed]

https://clinicaltrials.gov/ct2/show/NCT02257983?type=Intr&cond=Hearing+Loss&lupd_s=08%2F17%2F2020&lupd_d=14&sort=nwst

Condition :   Noise-induced Hearing Loss

Interventions :   Drug: EPI-743;   Drug: Placebo

Sponsor :   PTC Therapeutics

Completed

Protective Effects of EPI-743 on Noise-Induced Hearing Loss

NCT02257983

Tue, 07 Oct 2014 12:00:00 EDT

Last Update Posted: 08/31/20 07:19AM

Loss of RAD6B induces degeneration of the cochlea in mice

https://www.sciencedirect.com/science/article/abs/pii/S0006291X2031562X?via%3Dihub

https://pubmed.ncbi.nlm.nih.gov/32868078/

Loss of RAD6B induces degeneration of the cochlea in mice
Yangping Ma 1, Yanfeng Song 1, Rong Shen 1, Panpan Li 1, Han Ding 1, Zhao Guo 1, Xiangwen Liu 1, Degui Wang 2
Affiliations expand
PMID: 32868078 DOI: 10.1016/j.bbrc.2020.08.017
Abstract
Presbycusis is a form of age-related hearing loss (AHL). Many studies have shown that the degeneration of various structures in the cochlea of the inner ear is related to AHL, and DNA damage is an important factor leading to the above process. As an E2 ubiquitin-conjugated enzyme, RAD6B plays an important role in DNA damage repair (DDR) through histone ubiquitination. However, the molecular mechanism is still unclear. In this study, we investigated the role of RAD6B in the morphological changes and DDR mechanisms in aging-related degeneration of the cochlea of mice. We observed that the hair cells, stria vascularis and spiral ganglion in the cochlea of the RAD6B knockout mice showed significant degenerative changes and abnormal expression of proteins associated with DDR mechanisms compared with those of the littermate wild-type mice. In conclusion, our results suggest that the deletion of RAD6B may lead to abnormalities in DDR, thereby accelerating the degeneration of various structures in the cochlea and senescence and apoptosis of cochlea cells.

Keywords: Cochlea; DNA damage; Degeneration; RAD6B; Ubiquitin.

Systematic Transcriptome Analysis of Noise-Induced Hearing Loss Pathogenesis Suggests Inflammatory Activities and Multiple Susceptible Molecules and Pathways

CATEGORY:
Research

TITLE:
Systematic Transcriptome Analysis of Noise-Induced Hearing Loss Pathogenesis Suggests Inflammatory Activities and Multiple Susceptible Molecules and Pathways

DESCRIPTION:
Noise-induced hearing loss (NIHL) is characterized by damage to cochlear neurons and associated hair cells; however, a systematic evaluation of NIHL pathogenesis is still lacking. Here, we systematically evaluated differentially expressed genes of 22 cochlear samples in an NIHL mouse model. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and weighted gene co-expression network analysis (WGCNA). Core modules were detected using protein-protein interactions…

CONTENT:
Front Genet. 2020 Aug 28;11:968. doi: 10.3389/fgene.2020.00968. eCollection 2020.

ABSTRACT

Noise-induced hearing loss (NIHL) is characterized by damage to cochlear neurons and associated hair cells; however, a systematic evaluation of NIHL pathogenesis is still lacking. Here, we systematically evaluated differentially expressed genes of 22 cochlear samples in an NIHL mouse model. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and weighted gene co-expression network analysis (WGCNA). Core modules were detected using protein-protein interactions and WGCNA with functional annotation, diagnostic value evaluation, and experimental validation. Pooled functional annotation suggested the involvement of multiple inflammatory pathways, including the TNF signaling pathway, IL-17 signaling pathway, NF-kappa B signaling pathway, rheumatoid arthritis, and p53 signaling pathway. The core modules suggested that responses to cytokines, heat, cAMP, ATP, mechanical stimuli, and immune responses were important in NIHL pathogenesis. These activities primarily occurred on the external side of the plasma membrane, the extracellular region, and the nucleus. Binding activities, including CCR2 receptor binding, protein binding, and transcription factor binding, may be important. Additionally, the hub molecules with diagnostic value included Relb, Hspa1b, Ccl2, Ptgs2, Ldlr, Plat, and Ccl17. An evaluation of Relb and Hspa1b protein levels showed that Relb was upregulated in spiral ganglion neurons, which might have diagnostic value. In conclusion, this study indicates that the inflammatory response is involved in auditory organ changes in NIHL pathogenesis; moreover, several molecules and activities have essential and subtle influences that have translational potential for pharmacological intervention.

PMID:33005175 | PMC:PMC7483666 | DOI:10.3389/fgene.2020.00968

SOURCE:
Frontiers in genetics

DATE – PUBLISHED:
28 Aug 2020

DATE – ADDED:
Fri, 02 Oct 2020 06:00:00 -0400

DATE – FOUND:
10/02/20 07:34AM

PUBMED ID:
pubmed:33005175

DOI:
10.3389/fgene.2020.00968

PUBMED LINK:
https://pubmed.ncbi.nlm.nih.gov/33005175/

DOI LINK:
https://doi.org/10.3389/fgene.2020.00968

PUBLISHER LINK:
https://www.frontiersin.org/article/10.3389/fgene.2020.00968/full

Drug development for noise-induced hearing loss

https://www.tandfonline.com/doi/abs/10.1080/17460441.2020.1806232?journalCode=iedc20

https://pubmed.ncbi.nlm.nih.gov/32838572/

Drug development for noise-induced hearing loss
Isabel Varela-Nieto ,Silvia Murillo-Cuesta,Miryam Calvino,Rafael Cediel &Luis Lassaletta
Received 23 Mar 2020, Accepted 03 Aug 2020, Published online: 25 Aug 2020
Download citation https://doi.org/10.1080/17460441.2020.1806232 CrossMark LogoCrossMark

LIN28B/let-7 control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling

https://www.pnas.org/content/early/2020/08/20/2000417117

https://pubmed.ncbi.nlm.nih.gov/32826333/

RESEARCH ARTICLE
LIN28B/let-7 control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling
Xiao-Jun Li and View ORCID ProfileAngelika Doetzlhofer
PNAS first published August 21, 2020 https://doi.org/10.1073/pnas.2000417117

Decades-old model of slow adaptation in sensory hair cells is not supported in mammals

https://advances.sciencemag.org/content/6/33/eabb4922

Decades-old model of slow adaptation in sensory hair cells is not supported in mammals
View ORCID ProfileGiusy A. Caprara1, View ORCID ProfileAndrew A. Mecca1,2 and View ORCID ProfileAnthony W. Peng1,*
See all authors and affiliations

Science Advances 14 Aug 2020:
Vol. 6, no. 33, eabb4922
DOI: 10.1126/sciadv.abb4922

Frequency Therapeutics Expects to Share FX-322 Phase 2a Study Results in Q2 2021

https://www.businesswire.com/news/home/20200812005136/en/

expects to achieve target enrollment by early in the fourth quarter of 2020. Based on this timeline, the Company expects to report study data in the second quarter of 2021.

Frequency Therapeutics Provides Business Updates and Reports Second Quarter 2020 Financial Results
Expects to Complete Enrollment of FX-322 Phase 2a Study for Sensorineural Hearing Loss by Early Q4 2020; Study Readout Anticipated in Q2 2021

Recently Announced Clinical Data Show FX-322 Delivery to the Cochlea and Preliminary Evidence of a Durable Clinical Benefit; Plans New Studies in Additional Patient Populations

Raised $42.3 Million Private Placement, Providing Company Runway into 2023

August 12, 2020 07:30 AM Eastern Daylight Time
WOBURN, Mass.–(BUSINESS WIRE)–Frequency Therapeutics, Inc. (Nasdaq: FREQ), a clinical-stage biotechnology company focused on harnessing the body’s innate biology to repair or reverse damage caused by a broad range of degenerative diseases, today announced business updates and financial results for the second quarter ended June 30, 2020.

“We are pleased with the steady progress in our Phase 2a study, despite the challenges of the pandemic, and we anticipate completing enrollment early in the fourth quarter of 2020 and sharing data from the study in the second quarter of 2021,” said Frequency Therapeutics Chief Executive Officer David L. Lucchino. “In the last quarter, we generated compelling cochlear drug delivery data for FX-322, as well as important durability data suggesting that some patients who were given a single injection of FX-322 in our original Phase 1/2 study maintained statistically significant improvements in word recognition between 12 and 21 months following administration. We believe that these clinical advances are important building blocks as we work to further our understanding of FX-322 drug activity and the patient populations we hope to treat.

Application of Mesenchymal Stem Cell Therapy and Inner Ear Regeneration for Hearing Loss: A Review

https://www.mdpi.com/1422-0067/21/16/5764/htm

https://www.ncbi.nlm.nih.gov/pubmed/32796705?dopt=Abstract

Application of Mesenchymal Stem Cell Therapy and Inner Ear Regeneration for Hearing Loss: A Review.

Int J Mol Sci. 2020 Aug 11;21(16):

Authors: Kanzaki S, Toyoda M, Umezawa A, Ogawa K

Abstract

Inner and middle ear disorders are the leading cause of hearing loss, and are said to be among the greatest risk factors of dementia. The use of regenerative medicine for the treatment of inner ear disorders may offer a potential alternative to cochlear implants for hearing recovery. In this paper, we reviewed recent research and clinical applications in middle and inner ear regeneration and cell therapy. Recently, the mechanism of inner ear regeneration has gradually been elucidated. “Inner ear stem cells,” which may be considered the precursors of various cells in the inner ear, have been discovered in the cochlea and vestibule. Research indicates that cells such as hair cells, neurons, and spiral ligaments may form promising targets for inner ear regenerative therapies by the transplantation of stem cells, including mesenchymal stem cells. In addition, it is necessary to develop tests for the clinical monitoring of cell transplantation. Real-time imaging techniques and hearing rehabilitation techniques are also being investigated, and cell therapy has found clinical application in cochlear implant techniques.

PMID: 32796705 [PubMed – as supplied by publisher]

Insulin-like growth factor 1 (IGF-1): role in the auditory system and therapeutic potential in otology

https://journals.lww.com/co-otolaryngology/Abstract/9000/Insulin_like_growth_factor_1__role_in_the_auditory.99119.aspx

https://www.ncbi.nlm.nih.gov/pubmed/32796270?dopt=Abstract

Insulin-like growth factor 1: role in the auditory system and therapeutic potential in otology.

Curr Opin Otolaryngol Head Neck Surg. 2020 Aug 10;:

Authors: Gao L, Nakagawa T

Abstract

PURPOSE OF REVIEW: Insulin-like growth factor 1 (IGF-1) is a hormone necessary for the development, growth, and maintenance of various organs, and has been used as a therapeutic agent in clinical settings. This review aimed to illustrate its role in the auditory systems and its potential use as a therapeutic in the field of otology.

RECENT FINDINGS: Previous animal studies have indicated the critical role of IGF-1 in the development and maintenance of the auditory system, especially in the cochlea. A clinical study demonstrated a close relationship between the serum level of IGF-1 and the progression of age-related hearing impairment, suggesting its importance in the maintenance of hearing in humans. More recently, its effect on the regeneration of cochlear synapses has been reported using explant cultures, which could explain the course of hearing recovery in patients who underwent topical IGF-1 application for the treatment of sudden sensorineural hearing loss.

SUMMARY: Recent advances in experimental and clinical investigations have revealed the importance of IGF-1 in the maintenance of the auditory function. On the basis of broad targets, its clinical application will expand to the field of otology in the future.

PMID: 32796270 [PubMed – as supplied by publisher]

Three-Dimensional Otic Neuronal Progenitor Spheroids Derived from Human Embryonic Stem Cells

https://www.liebertpub.com/doi/10.1089/ten.tea.2020.0078

Three-Dimensional Otic Neuronal Progenitor Spheroids Derived from Human Embryonic Stem Cells
Rachel A. Heuer, Kevin T. Nella, Hsiang-Tsun Chang, Kyle S. Coots, Andrew M. Oleksijew, Christian B. Roque, Luisa H.A. Silva, Tammy L. McGuire, Kazuaki Homma, and Akihiro J. Matsuoka
Published Online: 7 Aug 2020 https://doi.org/10.1089/ten.tea.2020.0078

P2rx3 regulates spiral ganglion neuron (SGN) branch refinement, promotes auditory neuron maturation, and could play a role in regenerating lost auditory connections in hearing loss

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418533/

https://www.eneuro.org/content/eneuro/7/4/ENEURO.0179-20.2020.full.pdf

The Purinergic Receptor P2rx3 is Required for Spiral Ganglion Neuron Branch Refinement during Development
Zhirong Wang, Johnny S. Jung, Talya C. Inbar, Katherine M. Rangoussis, Christian Faaborg-Andersen,
and Thomas M. Coate
https://doi.org/10.1523/ENEURO.0179-20.2020
Department of Biology, Georgetown University, Washington, DC 20007

P2rx3 receptors are a class of ionotropic purinergic receptors that are expressed in sensory afferent neurons and have been shown to play essential roles in sensory transduction. However, little is known about how P2rx3 functions in neuronal morphogenesis and synaptic connectivity. Here, we found that P2rx3 is expressed by spiral ganglion neurons (SGNs) and hair cells during cochlear development. Using P2rx3 null mice combined with genetic sparse labeling, we discovered P2rx3 regulates SGN branch refinement, which is a function of P2rx3 distinguishable from the more conventionally-known role in neural transduction. These results offer new insights into how P2rx3 promotes auditory neuron maturation, which may be useful for endeavors aimed at regenerating lost auditory connections in hearing loss.

Efficacy and Safety of AM-111 as Acute Sudden Sensorineural Hearing Loss Treatment [Terminated]

https://clinicaltrials.gov/ct2/show/NCT02809118?type=Intr&cond=Hearing+Loss&lupd_s=07%2F24%2F2020&lupd_d=14&sort=nwst

Condition :   Hearing Loss, Idiopathic Sudden Sensorineural

Interventions :   Drug: AM-111 0.4 mg/ml;   Drug: AM-111 0.8 mg/ml;   Other: Placebo

Sponsor :   Auris Medical, Inc.

Terminated

Efficacy and Safety of AM-111 as Acute Sudden Sensorineural Hearing Loss Treatment

NCT02809118

Wed, 22 Jun 2016 12:00:00 EDT

Last Update Posted: 08/07/20 06:52AM

PIPE-505 Clinical Trial Update: Pipeline adds 4 new study locations across the United States…

As anticipated, Pipeline Therapeutics has added additional clinical trial sites to its phase 1/2a study of PIPE-505 for hearing loss.

The official study record (NCT04462198), updated on August 6, 2020, now includes five study locations across the U.S., four of which are now recruiting participants:

  • Boca Raton, Florida, United States, 33487 – added July 17 – Recruiting
  • Winston-Salem, North Carolina, United States, 27103 – added July 27 – Recruiting
  • New Albany, Indiana, United States, 47150 – added August 1 – Recruiting
  • Louisville, Kentucky, United States, 40220 – added August 1 – Recruiting
  • Kansas City, Kansas, United States, 66160 – added August 4 – Not yet recruiting

This post will be updated to include any further changes to the study record. For email updates (which will be starting soon), join the announcement list while it is still open.

Stem Cell-Based Therapeutic Approaches to Restore Sensorineural Hearing Loss in Mammals

https://www.hindawi.com/journals/np/2020/8829660/

Reestablishing Neural Plasticity in Regenerated Spiral Ganglion Neurons and Sensory Hair Cells for Hearing Loss 2020
View this Special Issue
Review Article | Open Access

Volume 2020 |Article ID 8829660 | 10 pages | https://doi.org/10.1155/2020/8829660
Stem Cell-Based Therapeutic Approaches to Restore Sensorineural Hearing Loss in Mammals

Recent Advancements in Understanding the Role of Epigenetics in the Auditory System

https://www.sciencedirect.com/science/article/abs/pii/S037811192030665X?via%3Dihub

Review Gene
2020 Jul 29;144996. doi: 10.1016/j.gene.2020.144996. Online ahead of print.
Recent Advancements in Understanding the Role of Epigenetics in the Auditory System
Rahul Mittal 1, Nicole Bencie 1, George Liu 1, Nicolas Eshraghi 1, Eric Nisenbaum 1, Susan H Blanton 2, Denise Yan 1, Jeenu Mittal 1, Christine T Dinh 1, Juan I Young 3, Feng Gong 4, Xue Zhong Liu 5
Affiliations expand
PMID: 32738421 DOI: 10.1016/j.gene.2020.144996

A metal-organic framework based inner ear delivery system for the treatment of noise-induced hearing loss

https://pubs.rsc.org/en/content/articlelanding/2020/NR/D0NR04860G#!divAbstract

https://www.ncbi.nlm.nih.gov/pubmed/32725028?dopt=Abstract

Related Articles

A metal-organic framework based inner ear delivery system for the treatment of noise-induced hearing loss.

Nanoscale. 2020 Jul 29;:

Authors: Xu X, Lin K, Wang Y, Xu K, Sun Y, Yang X, Yang M, He Z, Zhang Y, Zheng H, Chen X

Abstract

Noise-induced hearing loss (NIHL) is associated with both acute and chronic noise exposure. The application of steroid hormones is the first-line treatment for NIHL. However, a high dose of steroid hormone in the body is necessary to maintain its efficacy and causes side effects, such as headache and osteoporosis. In this work, we prepared a zeolitic imidazolate framework (ZIF)-based system for steroid hormone delivery in the inner ear. Methylprednisolone (MP), a typical steroid hormone, was encapsulated into ZIF-90 nanoparticles (NPs) using one-pot synthesis method. The obtained MP@ZIF-90 NPs are negatively charged and 120 nm in size and showed good biocompatibility and stability at a pH value of 7.4. After intraperitoneal injection, ZIF-90 could efficiently protect drugs during peripheral blood circulation, enter the inner ear via the blood labyrinthine barrier (BLB) and slowly release the drugs. Auditory brainstem response (ABR) tests indicated that MP@ZIF-90 exhibits better protection of mice from noise than those using the free MP and ZIF-8 with encapsulated MP (MP@ZIF-8). More importantly, MP@ZIF-90 showed no defects to the inner ear after being treated for noise and low nephrotoxicity during therapy, which demonstrates the biocompatibility of this material. We believe the ZIF-90 based delivery system is an efficient strategy for inner ear therapy of NIHL.

PMID: 32725028 [PubMed – as supplied by publisher]

Pipeline Therapeutics Initiates Phase 1/2a Clinical Trial of PIPE-505 in Sensorineural Hearing Loss – Topline results expected in early 2021…

https://www.pipelinetherapeutics.com/news/pr_07-23-2020.php

Pipeline Therapeutics Initiates Phase 1/2a Clinical Trial of PIPE-505 in Sensorineural Hearing Loss
PIPE-505 is the first small molecule developed specifically for the treatment of sensorineural hearing loss (SNHL) associated with speech-in-noise impairment
Topline results expected in early 2021
SAN DIEGO, July 23, 2020 – Pipeline Therapeutics, a biopharmaceutical company focused on the development and commercialization of first-in-class small molecules for neuroregeneration, today announced the initiation of a Phase 1/2a trial of the company’s lead product candidate, PIPE-505, a small molecule gamma secretase inhibitor (GSI), in sensorineural hearing loss (SNHL) associated with hearing speech in noisy environments.

Restoring hearing in mice

https://www.nature.com/articles/s41684-020-0605-2

In Brief
Published: 23 July 2020
GENE EDITING

Restoring hearing in mice
Alexandra Le Bras
Lab Animal volume 49, page220(2020)Cite this article

18 Accesses

Metricsdetails

Yeh, W-H. et al. Sci. Transl. Med. 12, eaay9101 (2020)

Genetic defects are a major cause of hearing loss (HL) in newborns. No curative treatments are available for genetic HL, but gene therapy-based strategies that replace an absent gene product or silence a pathological allele have shown promising results in mouse models.

A study describes a new base-editing approach aimed at correcting a point mutation in Tmc1 that causes deafness in Baringo mice. Adeno-associated virus (AAV) delivery of a cytosine base editor and guide RNA into the inner ears of Baringo mice at postnatal day 1 successfully corrected the Tmc1 mutation and partially rescued auditory function, thereby demonstrating the potential of base editing as a treatment for HL caused by recessive loss-of-function point mutations.

Antioxidants and Vasodilators for the Treatment of Noise-Induced Hearing Loss: Are They Really Effective?

https://www.frontiersin.org/articles/10.3389/fncel.2020.00226/full

https://www.ncbi.nlm.nih.gov/pubmed/32792910?dopt=Abstract

Related Articles

Antioxidants and Vasodilators for the Treatment of Noise-Induced Hearing Loss: Are They Really Effective?

Front Cell Neurosci. 2020;14:226

Authors: Alvarado JC, Fuentes-Santamaría V, Juiz JM

Abstract

We live in a world continuously immersed in noise, an environmental, recreational, and occupational factor present in almost every daily human activity. Exposure to high-level noise could affect the auditory function of individuals at any age, resulting in a condition called noise-induced hearing loss (NIHL). Given that by 2018, more than 400 million people worldwide were suffering from disabling hearing loss and that about one-third involved noise over-exposure, which represents more than 100 million people, this hearing impairment represents a serious health problem. As of today, there are no therapeutic measures available to treat NIHL. Conventional preventive measures, including public awareness and education and physical barriers to noise, do not seem to suffice, as the population is still being affected by damaging noise levels. Therefore, it is necessary to develop or test pharmacological agents that may prevent and/or diminish the impact of noise on hearing. Data availability about the pathophysiological processes involved in triggering NIHL has allowed researchers to use compounds, that could act as effective therapies, by targeting specific mechanisms such as the excess generation of free radicals and blood flow restriction to the cochlea. In this review, we summarize the advantages/disadvantages of these therapeutic agents, providing a critical view of whether they could be effective in the human clinic.

PMID: 32792910 [PubMed]

Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges

https://www.mdpi.com/2077-0383/9/7/2309/htm

https://pubmed.ncbi.nlm.nih.gov/32708116/

Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges
by Sedigheh Delmaghani *OrcID andAziz El-Amraoui *OrcID
Progressive Sensory Disorders, Pathophysiology and Therapy Unit, Institut Pasteur, Institut de l’Audition, INSERM-UMRS1120, Sorbonne Université, 63 rue de Charenton, 75012 Paris, France

Authors to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(7), 2309; https://doi.org/10.3390/jcm9072309
Received: 27 June 2020 / Revised: 13 July 2020 / Accepted: 15 July 2020 / Published: 21 July 2020

Ginsenoside Rd Ameliorates Auditory Cortex Injury Associated With Noise-Induced Hearing Loss by Activating SIRT1/PGC-1α Signaling Pathway

https://www.frontiersin.org/articles/10.3389/fphys.2020.00788/full

https://pubmed.ncbi.nlm.nih.gov/32792971/

ORIGINAL RESEARCH ARTICLE
Front. Physiol., 21 July 2020 | https://doi.org/10.3389/fphys.2020.00788
Ginsenoside Rd Ameliorates Auditory Cortex Injury Associated With Military Aviation Noise-Induced Hearing Loss by Activating SIRT1/PGC-1α Signaling Pathway

UPDATE: Pipeline Therapeutics Begins Recruiting Patients for Phase 1/2a Study of PIPE-505 for SNHL

This is a follow-up post to the previous PIPE-505 clinical trial update from July 8 where we explained how “patient recruitment could begin any day now.”

Today, less than two weeks later, that forecast proved accurate: the PIPE-505 trial is now RECRUITING, according to the official study record (NCT04462198), which had its Recruitment Status updated yesterday.

Here is an excerpt from that ClinicalTrials.gov record:

STUDY TITLE: A Phase I/IIa, Randomized, Double-Blind, Placebo-Controlled, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Unilateral Intratympanic PIPE-505 in Subjects With Sensorineural Hearing Loss Associated With Speech-in-Noise Impairment

Recruitment Status: Recruiting
First Posted: July 8, 2020
Last Update Posted: July 20, 2020

DESCRIPTION: This is a randomized-controlled, double-blind study of PIPE-505 or placebo given as an injection one time in subjects with sensorineural hearing loss associated with speech-in-noise difficulty. Visits to the clinic will occur at baseline, dosing, and days 1, 7, 14, 30, 60 and 90 after treatment. Safety will be assessed by periodic measurement of vital signs, ear examination, electrocardiogram (ECG), blood laboratory analyses and occurrence of adverse events (AE). Efficacy will be assessed by periodic audiometry and other audiological tests.

ClinicalTrials.gov Identifier: NCT04462198

Where is the PIPE-505 study located?

As of July 21, 2020, there is only one recruitment location (Florida) for the trial. But it is common for studies like this one to expand and add more locations across the country and sometimes internationally, too. We expect more recruitment sites to be added in the next 4-6 weeks, although we do not have an exact list of those locations… yet…

UPDATE: August 29, 2020 – A second recruitment location (North Carolina) has been added to the list. (More to come?)

More updates to follow for PIPE-505 and other up-and-coming hearing loss treatments. Keep an eye on the front page of this website for updates, or get email updates (it’s an upcoming once-weekly email newsletter – no spam, no third parties, privacy respected).

People on the email list will get first access to new versions of this website that track more research from more sources…

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

Cochlear synaptopathy: new findings in animal and human research including potential impact on therapeutic options for hidden hearing loss

https://www.ncbi.nlm.nih.gov/pubmed/32681786?dopt=Abstract

Cochlear synaptopathy: new findings in animal and human research.

Rev Neurosci. 2020 Jul 20;:

Authors: Aedo C, Aguilar E

Abstract

In animal models, prolonged exposure (2 h) to high-level noise causes an irreparable damage to the synapses between the inner hair cells and auditory nerve fibers within the cochlea. Nevertheless, this injury does not necessarily alter the hearing threshold. Similar findings have been observed as part of typical aging in animals. This type of cochlear synaptopathy, popularly called “hidden hearing loss,” has been a significant issue in neuroscience research and clinical audiology scientists. The results obtained in different investigations are inconclusive in their diagnosis and suggest new strategies for both prognosis and treatment of cochlear synaptopathy. Here we review the major physiological findings regarding cochlear synaptopathy in animals and humans and discuss mathematical models. We also analyze the potential impact of these results on clinical practice and therapeutic options.

PMID: 32681786 [PubMed – as supplied by publisher]

Age-related hearing loss is dominated by damage to inner ear sensory cells, not the cellular battery that powers them

https://www.jneurosci.org/content/early/2020/07/17/JNEUROSCI.0937-20.2020

https://www.ncbi.nlm.nih.gov/pubmed/32690619?dopt=Abstract

Related Articles

Age-related hearing loss is dominated by damage to inner ear sensory cells, not the cellular battery that powers them.

J Neurosci. 2020 Jul 20;:

Authors: Wu PZ, O’Malley JT, de Gruttola V, Liberman MC

Abstract

Age-related hearing loss arises from irreversible damage in the inner ear, where sound is transduced into electrical signals. Prior human studies suggested that sensory-cell loss is rarely the cause; correspondingly, animal work has implicated the stria vascularis, the cellular “battery” driving the amplification of sound by hair cell “motors”. Here, quantitative microscopic analysis of hair cells, auditory nerve fibers and strial tissues in 120 human inner ears obtained at autopsy, most of whom had recent audiograms in their medical records, shows that the degree of hearing loss is well predicted from the amount of hair cell loss and that inclusion of strial damage does not improve the prediction. Although many aging ears showed significant strial degeneration throughout the cochlea, our statistical models suggest that, by the time strial tissues are lost, hair cell death is so extensive that the loss of battery is no longer important to pure-tone thresholds and that audiogram slope is not diagnostic for strial degeneration. These data comprise the first quantitative survey of hair cell death in normal-aging human cochleas, and reveal unexpectedly severe hair cell loss in low-frequency cochlear regions, and dramatically greater loss in high-frequency regions than seen in any aging animal model. Comparison of normal-aging ears to an age-matched group with acoustic-overexposure history suggests that a lifetime of acoustic overexposure is to blame.Significance StatementThis report upends dogma about the causes of age-related hearing loss. Our analysis of over 120 autopsy specimens shows that inner-ear sensory cell loss can largely explain the audiometric patterns in aging, with minimal contribution from the stria vascularis, the “battery” that powers the inner ear, previously viewed as the major locus of age-related hearing dysfunction. Predicting inner ear damage from the audiogram is critical, now that clinical trials of therapeutics designed to regrow hair cells are underway. Our data also show that hair cell degeneration in aging humans is dramatically worse than that in aging animals, suggesting that the high-frequency hearing losses that define human presbycusis reflect avoidable contributions of chronic ear abuse to which aging animals are not exposed.

PMID: 32690619 [PubMed – as supplied by publisher]

Gene therapy development in hearing research in China

https://www.nature.com/articles/s41434-020-0177-1

https://www.ncbi.nlm.nih.gov/pubmed/32681137?dopt=Abstract

Related Articles

Gene therapy development in hearing research in China.

Gene Ther. 2020 Jul 17;:

Authors: Zhang Z, Wang J, Li C, Xue W, Xing Y, Liu F

Abstract

Sensorineural hearing loss, the most common form of hearing impairment, is mainly attributable to genetic mutations or acquired factors, such as aging, noise exposure, and ototoxic drugs. In the field of gene therapy, advances in genetic and physiological studies and profound increases in knowledge regarding the underlying mechanisms have yielded great progress in terms of restoring the auditory function in animal models of deafness. Nonetheless, many challenges associated with the translation from basic research to clinical therapies remain to be overcome before a total restoration of auditory function can be expected. In recent years, Chinese research teams have promoted various developmental efforts in this field, including gene sequencing to identify additional potential loci that cause deafness, studies to elucidate the underlying molecular mechanisms, and research to optimize vectors and delivery routes. In this review, we summarize the state of the field and focus mainly on the progress of gene therapy in animal model studies and the optimization of therapeutic strategies in China.

PMID: 32681137 [PubMed – as supplied by publisher]

Long-term exposure to low-intensity environmental noise aggravates age-related hearing loss via disruption of cochlear ribbon synapses

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407738/

https://www.ncbi.nlm.nih.gov/pubmed/32774726?dopt=Abstract

Long-term exposure to low-intensity environmental noise aggravates age-related hearing loss via disruption of cochlear ribbon synapses.

Am J Transl Res. 2020;12(7):3674-3687

Authors: Feng S, Yang L, Hui L, Luo Y, Du Z, Xiong W, Liu K, Jiang X

Abstract

Noise pollution is a major public hazard. Previous studies have shown that environmental noise affects the reorganization of the auditory cortex and leads to behavioral abnormality; however, the effects of long-term environmental noise exposure on the inner ear and hearing remain to be elucidated. In this study, we simulated environmental noise with a long-term 70 dB sound pressure level “white” noise, observed its effect on the inner ears of C57BL/6J mice, and developed an in vitro model for mechanistic studies. We found that environmental noise increased the hearing threshold, decreased the auditory response amplitude, and aggravated the range and extent of age-related hearing loss (ARHL), especially in the intermediate frequency band in mice. Cochlear ribbon synapse is the primary site of inner ear injury caused by environmental noise. We also verified, through an in vitro simulation of the excitatory toxicity of glutamate and aging effects, that the activation of NLRP3 inflammasome plays a vital role in the cochlear ribbon synaptic damage. Our results show that long-term exposure to low-intensity environmental noise can lead to hearing loss via the disruption of ribbon synapses, which is caused by an inflammatory reaction. Additionally, environmental noise can further aggravate the progression of ARHL. This study expounded the pathogenesis of the inner ear damage caused by environmental noise exposure and provides a new direction for the prevention and treatment of hearing loss.

PMID: 32774726 [PubMed – as supplied by publisher]

SIRT3 may promote spiral ganglion neuron function

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235491

https://pubmed.ncbi.nlm.nih.gov/32658908/

SIRT3 promotes auditory function in young adult FVB/nJ mice but is dispensable for hearing recovery after noise exposure
Sally Patel,Lisa Shah,Natalie Dang,Xiaodong Tan,Anthony Almudevar,Patricia M. White
Published: July 13, 2020https://doi.org/10.1371/journal.pone.0235491

Noise-Induced Hearing Loss and its Prevention: Current Issues in Mammalian Hearing

New item found in Research category.

TITLE:
Noise-Induced Hearing Loss and its Prevention: Current Issues in Mammalian Hearing

DESCRIPTION:
Noise-induced hearing loss (NIHL) has been well investigated across diverse mammalian species and the potential for prevention of NIHL is of broad interest. To most efficiently develop novel therapeutic interventions, a good understanding of the current state of knowledge regarding mechanisms of injury is essential. The overarching goals of this review are to 1) concisely summarize the current state of knowledge, and 2) provide opinions on the most significant future trends and developments.

CONTENT:
Curr Opin Physiol. 2020 Dec;18:32-36. doi: 10.1016/j.cophys.2020.07.004. Epub 2020 Jul 12.

ABSTRACT

Noise-induced hearing loss (NIHL) has been well investigated across diverse mammalian species and the potential for prevention of NIHL is of broad interest. To most efficiently develop novel therapeutic interventions, a good understanding of the current state of knowledge regarding mechanisms of injury is essential. The overarching goals of this review are to 1) concisely summarize the current state of knowledge, and 2) provide opinions on the most significant future trends and developments.

PMID:32984667 | PMC:PMC7511084 | DOI:10.1016/j.cophys.2020.07.004

DATE – PUBLISHED:
2020 Dec;18:32-36

DATE – ADDED:
Mon, 28 Sep 2020 06:00:00 -0400

DATE – FOUND:
09/29/20 06:03PM

PUBMED ID:
pubmed:32984667

DOI:
10.1016/j.cophys.2020.07.004

SOURCE LINK:
https://pubmed.ncbi.nlm.nih.gov/32984667/?utm_source=Other&utm_medium=rss&utm_campaign=pubmed-2&utm_content=14YzNBPGjPa6Oq9tGLyUqPsF9afEhga7LmkzI3a3dlOprEmYeN&fc=20200920235320&ff=20200929180321&v=2.11.5

PUBMED LINK:
https://pubmed.ncbi.nlm.nih.gov/32984667/

DOI LINK:
https://doi.org/10.1016/j.cophys.2020.07.004

PUBLISHER LINK:
resolve

Pipeline Therapeutics Initiates Phase 1/2 Clinical Trial of PIPE-505 for Sensorineural Hearing Loss

The study titled, Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss, was added to the official ClinicalTrials.gov databased on July 8, 2020.

The recruitment status of the clinical trial is currently set to “Not yet recruiting.” However, that could change very soon, considering a) the follow-up period for trial participants after the initial drug administration lasts 3 months, and b) the anticipated primary completion date of the study is four months away, in November 2020.

These details suggest that patient recruitment could begin any day now and – assuming there are no changes to the study’s current schedule – probably no later than 4-6 weeks from now.

UPDATE (current as of July 21, 2020): the PIPE-505 study is now recruiting patients… see this follow-up post for details or visit the official study page using the link below:

https://clinicaltrials.gov/ct2/show/NCT04462198

Here is further reading about PIPE-505, a small molecule gamma secretase inhibitor (GSI) that will be delivered to select trial participants as a one-time intratympanic injection:

PIPE-505 is the first small molecule developed specifically for the treatment of sensorineural hearing loss (SNHL) associated with cochlear synaptopathy. The therapeutic focus, regeneration of the cochlear synapse, should augment signal-to-noise processing and manifest as improved speech-in-noise comprehension, a chief auditory complaint and unmet need of patients with SNHL.

Source: https://www.pipelinetherapeutics.com/science/synaptogenesis.html

Nimodipine, a calcium channel blocker, for the prevention and treatment of sensorineural hearing loss

https://www.ncbi.nlm.nih.gov/pubmed/32628375?dopt=Abstract

https://www.mediasphera.ru/issues/vestnik-otorinolaringologii/2020/3/1004246682020031006

[Modern aspects of pathogenetic treatment of sensorineural hearing loss].

Vestn Otorinolaringol. 2020;85(3):6-10

Authors: Zolotova TV, Dubinskaya NV, Davydova AP

Abstract

OBJECTIVE: Optimization of the treatment of sensorineural hearing loss (SHL) using a calcium channel blocker – nimodipine.

MATERIAL AND METHODS: The study consists of experimental and clinical sections. The experiment involved 42 white outbred rats, which were used for modeling SHL according to the original method and treatment with nimodipine followed by histological control. The clinical study involved 115 patients with chronic SHL. Calcium metabolism was evaluated by quantifying the mineral density of bone tissue during osteodensitometry of the radial bones of patients.

RESULTS AND DISCUSSION: Histological studies after rats were removed from the experiment showed that modeling SHL by noise exposure against the background of immobilization of experimental animals is effective and is accompanied by early signs of apoptosis of the external hair and auxiliary cells, degenerative changes in spiral ganglion neurocytes. The role of calcium metabolism disorders in the initiation of the described disorders is shown. The use of nimodipine in experimental animals reduces the severity of histological changes. When examining patients with SHL, signs of impaired calcium metabolism in bone tissue were detected in 60% of the examined patients.

CONCLUSION: The obtained data determine the special role of disorders in the ratios of micro-elements in the body, especially calcium, in the development of SHL, and dictate the need for their correction using calcium channel blockers. The clinical use of nimodipine is possible both for prevention and for the treatment of sensorineural hearing loss.

PMID: 32628375 [PubMed – as supplied by publisher]

Emerging Approaches for Restoration of Hearing and Vision

https://journals.physiology.org/doi/abs/10.1152/physrev.00035.2019

Emerging Approaches for Restoration of Hearing and Vision
Sonja Kleinlogel, Christian Vogl, Marcus Jeschke, Jakob Neef, and Tobias Moser
6 JUL 2020 https://doi.org/10.1152/physrev.00035.2019

Anti-oxidant and anti-inflammatory effects of caffeic acid: in vivo evidences in a model of noise-induced hearing loss

https://www.sciencedirect.com/science/article/pii/S0278691520304452?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32640333?dopt=Abstract

Anti-oxidant and anti-inflammatory effects of caffeic acid: in vivo evidences in a model of noise-induced hearing loss.

Food Chem Toxicol. 2020 Jul 05;:111555

Authors: Paciello F, Di Pino A, Rolesi R, Troiani D, Paludetti G, Grassi C, Fetoni AR

Abstract

SCOPE: The imbalance of cellular redox status, in conjunction with the activation of inflammatory processes, have been considered common predominant mechanisms of noise-induced hearing loss. The identification of novel natural products as potential therapeutics, targeting oxidative stress and inflammatory pathways, is an emerging field. Here, we focused on the polyphenol caffeic acid (CA), the major representative of hydroxycinnamic acids and phenolic acid, in order to investigate its protective capacity in a model of sensorineural hearing loss induced by noise.

METHODS AND RESULTS: Hearing loss was induced by exposing animals (Wistar rats) to a pure tone, 120 dB, 10 kHz for 60 min. By using auditory brainstem responses (ABRs) and immunofluorescence analysis, we found that CA protects auditory function and limits cell death in the cochlear middle/basal turn, damaged by noise exposure. Immunofluorescence analysis provided evidence that CA mediates multiple cell protection mechanisms, involving both anti-inflammatory and anti-oxidant effects by decreasing NF-κB and IL-1β expression in the cochlea and opposing the oxidative/nitrosative damage induced by noise insult.

CONCLUSIONS: These results demonstrate that the supplementation of polyphenol CA can be considered a valid therapeutic strategy for attenuating noise-induced hearing loss and cochlear damage, targeting both inflammatory signalling and cochlear redox balance.

PMID: 32640333 [PubMed – as supplied by publisher]

Trk Agonist Drugs Rescue Noise-Induced Hidden Hearing Loss [Preprint]

https://www.biorxiv.org/content/10.1101/2020.07.01.182931v1.full

https://www.biorxiv.org/content/10.1101/2020.07.01.182931v1

Trk Agonist Drugs Rescue Noise-Induced Hidden Hearing Loss
Katharine A. Fernandez, Takahisa Watabe, Mingjie Tong, Xiankai Meng, Kohsuke Tani, Sharon G. Kujawa, View ORCID ProfileAlbert S. B. Edge
doi: https://doi.org/10.1101/2020.07.01.182931
This article is a preprint and has not been certified by peer review [what does this mean?].
AbstractFull TextInfo/HistoryMetrics Preview PDF
Abstract
TrkB agonist drugs are shown here to have a significant effect on the regeneration of afferent cochlear synapses after noise-induced synaptopathy. The effects were consistent with regeneration of cochlear synapses that we observed in vitro after synaptic loss due to kainic acid-induced glutamate toxicity and were elicited by administration of TrkB agonists, amitriptyline and 7,8-dihydroxyflavone, directly into the cochlea via the posterior semicircular canal 48 h after exposure to noise. Synaptic counts at the inner hair cell and wave 1 amplitudes in the ABR were partially restored 2 weeks after drug treatment. Effects of amitriptyline on wave 1 amplitude and afferent auditory synapse numbers in noise-exposed ears after systemic (as opposed to local) delivery were profound and long-lasting; synapses in the treated animals remained intact one year after the treatment. However, the effect of systemically delivered amitriptyline on synaptic rescue was dependent on dose and the time window of administration: it was only effective when given before noise exposure at the highest injected dose. The long-lasting effect and the efficacy of post-exposure treatment indicate a potential broad application for the treatment of synaptopathy, which often goes undetected until well after the original damaging exposure(s).

An Antibody to RGMa Promotes Regeneration of Cochlear Synapses after Noise Exposure [Preprint]

https://www.biorxiv.org/content/10.1101/2020.07.01.183269v1.full

https://www.researchgate.net/publication/342660327_An_Antibody_to_RGMa_Promotes_Regeneration_of_Cochlear_Synapses_after_Noise_Exposure

An Antibody to RGMa Promotes Regeneration of Cochlear Synapses after Noise Exposure

SUMMARY
Auditory neuropathy is caused by the loss of afferent input to the brainstem via the components of the neural pathway comprising inner hair cells and the first order neurons of the spiral ganglion. Recent work has identified the synapse between cochlear primary afferent neurons and sensory hair cells as a particularly vulnerable component of this pathway. Loss of these synapses due to noise exposure or aging results in the pathology identified as hidden hearing loss, an initial stage of cochlear dysfunction that goes undetected in standard hearing tests. We show here that repulsive axonal guidance molecule a (RGMa) acts to prevent regrowth and synaptogenesis of peripheral auditory nerve fibers with inner hair cells. 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.

A simpler way to make sensory hearing cells

https://www.sciencedaily.com/releases/2020/07/200701134242.htm

A simpler way to make sensory hearing cells
Date:
July 1, 2020
Source:
Keck School of Medicine of USC
Summary:
Scientists are whispering the secrets of a simpler way to generate the sensory cells of the inner ear. Their approach uses direct reprogramming to produce sensory cells known as ‘hair cells,’ due to their hair-like protrusions that sense sound waves.

Development of nanoparticle drug-delivery systems for the inner ear: targeted NP-based drug-delivery systems as effective treatments for hearing loss

https://www.futuremedicine.com/doi/10.2217/nnm-2020-0198

https://www.ncbi.nlm.nih.gov/pubmed/32605499?dopt=Abstract

Related Articles

Development of nanoparticle drug-delivery systems for the inner ear.

Nanomedicine (Lond). 2020 Jul 01;:

Authors: An X, Zha D

Abstract

Hearing loss has become the most common sensory nerve disorder worldwide, with no effective treatment strategy. Low-permeability and limited blood supply to the blood-labyrinth barrier limit the effective delivery and efficacy of therapeutic drugs in the inner ear. Nanoparticle (NP)-based drugs have shown benefits of stable controlled release and functional surface modification, and NP-based delivery systems have become a research hotspot. In this review, we discuss the development of new targeted drug-delivery systems based on the biocompatibility and safety of different NPs in the cochlea, as well as the advantages and disadvantages of their prescription methods and approaches. We believe that targeted NP-based drug-delivery systems will be effective treatments for hearing loss.

PMID: 32605499 [PubMed – as supplied by publisher]

Generation of inner ear hair cells by direct lineage conversion of primary somatic cells

https://elifesciences.org/articles/55249

https://www.ncbi.nlm.nih.gov/pubmed/32602462?dopt=Abstract

Related Articles

Generation of inner ear hair cells by direct lineage conversion of primary somatic cells.

Elife. 2020 Jun 30;9:

Authors: Menendez L, Trecek T, Gopalakrishnan S, Tao L, Markowitz AL, Yu HV, Wang X, Llamas J, Huang C, Lee J, Kalluri R, Ichida J, Segil N

Abstract

The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing.

PMID: 32602462 [PubMed – in process]

Near-infrared-light pre-treatment attenuates noise-induced hearing loss in mice

https://peerj.com/articles/9384/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305775/

https://www.ncbi.nlm.nih.gov/pubmed/32596055?dopt=Abstract

Related Articles

Near-infrared-light pre-treatment attenuates noise-induced hearing loss in mice.

PeerJ. 2020;8:e9384

Authors: Basta D, Gröschel M, Strübing I, Boyle P, Fröhlich F, Ernst A, Seidl R

Abstract

Noise induced hearing loss (NIHL) is accompanied by a reduction of cochlear hair cells and spiral ganglion neurons. Different approaches have been applied to prevent noise induced apoptosis / necrosis. Physical intervention is one technique currently under investigation. Specific wavelengths within the near-infrared light (NIR)-spectrum are known to influence cytochrome-c-oxidase activity, which leads in turn to a decrease in apoptotic mechanisms. It has been shown recently that NIR can significantly decrease the cochlear hair cell loss if applied daily for 12 days after a noise exposure. However, it is still unclear if a single NIR-treatment, just before a noise exposure, could induce similar protective effects. Therefore, the present study was conducted to investigate the effect of a single NIR-pre-treatment aimed at preventing or limiting NIHL. The cochleae of adult NMRI-mice were pre-treated with NIR-light (808 nm, 120 mW) for 5, 10, 20, 30 or 40 minutes via the external ear canal. All animals were noised exposed immediately after the pre-treatment by broad band noise (5-20 kHz) for 30 minutes at 115 dB SPL. Frequency specific ABR-recordings to determine auditory threshold shift were carried out before the pre-treatment and two weeks after the noise exposure. The amplitude increase for wave IV and cochlear hair cell loss were determined. A further group of similar mice was noise exposed only and served as a control for the NIR pre-exposed groups. Two weeks after noise exposure, the ABR threshold shifts of NIR-treated animals were significantly lower (p < 0.05) than those of the control animals. The significance was at three frequencies for the 5-minute pre-treatment group and across the entire frequency range for all other treatment groups. Due to NIR light, the amplitude of wave four deteriorates significantly less after noise exposure than in controls. The NIR pre-treatment had no effect on the loss of outer hair cells, which was just as high with or without NIR-light pre-exposure. Relative to the entire number of outer hair cells across the whole cochlea, outer hair cell loss was rather negligible. No inner hair cell loss whatever was detected. Our results suggest that a single NIR pre-treatment induces a very effective protection of cochlear structures from noise exposure. Pre-exposure of 10 min seems to emerge as the optimal dosage for our experimental setup. A saturated effect occurred with higher dosage-treatments. These results are relevant for protection of residual hearing in otoneurosurgery such as cochlear implantation. PMID: 32596055 [PubMed]

Otonomy Provides Update on OTO-413 Clinical Trial: Results from Phase 1/2 study of OTO-413 for hearing loss expected in fourth quarter of 2020

https://www.globenewswire.com/news-release/2020/06/15/2048357/0/en/Otonomy-Provides-Update-on-Clinical-Trials-and-Development-Programs.html

Otonomy Provides Update on Clinical Trials and Development Programs

June 15, 2020 16:05 ET | Source: Otonomy, Inc.

  • Results from Phase 3 trial of OTIVIDEX® in Ménière’s disease expected in first quarter of 2021
  • Results from Phase 1/2 trial of OTO-313 in tinnitus expected in July 2020
  • Results from Phase 1/2 trial of OTO-413 in hearing loss expected in fourth quarter of 2020

SAN DIEGO, June 15, 2020 (GLOBE NEWSWIRE) — Otonomy, Inc. (Nasdaq: OTIC), a biopharmaceutical company dedicated to the development of innovative therapeutics for neurotology, today provided an update on its product pipeline and the timeline to results for the company’s three ongoing clinical trials, including the Phase 3 trial of OTIVIDEX in Ménière’s disease. The company will host a conference call and webcast today at 4:30 p.m. ET to review these updates.

Hair cell regeneration from inner ear progenitors in the mammalian cochlea

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364385/

Hair cell regeneration from inner ear progenitors in the mammalian cochlea
Shasha Zhang,1 Ruiying Qiang,1 Ying Dong,1 Yuan Zhang,1 Yin Chen,5 Han Zhou,5 Xia Gao,5 and Renjie Chai1,2,3,4,5
Author information Article notes Copyright and License information Disclaimer
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Abstract
Cochlear hair cells (HCs) are the mechanoreceptors of the auditory system, and because these cells cannot be spontaneously regenerated in adult mammals, hearing loss due to HC damage is permanent. However, cochleae of neonatal mice harbor some progenitor cells that retain limited ability to give rise to new HCs in vivo. Here we review the regulatory factors, signaling pathways, and epigenetic factors that have been reported to play roles in HC regeneration in the neonatal mammalian cochlea.

Keywords: Cochlea, inner ear progenitor, hair cell regeneration, transcription factor, signaling pathway

Involvement of Cholesterol Metabolic Pathways in Recovery from Noise-Induced Hearing Loss

https://www.hindawi.com/journals/np/2020/6235948/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306080/

https://www.ncbi.nlm.nih.gov/pubmed/32617095?dopt=Abstract

Related Articles

Involvement of Cholesterol Metabolic Pathways in Recovery from Noise-Induced Hearing Loss.

Neural Plast. 2020;2020:6235948

Authors: Sai N, Shi X, Zhang Y, Jiang QQ, Ji F, Yuan SL, Sun W, Guo WW, Yang SM, Han WJ

Abstract

The objective of this study was to explore the molecular mechanisms of acute noise-induced hearing loss and recovery of steady-state noise-induced hearing loss using miniature pigs. We used miniature pigs exposed to white noise at 120 dB (A) as a model. Auditory brainstem response (ABR) measurements were made before noise exposure, 1 day and 7 days after noise exposure. Proteomic Isobaric Tags for Relative and Absolute Quantification (iTRAQ) was used to observe changes in proteins of the miniature pig inner ear following noise exposure. Western blot and immunofluorescence were performed for further quantitative and qualitative analysis of proteomic changes. The average ABR-click threshold of miniature pigs before noise exposure, 1 day and 7 days after noise exposure, were 39.4 dB SPL, 67.1 dB SPL, and 50.8 dB SPL, respectively. In total, 2,158 proteins were identified using iTRAQ. Both gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) database analyses showed that immune and metabolic pathways were prominently involved during the impairment stage of acute hearing loss. During the recovery stage of acute hearing loss, most differentially expressed proteins were related to cholesterol metabolism. Western blot and immunofluorescence showed accumulation of reactive oxygen species and nuclear translocation of NF-κB (p65) in the hair cells of miniature pig inner ears during the acute hearing loss stage after noise exposure. Nuclear translocation of NF-κB (p65) may be associated with overexpression of downstream inflammatory factors. Apolipoprotein (Apo) A1 and Apo E were significantly upregulated during the recovery stage of hearing loss and may be related to activation of cholesterol metabolic pathways. This is the first study to use proteomics analysis to analyze the molecular mechanisms of acute noise-induced hearing loss and its recovery in a large animal model (miniature pigs). Our results showed that activation of metabolic, inflammatory, and innate immunity pathways may be involved in acute noise-induced hearing loss, while cholesterol metabolic pathways may play an important role in recovery of hearing ability following noise-induced hearing loss.

PMID: 32617095 [PubMed – in process]

Hair Cell Transduction Efficiency of Single- and Dual-AAV Serotypes in Adult Murine Cochleae: findings broaden the application of cochlear gene therapy targeting hair cells [PDF]

https://www.cell.com/molecular-therapy-family/methods/pdf/S2329-0501(20)30094-2.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2329050120300942%3Fshowall%3Dtrue

https://www.ncbi.nlm.nih.gov/pubmed/32518805?dopt=Abstract

Related Articles

Hair Cell Transduction Efficiency of Single- and Dual-AAV Serotypes in Adult Murine Cochleae.

Mol Ther Methods Clin Dev. 2020 Jun 12;17:1167-1177

Authors: Omichi R, Yoshimura H, Shibata SB, Vandenberghe LH, Smith RJH

Abstract

Gene delivery is a key component for the treatment of genetic hearing loss. To date, a myriad of adeno-associated virus (AAV) serotypes and surgical approaches have been employed to deliver transgenes to cochlear hair cells, but the efficacy of dual transduction remains unclear. Herein, we investigated cellular tropism of single injections of AAV serotype 1 (AAV1), AAV2, AAV8, AAV9, and Anc80L65, and quantitated dual-vector co-transduction rates following co-injection of AAV2 and AAV9 vectors in adult murine cochlea. We used the combined round window membrane and canal fenestration (RWM+CF) injection technique for vector delivery. Single AAV2 injections were most robust and transduced 96.7% ± 1.1% of inner hair cells (IHCs) and 83.9% ± 2.0% of outer hair cells (OHCs) throughout the cochlea without causing hearing impairment or hair cell loss. Dual AAV2 injection co-transduced 96.9% ± 1.7% of IHCs and 65.6% ± 8.95% of OHCs. Together, RWM+CF-injected single or dual AAV2 provides the highest auditory hair cell transduction efficiency of the AAV serotypes we studied. These findings broaden the application of cochlear gene therapy targeting hair cells.

PMID: 32518805 [PubMed]

Progress in Modeling and Targeting Inner Ear Disorders with Pluripotent Stem Cells

https://www.cell.com/stem-cell-reports/pdf/S2213-6711(20)30148-X.pdf

Progress in Modeling and Targeting Inner Ear Disorders with Pluripotent Stem Cells
Pei-Ciao Tang,1 Eri Hashino,1,2 and Rick F. Nelson1,
* 1Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
*Correspondence: ricnelso@iupui.edu
https://doi.org/10.1016/j.stemcr.2020.04.008

Brain-derived nerve growth factor in the cochlea: Intracochlear BDNF can improve hearing in guinea pigs but improvement is currently too small for clinical application

https://journalotohns.biomedcentral.com/articles/10.1186/s40463-020-00432-7

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275362/

https://www.ncbi.nlm.nih.gov/pubmed/32503640?dopt=Abstract

Related Articles

Brain-derived nerve growth factor in the cochlea – a reproducibility study.

J Otolaryngol Head Neck Surg. 2020 Jun 05;49(1):37

Authors: Blakley BW, Seaman M, Alenezi A

Abstract

OBJECTIVE: Brain-derived nerve growth factor (BDNF) plays an important role in cochlear development so it is plausible that it could restore hearing loss if delivered directly into the cochlea. We wished to confirm our previous report that a single intracochlear injection of brain-derived nerve growth factor (BDNF) was beneficial for hearing in guinea pigs. We wished to assess the reproducibility of our results and assess possible improved methods with a view to developing a clinical treatment for sensorineural hearing loss.

METHODS: CDDP was used to create partial hearing loss in 25 guinea pigs. After 30 days the animals underwent ABR testing and unilateral BDNF injection through the round window in one ear and saline injection into the other ear. After allowing possible effects to stabilize, thirty days later, ABR threshold testing was repeated to assess change in threshold.

RESULTS: Final ABR thresholds were 60-70 dB and were about 11 dB better in the ears treated with BDNF.

CONCLUSION: Our original finding that Intracochlear BDNF can improve hearing in guinea pigs was confirmed, but the improvement demonstrated by the methods in this paper is too small for clinical application.

PMID: 32503640 [PubMed – as supplied by publisher]

In vivo base editing restores sensory transduction and transiently improves auditory function in a mouse model of recessive deafness

https://stm.sciencemag.org/content/12/546/eaay9101

https://www.ncbi.nlm.nih.gov/pubmed/32493795?dopt=Abstract

Related Articles

In vivo base editing restores sensory transduction and transiently improves auditory function in a mouse model of recessive deafness.

Sci Transl Med. 2020 Jun 03;12(546):

Authors: Yeh WH, Shubina-Oleinik O, Levy JM, Pan B, Newby GA, Wornow M, Burt R, Chen JC, Holt JR, Liu DR

Abstract

Most genetic diseases arise from recessive point mutations that require correction, rather than disruption, of the pathogenic allele to benefit patients. Base editing has the potential to directly repair point mutations and provide therapeutic restoration of gene function. Mutations of transmembrane channel-like 1 gene (TMC1) can cause dominant or recessive deafness. We developed a base editing strategy to treat Baringo mice, which carry a recessive, loss-of-function point mutation (c.A545G; resulting in the substitution p.Y182C) in Tmc1 that causes deafness. Tmc1 encodes a protein that forms mechanosensitive ion channels in sensory hair cells of the inner ear and is required for normal auditory function. We found that sensory hair cells of Baringo mice have a complete loss of auditory sensory transduction. To repair the mutation, we tested several optimized cytosine base editors (CBEmax variants) and guide RNAs in Baringo mouse embryonic fibroblasts. We packaged the most promising CBE, derived from an activation-induced cytidine deaminase (AID), into dual adeno-associated viruses (AAVs) using a split-intein delivery system. The dual AID-CBEmax AAVs were injected into the inner ears of Baringo mice at postnatal day 1. Injected mice showed up to 51% reversion of the Tmc1 c.A545G point mutation to wild-type sequence (c.A545A) in Tmc1 transcripts. Repair of Tmc1 in vivo restored inner hair cell sensory transduction and hair cell morphology and transiently rescued low-frequency hearing 4 weeks after injection. These findings provide a foundation for a potential one-time treatment for recessive hearing loss and support further development of base editing to correct pathogenic point mutations.

PMID: 32493795 [PubMed – in process]

Viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss: new strategies to induce sensory cell regeneration

https://www.pnas.org/content/117/24/13552

Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal

Role of Yap/Tead transcription factor complex in maintaining inner ear progenitors during development: new strategies to induce sensory cell regeneration

View ORCID ProfileKsenia Gnedeva, View ORCID ProfileXizi Wang, Melissa M. McGovern, Matthew Barton, Litao Tao, Talon Trecek, View ORCID ProfileTanner O. Monroe, Juan Llamas, Welly Makmura, James F. Martin, Andrew K. Groves, Mark Warchol, and View ORCID ProfileNeil Segil
PNAS June 16, 2020 117 (24) 13552-13561; first published June 1, 2020 https://doi.org/10.1073/pnas.2000175117

Edited by Marianne E. Bronner, California Institute of Technology, Pasadena, CA, and approved April 21, 2020 (received for review January 6, 2020)

Significance
While Yap/Tead signaling is well known to influence tissue growth and organ size during development, the molecular outputs of the pathway are tissue- and context-dependent and remain poorly understood. Our work expands the mechanistic understanding of how Yap/Tead signaling controls the precise number of progenitor cells that will be laid down within the developing inner ear to ultimately regulate the final size and function of the sensory organs. We also provide evidence that restoration of hearing and vestibular function may be amenable to YAP-mediated regeneration. Our data show that reactivation of Yap/Tead signaling after hair cell loss induces a proliferative response in vivo—a process thought to be permanently repressed in the mammalian inner ear.

Abstract
Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium—the organ of Corti—progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2-positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of the Yap gene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version of Yap, Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration.

Distinct roles of stereociliary links in the nonlinear sound processing and noise resistance of cochlear outer hair cells

https://www.pnas.org/content/117/20/11109

https://www.ncbi.nlm.nih.gov/pubmed/32358189?dopt=Abstract

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Distinct roles of stereociliary links in the nonlinear sound processing and noise resistance of cochlear outer hair cells.

Proc Natl Acad Sci U S A. 2020 05 19;117(20):11109-11117

Authors: Han W, Shin JO, Ma JH, Min H, Jung J, Lee J, Kim UK, Choi JY, Moon SJ, Moon DW, Bok J, Kim CH

Abstract

Outer hair cells (OHCs) play an essential role in hearing by acting as a nonlinear amplifier which helps the cochlea detect sounds with high sensitivity and accuracy. This nonlinear sound processing generates distortion products, which can be measured as distortion-product otoacoustic emissions (DPOAEs). The OHC stereocilia that respond to sound vibrations are connected by three kinds of extracellular links: tip links that connect the taller stereocilia to shorter ones and convey force to the mechanoelectrical transduction channels, tectorial membrane-attachment crowns (TM-ACs) that connect the tallest stereocilia to one another and to the overlying TM, and horizontal top connectors (HTCs) that link adjacent stereocilia. While the tip links have been extensively studied, the roles that the other two types of links play in hearing are much less clear, largely because of a lack of suitable animal models. Here, while analyzing genetic combinations of tubby mice, we encountered models missing both HTCs and TM-ACs or HTCs alone. We found that the tubby mutation causes loss of both HTCs and TM-ACs due to a mislocalization of stereocilin, which results in OHC dysfunction leading to severe hearing loss. Intriguingly, the addition of the modifier allele modifier of tubby hearing 1 in tubby mice selectively rescues the TM-ACs but not the HTCs. Hearing is significantly rescued in these mice with robust DPOAE production, indicating an essential role of the TM-ACs but not the HTCs in normal OHC function. In contrast, the HTCs are required for the resistance of hearing to damage caused by noise stress.

PMID: 32358189 [PubMed – indexed for MEDLINE]

Efficacy of SENS 401 in Subjects With Severe or Profound Sudden Sensorineural Hearing Loss

https://clinicaltrials.gov/ct2/show/NCT03603314?type=Intr&cond=Hearing+Loss&lupd_s=05%2F05%2F2020&lupd_d=14&sort=nwst

Condition :   Severe Sudden Sensorineural Hearing Loss

Interventions :   Drug: SENS-401;   Other: Placebo Oral Tablet

Sponsor :   Sensorion

Recruiting

Efficacy of SENS 401 in Subjects With Severe or Profound Sudden Sensorineural Hearing Loss

NCT03603314

Fri, 27 Jul 2018 12:00:00 EDT

Last Update Posted: 05/19/20 06:40AM

Recent development of AAV-based gene therapies for inner ear disorders

https://www.nature.com/articles/s41434-020-0155-7

https://www.ncbi.nlm.nih.gov/pubmed/32424232?dopt=Abstract

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Recent development of AAV-based gene therapies for inner ear disorders.

Gene Ther. 2020 May 18;:

Authors: Lan Y, Tao Y, Wang Y, Ke J, Yang Q, Liu X, Su B, Wu Y, Lin CP, Zhong G

Abstract

Gene therapy for auditory diseases is gradually maturing. Recent progress in gene therapy treatments for genetic and acquired hearing loss has demonstrated the feasibility in animal models. However, a number of hurdles, such as lack of safe viral vector with high efficiency and specificity, robust deafness large animal models, translating animal studies to clinic etc., still remain to be solved. It is necessary to overcome these challenges in order to effectively recover auditory function in human patients. Here, we review the progress made in our group, especially our efforts to make more effective and cell type-specific viral vectors for targeting cochlea cells.

PMID: 32424232 [PubMed – as supplied by publisher]

Threshold sound conditioning in the treatment of sensorineural hearing loss

https://onlinelibrary.wiley.com/doi/full/10.1002/lio2.399

https://www.ncbi.nlm.nih.gov/pubmed/32596485?dopt=Abstract

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Threshold sound conditioning in the treatment of sensorineural hearing loss.

Laryngoscope Investig Otolaryngol. 2020 Jun;5(3):438-444

Authors: Kwak E, Kwak S

Abstract

Objectives/hypothesis: Sensorineural hearing loss is one of the most common human disorders, with increasing incidence in elderly patients, severely restricting normal activities, and lowering quality of life. The introduction of sound conditioning has the potential to activate auditory pathway plasticity and improve basal frequency hearing. Our objective was to evaluate the safety and efficacy of threshold sound conditioning (TSC). The null hypothesis in this study was that TSC does not have a significant effect on auditory threshold amelioration.

Methods: Pure tone audiometry (PTA) was performed and hearing thresholds were measured once at baseline, and a second time following TSC intervention. Data were analyzed using an intention-to treat design.

Results: The TSC group (78%) significantly differed from the control group (44%) on auditory threshold amelioration; P = .008091 in DV1, P = .000546 in DV2 by Scheffe’s post hoc test. Female subjects (77%) showed a significant difference in DV1 from male subjects (47%); P = .025468 in DV1 by Scheffe’s post hoc test. Older subjects (75%) showed no significant difference from younger subjects (53%); P = .139149 in DV1, P = .082920 in DV2 by Scheffe’s post hoc test.

Conclusions: We observed a significant improvement in a narrow band frequency threshold in this randomized controlled prospective clinical study in a broad range of subjects. These data have important clinical implications since there is no current long-term therapy for this widespread and growing disability. Additional physiologic, mechanistic, and molecular studies are necessary to fully elucidate the pathophysiology and mechanism of action of TSC.

Level of Evidence: 1a.

PMID: 32596485 [PubMed]

Progress in Modeling and Targeting Inner Ear Disorders with Pluripotent Stem Cells [PDF]

https://www.cell.com/stem-cell-reports/pdf/S2213-6711(20)30148-X.pdf

https://www.cell.com/stem-cell-reports/pdf/S2213-6711(20)30148-X.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS221367112030148X%3Fshowall%3Dtrue

https://www.ncbi.nlm.nih.gov/pubmed/32442531?dopt=Abstract

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Progress in Modeling and Targeting Inner Ear Disorders with Pluripotent Stem Cells.

Stem Cell Reports. 2020 May 06;:

Authors: Tang PC, Hashino E, Nelson RF

Abstract

Sensorineural hearing loss and vestibular dysfunction are caused by damage to neurons and mechanosensitive hair cells, which do not regenerate to any clinically relevant extent in humans. Several protocols have been devised to direct pluripotent stem cells (PSCs) into inner ear hair cells and neurons, which display many properties of their native counterparts. The efficiency, reproducibility, and scalability of these protocols are enhanced by incorporating knowledge of inner ear development. Modeling human diseases in vitro through genetic manipulation of PSCs is already feasible, thereby permitting the elucidation of mechanistic understandings of a wide array of disease etiologies. Early studies on transplantation of PSC-derived otic progenitors have been successful in certain animal models, yet restoration of function and long-term cell survival remain unrealized. Through further research, PSC-based approaches will continue to revolutionize our understanding of inner ear biology and contribute to the development of therapeutic treatments for inner ear disorders.

PMID: 32442531 [PubMed – as supplied by publisher]

Gene therapy for hair cell regeneration: Review and new data

https://www.sciencedirect.com/science/article/abs/pii/S0378595519304964?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32563621?dopt=Abstract

Gene therapy for hair cell regeneration: Review and new data.

Hear Res. 2020 May 05;:107981

Authors: Shibata SB, West MB, Du X, Iwasa Y, Raphael Y, Kopke RD

Abstract

Hair cells (HCs) in the cochlea are responsible for transducing mechanical sound energy into neural impulses which lead to the perception of sound. Loss of these sensory cells is the most common cause of sensorineural hearing loss, and spontaneous HC regeneration does not occur in mature mammals. Among the future potential treatment modalities is gene therapy, which is defined as the administration of either DNAs or RNAs as active pharmaceutical ingredients for inducing a clinically-beneficial response. Gene therapy is being envisioned and evaluated as a potential tool for addressing a number of human inner ear disorders. This paper is a hybrid Review and Research Paper, including unpublished data and a review of HC regeneration studies in live animal models. Current gene therapeutic approaches for replacing lost HC populations have been aimed at converting supporting cells surviving within the neuro-epithelium to new HCs by inducing upregulation of bHLH transcription factors such as Atoh1 or reciprocal silencing of Notch signaling with siRNAs, to tip the balance of transcriptional regulation toward a HC fate. Development of one or more of these techniques may yield a path to effective restoration of inner ear form and function. This review also describes other approaches and molecular targets that may prove efficacious and provides perspectives on future clinical challenges and opportunities for gene therapy to become a valuable weapon for the long-anticipated realization of this regenerative treatment.

PMID: 32563621 [PubMed – as supplied by publisher]

Role of microRNA in inner ear stem cells and related research progress: solving the medical problem of inner ear hair cell regeneration

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218733/

https://www.ncbi.nlm.nih.gov/pubmed/32419976?dopt=Abstract

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Role of microRNA in inner ear stem cells and related research progress.

Am J Stem Cells. 2020;9(2):16-24

Authors: Wu X, Zou S, Wu F, He Z, Kong W

Abstract

Deafness is one of the major global health problems that seriously affects the quality of human life. At present, there are no successful treatments for deafness caused by cochlear hair cell (HC) damage. The irreversibility of mammalian hearing impairment is that the inner ear’s sensory epithelium cannot repair lost hair cells and neurons through spontaneous regeneration. The goal of stem cell therapy for sensorineural hearing loss is to reconstruct the damaged inner ear structure and achieve functional repair. microRNA (miRNA), as a class of highly conserved endogenous non-coding small RNAs, plays an important role in the development of cochlea and HCs. miRNA also participates in the regulation of stem cell proliferation and differentiation, and plays an important role in the process of regeneration of inner ear HCs, miRNA has a broad application prospect of clinical treatment of hearing loss, which is conducive to solving the medical problem of inner ear HC regeneration.

PMID: 32419976 [PubMed]

Possibility of reprogramming endogenous fibroblasts into functional inner ear hair cells for regenerative therapeutic purposes

https://www.sciencedirect.com/science/article/abs/pii/S0304394020302809?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32344104?dopt=Abstract

Possibility of reprogramming endogenous fibroblasts into functional inner ear hair cells for regenerative purposes

Direct reprogramming adult fibroblast into cells with partial inner ear hair cell characteristics through cell activation and signal directed approach.

Neurosci Lett. 2020 Apr 25;:135010

Authors: Zhao M, Ma R, Huang YB, Cong N, Chi FL, Yuan YS, Gao Z

Abstract

Loss of inner ear hair cell (HC) is an irreversible process in mammals and is the most common cause of human hearing and balance disorders especially in the elderly. Cell therapy based on highly scalable generation of HC linage and inner ear transplantation is one of the most promising therapeutic approaches for HC impairment. For fibroblast is quite abundant and readily available in human body, it is an ideal endogenous cell source to generate HC lineage for transplantation purpose. In the present study, by using a cell activation and signaling directed method, we demonstrate that adult fibroblast can be direct reprogrammed into a kind of cell which expresses lots of HC markers. At the same time, an intermediate progenitor stage exists during such a lineage conversion and activation of FGF pathway is critical for its formation. Although these reprogrammed cells still lack some of the key features of HC such as mechanosensitive ion channel hence have not acquired the functional properties of HC, the findings reported here raise the possibility of reprogramming endogenous fibroblasts into functional HC for regenerative purpose.

PMID: 32344104 [PubMed – as supplied by publisher]

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