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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
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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

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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

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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

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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

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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]

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]

Mesenchymal stem cells for sensorineural hearing loss: a systematic review of preclinical studies

https://link.springer.com/article/10.1007/s11033-020-05460-0

https://www.ncbi.nlm.nih.gov/pubmed/32323262?dopt=Abstract

Mesenchymal stem cells for sensorineural hearing loss: a systematic review of preclinical studies.

Mol Biol Rep. 2020 Apr 22;:

Authors: Chorath K, Willis M, Morton-Gonzaba N, Moreira A

Abstract

Sensorineural hearing loss (SNHL) is the most common form of hearing loss that is routinely treated with hearing aids or cochlear implants. Advances in regenerative medicine have now led to animal studies examining the possibility of restoring injured hair cells with mesenchymal stem/stromal cell (MSC) administration. We conducted a systematic review and meta-analysis to collate the existing preclinical literature evaluating MSCs as a treatment for SNHL and quantify the effect of MSCs on functional hearing. Our protocol was published online on CAMARADES. Searches were conducted in four medical databases by two independent investigators. Twelve studies met inclusion and were evaluated for risk of bias using SYRCLE. Rodent models were commonly used (n = 8, 66%), while auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) were the most frequent measures assessing hearing loss. MSCs were derived from multiple tissue sources, including bone marrow, adipose tissue, and umbilical cord blood and the dose ranged from 4 × 103 to 1 × 107 cells. Treatment with MSCs resulted in an improvement in ABR and DPOAE (mean difference-15.22, + 9.10, respectively). Despite high heterogeneity and multiple “unclear” domains in the risk of bias, this review provides evidence that MSCs may have a beneficial effect in hearing function.

PMID: 32323262 [PubMed – as supplied by publisher]

Making the Case for Research on Disease-Modifying Treatments to Tackle Post-lingual Progressive Sensorineural Hearing Loss

https://www.frontiersin.org/articles/10.3389/fneur.2020.00290/full

Front. Neurol., 21 April 2020 | https://doi.org/10.3389/fneur.2020.00290
Making the Case for Research on Disease-Modifying Treatments to Tackle Post-lingual Progressive Sensorineural Hearing Loss
Vincent Van Rompaey1,2*
1Department of Otorhinolaryngology and Head & Neck Surgery, Antwerp University Hospital, Edegem, Belgium
2Department of Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

Influence of Cochlear Dead Regions on Hearing Outcome in Sudden Sensorineural Hearing Loss

https://journals.lww.com/otology-neurotology/Citation/2020/08000/Influence_of_Cochlear_Dead_Regions_on_Hearing.6.aspx

https://www.ncbi.nlm.nih.gov/pubmed/32658395?dopt=Abstract

Influence of Cochlear Dead Regions on Hearing Outcome in Sudden Sensorineural Hearing Loss.

Otol Neurotol. 2020 Aug;41(7):889-894

Authors: Choi JE, Shim HJ, An YH, Yoo S, Mun SK, Chang MY, Park MH, Jun BC, Moon IJ

Abstract

OBJECTIVE: The aims of this multicenter study were to prospectively evaluate the prevalence of dead regions (DRs) in sudden sensorineural hearing loss (SSNHL) and compare the clinical characteristics and hearing outcomes of SSNHL according to the presence of DRs.

STUDY DESIGN: Prospective study.

SETTING: Multicenter study.

PATIENTS AND METHODS: The threshold-equalizing noise (TEN) test was prospectively performed on a total of 130 patients diagnosed with SSNHL. All patients received systemic steroid therapy and/or intratympanic steroid injection within 1 month after onset. Pure-tone audiograms and the TEN test were conducted before and after steroid treatment. Age, sex, side of affected ear, recurrence, onset of symptoms, presence of dizziness, and comorbid diseases were also collected. The prevalence of DRs in SSNHL and clinical factors related to the DRs were assessed. Hearing outcomes for SSNHL according to DRs were evaluated in 68 patients who followed a pure-tone audiogram.

RESULTS: The overall prevalence of one or more DRs in SSNHL evaluated using the TEN test was 20.8% (27/130 subjects) and the overall frequency-specific prevalence of DR was 6.7% (61/910 DRs). Although the DRs (+)and DR (-) groups had similar initial pure-tone thresholds, the DRs (+) group had significantly worse initial WRS compared to the DRs (-) group (p = 0.015). The presence of DRs was not associated with hearing recovery in a multivariate logistic regression model, but it was significantly associated with the degree of hearing gain in a multivariate linear regression model (p = 0.018).

CONCLUSIONS: The presence of DRs can be considered one of the poor prognostic factors for SSNHL and the TEN test may contribute to assess the prognosis of SSNHL in clinical settings.

PMID: 32658395 [PubMed – as supplied by publisher]

Diagnostic and Therapeutic Applications of Genomic Medicine in Sensorineural Hearing Loss

https://www.sciencedirect.com/science/article/abs/pii/S0378111920303462?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32304785?dopt=Abstract

Related Articles

Diagnostic and Therapeutic Applications of Genomic Medicine in Progressive, Late-Onset, Nonsyndromic Sensorineural Hearing Loss.

Gene. 2020 Apr 15;:144677

Authors: Jimenez JE, Nourbakhsh A, Colbert B, Mittal R, Yan D, Green CL, Nisenbaum E, Liu G, Bencie N, Rudman J, Blanton SH, Zhong Liu X

Abstract

The progressive, late-onset, nonsyndromic, sensorineural hearing loss (PNSHL) is the most common cause of sensory impairment globally, with presbycusis affecting greater than a third of individuals over the age of 65. The etiology underlying PNSHL include presbycusis, noise-induced hearing loss, drug ototoxicity, and delayed-onset autosomal dominant hearing loss (AD PNSHL). The objective of this article is to discuss the potential diagnostic and therapeutic applications of genomic medicine in PNSHL. Genomic factors contribute greatly to PNSHL. The heritability of presbycusis ranges from 25 to 75%. Current therapies for PNSHL range from sound amplification to cochlear implantation (CI). PNSHL is an excellent candidate for genomic medicine approaches as it is common, has well-described pathophysiology, has a wide time window for treatment, and is amenable to local gene therapy by currently utilized procedural approaches. AD PNSHL is especially suited to genomic medicine approaches that can disrupt the expression of an aberrant protein product. Gene therapy is emerging as a potential therapeutic strategy for the treatment of PNSHL. Viral gene delivery approaches have demonstrated promising results in human clinical trials for two inherited causes of blindness and are being used for PNSHL in animal models and a human trial. Non-viral gene therapy approaches are useful in situations where a transient biologic effect is needed or for delivery of genome editing reagents (such as CRISPR/Cas9) into the inner ear. Many gene therapy modalities that have proven efficacious in animal trials have potential to delay or prevent PNSHL in humans. The development of new treatment modalities for PNSHL will lead to improved quality of life of many affected individuals and their families.

PMID: 32304785 [PubMed – as supplied by publisher]

Potential benefits of salvage intratympanic dexamethasone injection in profound idiopathic sudden sensorineural hearing loss

https://link.springer.com/article/10.1007%2Fs00405-020-05967-z

https://www.ncbi.nlm.nih.gov/pubmed/32296977?dopt=Abstract

Related Articles

Potential benefits of salvage intratympanic dexamethasone injection in profound idiopathic sudden sensorineural hearing loss.

Eur Arch Otorhinolaryngol. 2020 Apr 15;:

Authors: Choi JW, Lee CK, Kim SB, Lee DY, Ko SC, Park KH, Choi SJ

Abstract

PURPOSES: To compare hearing recovery levels after initial treatment or salvage intratympanic dexamethasone injection (ITDI), and to find the prognostic factor on salvage ITDI therapy in profound ISSNHL.

METHODS: We retrospectively reviewed 115 patients with profound ISSNHL. All patients were treated with combination or systemic steroid therapy as the initial treatment. Next, we used salvage ITDI therapy on patients who showed slight or no improvement according to Siegel’s criteria. To find the prognostic factors for the effectiveness of salvage ITDI therapy, we analyzed clinical data, such as, age, sex, vertigo, symptom duration, diabetes, hypertension, initial PTA, pre-salvage PTA, and treatment methods, using multiple regression analyses.

RESULTS: The rate of serviceable hearing recovery were 10.4% (12/115) in the initial-treatment group and 20.4% (21/103) in the salvage group. The difference was statistically significant (p = 0.041). Pre-salvage PTA, diabetes mellitus, and symptom duration were affective factors for the effectiveness of salvage ITDI therapy in profound ISSNHL refractory to initial treatment, with odds ratios of 1.169 (95% confidence interval, 1.088-1.256), 0.069 (95% confidence interval, 0.005-0.889), and 9.242 (95% confidence interval, 1.079-79.146).

CONCLUSIONS: Salvage therapy should be considered for profound ISSNHL, which is expected to result in poor prognosis or hearing recovery: ITSI therapy might be an effective treatment as salvage therapy.

PMID: 32296977 [PubMed – as supplied by publisher]

NO COVID-19 SLOWDOWN: Frequency Therapeutics Adds Another Recruitment Site for FX-322 Phase 2a Study

Frequency Therapeutics has once again updated the official Study Record of its Phase 2a clinical trial of FX-322 in Adults With Stable Sensorineural Hearing Loss.

The update – which includes a new clinical trial site in Austin, Texas – was posted to ClinicalTrials.gov on April 10, 2020.

No Slowdown Due to COVID-19?

It looks like the FX-322 trial is still moving forward as expected, running on schedule.

Usually, a small change to a study record would not seem like such big news.

However, in the context of COVID-19, it is noteworthy. And uplifting! Why?

Consider this: while many clinical trials across the world are experiencing massive slowdowns and stoppages due to COVID-19, the FX-322 Phase 2a trial is expanding its presence to yet another location in the United States. Expanding!

That is not to say the trial has not been affected by COVID-19. For example, patient recruitment efforts and other logistics have probably become more challenging.

However, despite all that is happening, what we see with this update is more activity and signs of life. Things are happening. Plus, we have proof that the study is not paused or stopped. In fact, there is no sign of any delay at all…

FULL SPEED AHEAD!

The estimated study completion date (September 30, 2020) remains unchanged. Repeat: the estimated completion date of the FX-322 trial has NOT been pushed back despite the impact of COVID-19, according to the latest study record.

Small update, big news.

Link to official study page:

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

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Phase 2a Study of FX-322 Administered by Intratympanic Injection in Adults With Stable Sensorineural Hearing Loss

https://clinicaltrials.gov/ct2/show/NCT04120116?type=Intr&cond=Hearing+Loss&lupd_s=09%2F25%2F2019&lupd_d=14&sort=nwst

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

Interventions :   Drug: FX-322;   Drug: Placebo

Sponsor :   Frequency Therapeutics

Recruiting

FX-322 in Adults With Stable Sensorineural Hearing Loss

NCT04120116

Wed, 09 Oct 2019 12:00:00 EDT

Last Update Posted: 10/09/19 10:49AM

Otoprotective Effects of α-lipoic Acid on A/J Mice With Age-related Hearing Loss

https://journals.lww.com/otology-neurotology/Abstract/publishahead/Otoprotective_Effects_of___lipoic_Acid_on_A_J_Mice.96143.aspx

https://www.ncbi.nlm.nih.gov/pubmed/32282782?dopt=Abstract

Otoprotective Effects of α-lipoic Acid on A/J Mice With Age-related Hearing Loss.

Otol Neurotol. 2020 Apr 10;:

Authors: Huang S, Xu A, Sun X, Shang W, Zhou B, Xie Y, Zhao M, Li P, Lu P, Liu T, Han F

Abstract

OBJECTIVE: A/J mice are a mouse model of age-related hearing loss (AHL) with progressive degeneration of outer hair cells (OHCs), spiral ganglion neurons (SGNs), and stria vascularis. This study was carried out to observe the otoprotective effects of α-lipoic acid on A/J mice.

METHODS: A/J mouse pups at postnatal day 7 were randomly distributed into the untreated group, the dimethyl sulfoxide (DMSO) group, and the α-lipoic acid + DMSO group. α-lipoic acid was given to the mice intraperitoneally at a dosage of 50 μg/g body weight every other day. Time course auditory-evoked brainstem response (ABR) thresholds were tested. OHC loss was counted and the densities of SGNs and the width of stria vascularis were measured at 4 and 8 weeks of age.

RESULTS: Measurement of the ABR thresholds revealed that hearing loss in A/J mice was attenuated by α-lipoic acid at age from 3 to 8 weeks. Moreover, preservation effects of OHCs, SGNs, and stria vascularis by α-lipoic acid were observed in the cochleae of A/J mice at 4 and 8 weeks of age.

CONCLUSION: Hearing loss in A/J mice can be attenuated by α-lipoic acid. The otoprotective effects of α-lipoic acid on A/J mice may be obtained by preserving OHCs, SGNs, and stria vascularis in the cochleae. The oxidative damage related to gene mutations may be a potential target for AHL prevention and therapy.

PMID: 32282782 [PubMed – as supplied by publisher]

FGF22 promotes generation of cochlear ribbon synapses through downregulating MEF2D

https://www.aging-us.com/article/103042/text

ribbon synapses may be regulated by FGF22/calcium/CalN/MEF2D signaling, which implied novel therapeutic targets for hearing loss.

FGF22 promotes generation of ribbon synapses through downregulating MEF2D
Shuna Li1 , Jingchun He1 , Yupeng Liu1 , Jun Yang1
1 Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
Received: January 22, 2020       Accepted: March 10, 2020       Published: April 9, 2020https://doi.org/10.18632/aging.103042

High Dose Oral Steroids in Sudden Sensorineural Hearing Loss [Suspended] (On hold due to COVID-19 outbreak)

https://clinicaltrials.gov/ct2/show/NCT03255473

High Dose Oral Steroids in Sudden Sensorineural Hearing Loss

Study Type : Interventional
Estimated Enrollment : 208 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Compare hearing outcomes between treatment with dexamethasone versus prednisone in participants who have been diagnosed with unilateral SSNHL within six weeks, and compare side effect profiles between the two treatment regimens of either dexamethasone or prednisone.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: High Dose Oral Steroids in Sudden Sensorineural Hearing Loss
Actual Study Start Date : August 30, 2017
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : February 2020

Regulation of Noise-Induced Loss of Serotonin Transporters with Resveratrol in a Rat Model: Resveratrol has protective effects against noise-induced loss of SERT

https://www.mdpi.com/1420-3049/24/7/1344

https://www.ncbi.nlm.nih.gov/pubmed/30959762?dopt=Abstract

Related Articles

Regulation of Noise-Induced Loss of Serotonin Transporters with Resveratrol in a Rat Model Using 4-[18F]-ADAM/Small-Animal Positron Emission Tomography.

Molecules. 2019 Apr 05;24(7):

Authors: Li IH, Shih JH, Jhao YT, Chen HC, Chiu CH, Chen CF, Huang YS, Shiue CY, Ma KH

Abstract

Serotonin (5-HT) plays a crucial role in modulating the afferent fiber discharge rate in the inferior colliculus, auditory cortex, and other nuclei of the ascending auditory system. Resveratrol, a natural polyphenol phytoalexin, can inhibit serotonin transporters (SERT) to increase synaptic 5-HT levels. In this study, we investigated the effects of resveratrol on noise-induced damage in the serotonergic system. Male Sprague-Dawley rats were anaesthetized and exposed to an 8-kHz tone at 116 dB for 3.5 h. Resveratrol (30 mg/kg, intraperitoneal injection [IP]) and citalopram (20 mg/kg, IP), a specific SERT inhibitor used as a positive control, were administered once a day for four consecutive days, with the first treatment occurring 2 days before noise exposure. Auditory brainstem response testing and positron emission tomography (PET) with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM, a specific radioligand for SERT) were used to evaluate functionality of the auditory system and integrity of the serotonergic system, respectively, before and after noise exposure. Finally, immunohistochemistry was performed 1 day after the last PET scan. Our results indicate that noise-induced serotonergic fiber loss occurred in multiple brain regions including the midbrain, thalamus, hypothalamus, striatum, auditory cortex, and frontal cortex. This noise-induced damage to the serotonergic system was ameliorated in response to treatment with resveratrol and citalopram. However, noise exposure increased the hearing threshold in the rats regardless of drug treatment status. We conclude that resveratrol has protective effects against noise-induced loss of SERT.

PMID: 30959762 [PubMed – in process]

Neurotrophin gene therapy to promote survival of spiral ganglion neurons after deafness

https://www.sciencedirect.com/science/article/abs/pii/S0378595519304563?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32331858?dopt=Abstract

Related Articles

Neurotrophin gene therapy to promote survival of spiral ganglion neurons after deafness.

Hear Res. 2020 Apr 05;:107955

Authors: Leake PA, Akil O, Lang H

Abstract

Hearing impairment is a major health and economic concern worldwide. Currently, the cochlear implant (CI) is the standard of care for remediation of severe to profound hearing loss, and in general, contemporary CIs are highly successful. But there is great variability in outcomes among individuals, especially in children, with many CI users deriving much less or even marginal benefit. Much of this variability is related to differences in auditory nerve survival, and there has been substantial interest in recent years in exploring potential therapies to improve survival of the cochlear spiral ganglion neurons (SGN) after deafness. Preclinical studies using osmotic pumps and other approaches in deafened animal models to deliver neurotrophic factors (NTs) directly to the cochlea have shown promising results, especially with Brain-Derived Neurotrophic Factor (BDNF). More recent studies have focused on the use of NT gene therapy to force expression of NTs by target cells within the cochlea. This could provide the means for a one-time treatment to promote long-term NT expression and improve neural survival after deafness. This review summarizes the evidence for the efficacy of exogenous NTs in preventing SGN degeneration after hearing loss and reviews the animal research to date suggesting that NT gene therapy can elicit long-term NT expression in the cochlea, resulting in significantly improved SGN and radial nerve fiber survival after deafness. In addition, we discuss NT gene therapy in other non-auditory applications and consider some of the remaining issues with regard to selecting optimal vectors, timing of treatment, and place/method of delivery, etc. that must be resolved prior to considering clinical application.

PMID: 32331858 [PubMed – as supplied by publisher]

Lin28 reprograms inner ear glia to a neuronal fate: possibility of a new avenue for regeneration that could replace dying neurons in auditory neuropathy

https://stemcellsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/stem.3181

https://www.ncbi.nlm.nih.gov/pubmed/32246510?dopt=Abstract

Related Articles

Lin28 reprograms inner ear glia to a neuronal fate.

Stem Cells. 2020 Apr 03;:

Authors: Kempfle JS, Luu NC, Petrillo M, Al-Asad R, Zhang A, Edge ASB

Abstract

Sensorineural hearing loss is irreversible and can be caused by loss of auditory neurons. Regeneration of neural cells from endogenous cells may offer a future tool to restore the auditory circuit and to enhance the performance of implantable hearing devices. Neurons and glial cells in the peripheral nervous system are closely related and originate from a common progenitor. Prior work in our lab indicated that in the early postnatal mouse inner ear, proteolipid protein 1 (Plp1) expressing glial cells could act as progenitor cells for neurons in vitro. Here we used a transgenic mouse model to transiently overexpress Lin28, a neural stem cell regulator, in Plp1-positive glial cells. Lin28 promoted proliferation and conversion of auditory glial cells into neurons in vitro. To study the effects of Lin28 on endogenous glial cells after loss of auditory neurons in vivo, we produced a model of auditory neuropathy by selectively damaging auditory neurons with ouabain. After neural damage was confirmed by the auditory brainstem response, we briefly upregulated Lin28 in Plp1-expressing inner ear glial cells. One month later, we analyzed the cochlea for neural marker expression by quantitative RT-PCR and immunohistochemistry. We found that transient Lin28 overexpression in Plp1-expressing glial cells induced expression of neural stem cell markers and subsequent conversion into neurons. This suggests the potential for inner ear glia to be converted into neurons as a regeneration therapy for neural replacement in auditory neuropathy. © AlphaMed Press 2020 SIGNIFICANCE STATEMENT: Loss or damage of auditory neurons is associated with sensorineural hearing loss and deafness. To date, no cure is available and amplification, as well as cochlear implants, rely on surviving neurons to convey the auditory signal to the brain. Regeneration strategies focusing on endogenous cell therapy may offer a future treatment option for replacement of lost neurons to restore the auditory circuit. We show here that in a transgenic mouse model, Plp1-positive glial cells of the inner ear have a capacity for regeneration and differentiate into neurons after transient activation of neural stem cell regulator Lin28 in vitro and in vivo. We present evidence that Lin28 acts through stem cell regulatory genes, Sox2 and Hmga2, to stimulate proliferation and reprogramming of inner ear glia to neurons raising the possibility of a new avenue for regeneration that could replace dying neurons in auditory neuropathy.

PMID: 32246510 [PubMed – as supplied by publisher]

Both vitamin D deficiency and hypocalcemia were found to be independently associated with sensorineural hearing loss (SNHL) in children

https://journals.lww.com/otology-neurotology/Abstract/2020/08000/Vitamin_D_Deficiency,_Hypocalcemia,_and_Hearing.24.aspx

https://www.ncbi.nlm.nih.gov/pubmed/32658400?dopt=Abstract

Vitamin D Deficiency, Hypocalcemia, and Hearing Loss in Children.

Otol Neurotol. 2020 Aug;41(7):940-947

Authors: Mehta CH, Close MF, Dornhoffer JR, Liu YF, Nguyen SA, McRackan TR, Meyer TA

Abstract

OBJECTIVE: Characterize relations between vitamin D deficiency (VDD), hypocalcemia, and hearing loss (HL) in children.

STUDY DESIGN: Retrospective review.

SETTING: Tertiary referral hospital.

PATIENTS: Children in the Audiological and Genetic Database with a diagnosis of VDD, rickets, or osteomalacia.

INTERVENTION: None.

MAIN OUTCOME MEASURES: Prevalence, type, severity (4-tone pure-tone average, PTA), and progression of HL. HL was defined as greater than 15 dB HL at any threshold by pure tone, greater than 20 dB HL by sound field audiometry, or greater than 25 dB in infants less than 1 year of age.

RESULTS: Of 888 children with VDD, 474 (53.4%) had HL, with 17% having moderate-profound HL. Compared with an age-matched cohort of 13,320 children drawn from the same database, children with VDD were significantly more likely to have sensorineural HL (SNHL) (adjusted odds ratios [aOR] 1.26 [95% confidence interval [CI] 1.01-1.58]). Among children with VDD, children with femur fracture had a significantly higher rate of HL (81% versus 53%, p = 0.008) and children with hypocalcemia had a significantly higher rate of moderate-profound HL (36% versus 18%, p = 0.016). Additionally, hypocalcemia with and without VDD was associated with SNHL (aOR 2.30 [1.07-4.56]).

CONCLUSIONS: Both vitamin D deficiency and hypocalcemia were found to be independently associated with SNHL, a type of HL that is less likely to improve over time. Recognition of VDD and hypocalcemia as independent risk factors for the development of SNHL could allow for better evaluation and treatment of this patient population. Routine audiological evaluation should be considered in this population.

PMID: 32658400 [PubMed – as supplied by publisher]

Strekin AG Completes Phase 3 Clinical Study of STR001 to Restore Hearing in Patients with SSNHL

Strekin AG, a Swiss-based biopharmaceutical company focused on developing new treatments to reverse hearing loss, has completed its Phase 3 clinical trial of the investigational drug STR001 in patients with Sudden Sensorineural Hearing Loss (SSNHL).

According to the official study record (Source: ClinicalTrials.gov), the Status of Study NCT03331627, Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL, was changed from “Recruiting” to “Completed” on March 25, 2020. The actual completion date of the study was updated to February 6, 2020.

The purpose of this international, randomized, placebo-controlled, Phase 3 study, officially titled Phase III Multicenter, Double-blind, Placebo-controlled, Study Evaluating the Safety, and Efficacy of STR001 Treatment in Adults With Sudden Sensorineural Hearing Loss, was to evaluate the ability of STR001 to restore hearing in patients following a SSNHL event.

If the results are promising, STR001 could become the first approved treatment for SSNHL patients.

The previous update related to this clinical trial of STR001 was from over six months ago, on September 12, 2019. That is when Strekin AG announced in a press release the completion of patient recruitment for the study (which involved 165 patients).

Prior to that, the last change to the study record was almost a year ago, on April 10, 2019. That is when the study began recruiting patients, according to the official study page.

Source:

https://clinicaltrials.gov/ct2/show/NCT03331627?type=Intr

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P.S. Here are three other hearing-related “treatment report” sites that might interest you:

Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL [Completed]

https://clinicaltrials.gov/ct2/show/NCT03331627?type=Intr&cond=Hearing+Loss&lupd_s=03%2F27%2F2019&lupd_d=14&sort=nwst

Condition :   Acute Hearing Loss

Intervention :   Drug: STR001-IT and STR001-ER

Sponsor :   Strekin AG

Recruiting

Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL

NCT03331627

Mon, 06 Nov 2017 12:00:00 EST

Last Update Posted: 04/10/19 08:35AM

COMPLETED: Novartis Phase 1/2 Trial of CGF166, an Inner Ear Gene Therapy for Hearing Loss

The status of study NCT02132130 (Safety, Tolerability and Efficacy for CGF166 in Patients With Unilateral or Bilateral Severe-to-profound Hearing Loss), was changed from “Active, not recruiting” to “Completed” on March 19, 2020.

According to the official study record, the actual completion date of the trial was December 9, 2019.

The previous update to this clinical trial of CGF166 was posted just over four months ago, on November 15, 2019. That is when the study status was changed from “Recruiting” to “Active, not recruiting.”

Source:
https://clinicaltrials.gov/ct2/show/NCT02132130

Sesamum indicum L. Oil and Sesamin Induce Auditory-Protective Effects Through Changes in Hearing Loss-Related Gene Expression

https://www.liebertpub.com/doi/10.1089/jmf.2019.4542

https://www.ncbi.nlm.nih.gov/pubmed/32186941?dopt=Abstract

Sesamum indicum L. Oil and Sesamin Induce Auditory-Protective Effects Through Changes in Hearing Loss-Related Gene Expression.

J Med Food. 2020 Mar 18;:

Authors: Kim YH, Kim EY, Rodriguez I, Nam YH, Jeong SY, Hong BN, Choung SY, Kang TH

Abstract

Changing consumption patterns and increasing health awareness, especially in Europe, are resulting in an increased demand for sesame seeds. In 2016, Asia imported the highest quantity of sesame seeds, followed by Europe and North America. We examined, for the first time, the effects of treatment with sesame oil and sesamin in hearing impairment models. Sesame oil exhibited an ameliorative effect on auditory impairment in a hair cell line in zebrafish and mice. In ototoxic zebrafish larvae, neuromasts and otic cells increased in numbers because of sesame oil. Furthermore, auditory function in noise-induced hearing loss (NIHL) was studied through auditory brainstem response to evaluate the therapeutic effects of sesame oil. Sesame oil reduced the hearing threshold shift in response to clicks and 8, 16-kHz tone bursts in NIHL mice. Auditory-protective effect of sesame oil was seen in zebrafish and mice; therefore, we used chromatographic analysis to study sesamin, which is the major effective factor in sesame oil. To investigate its effects related to auditory function, we studied the hearing-related gene, Tecta, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) assay. Auditory cell proliferation was induced by treatment with sesame oil and sesamin using Tecta (Tectorin Alpha) regulation. The expression of Tecta increases in the apex area of the cochlear hair cells as they grow, and their activity is enhanced by sesame oil and sesamin. These results provide a novel mechanistic insight into the sesame oil activities and suggest that sesamin, the key constituent in sesame oil, is responsible for its auditory function related benefits, including protection of auditory cells and reversal of their impairments.

PMID: 32186941 [PubMed – as supplied by publisher]

Safety, Tolerability and Efficacy for CGF166 in Patients With Unilateral or Bilateral Severe-to-profound Hearing Loss [Completed]

https://clinicaltrials.gov/ct2/show/NCT02132130?type=Intr&cond=Hearing+Loss&lupd_s=04%2F29%2F2019&lupd_d=14&sort=nwst

Condition :   Unilateral Severe to Profound Hearing Loss OR Bilateral Severe to Profound Hearing Loss

Intervention :   Drug: CGF166

Sponsor :   Novartis Pharmaceuticals

Recruiting

Safety, Tolerability and Efficacy for CGF166 in Patients With Unilateral or Bilateral Severe-to-profound Hearing Loss

NCT02132130

Wed, 07 May 2014 12:00:00 EDT

Last Update Posted: 05/13/19 07:50AM

Using Sox2 to alleviate the hallmarks of age-related hearing loss

https://www.sciencedirect.com/science/article/pii/S1568163719304258?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32173536?dopt=Abstract

Related Articles

Using Sox2 to alleviate the hallmarks of age-related hearing loss.

Ageing Res Rev. 2020 Mar 12;:101042

Authors: Yamoah EN, Li M, Shah A, Elliott KL, Cheah K, Xu PX, Phillips S, Young SM, Eberl DF, Fritzsch B

Abstract

Age-related hearing loss (ARHL) is the most prevalent age-related sensory deficit. ARHL reduces the quality of life of the growing aging population, setting seniors up for the enhanced mental decline. The size of the needy population, the structural deficit, and a likely research strategy for effective treatment of chronic neurosensory hearing in the elderly are needed. Although there has been profound advancement in auditory regenerative research, there remain multiple challenges to restore hearing loss. Thus, additional investigations are required, using novel tools. We propose how the flat epithelium, remaining after the organ of Corti has deteriorated, can be converted to the repaired-sensory epithelium, using Sox2. This will include developing an artificial gene regulatory network transmitted by large viral vectors to the flat epithelium to stimulate remnants of the organ of Corti to restore hair cells. We hope to unite with our proposal toward the common goal, eventually restoring a functional human hearing organ by transforming the flat epithelial cells left after the organ of Corti loss.

PMID: 32173536 [PubMed – as supplied by publisher]

Microenvironment Can Induce Development of Auditory Progenitor Cells from Human Gingival Mesenchymal Stem Cells

https://pubs.acs.org/doi/abs/10.1021/acsbiomaterials.9b01795

Microenvironment Can Induce Development of Auditory Progenitor Cells from Human Gingival Mesenchymal Stem Cells
Sevda Pouraghaei, Fathollah Moztarzadeh*, Chider Chen, Sahar Ansari, and Alireza Moshaverinia*
Cite this: ACS Biomater. Sci. Eng. 2020, 6, 4, 2263–2273
Publication Date:March 10, 2020
https://doi.org/10.1021/acsbiomaterials.9b01795

Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex

https://febs.onlinelibrary.wiley.com/doi/abs/10.1111/febs.15266

https://www.ncbi.nlm.nih.gov/pubmed/32112499?dopt=Abstract

Related Articles

Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex.

FEBS J. 2020 Feb 28;:

Authors: Chen X, Li D, Sun HY, Wang WW, Wu H, Kong W, Kong WJ

Abstract

Central presbycusis is caused by degradation of the auditory centre during ageing. Its main characteristics are difficulties in understanding language and localizing sound. Presbycusis is an increasingly critical public health problem, but the underlying molecular mechanism has not been fully elucidated. Ferroptosis is a form of regulated cell death caused by iron- and reactive oxygen species-induced lipid peroxidation. Ferroptosis is related to many pathological processes, but whether it participates in the degeneration of the auditory system remains unclear. To investigate this, we measured iron levels in a simulated ageing model established by the addition of D-galactose (D-gal). We found, for the first time that iron accumulated within cells and that the ultrastructural features of ferroptosis appeared in the auditory cortex with ageing. These changes were accompanied by upregulation of iron regulatory protein 2 (IRP-2), which led to an increase in transferrin receptor 1 (TfR-1), thus increasing iron entry into cells and potentially leading to ferroptosis. In addition, the malondialdehyde (MDA) content and the occurrence of mitochondrial DNA common deletions (CDs) increased, neuron degeneration appeared, and glutathione (GSH) and superoxide dismutase (SOD) activity decreased. Furthermore, we found that treatment with the iron chelator deferoxamine (DFO) and knockdown of IRP-2 both relieved ferroptosis during the simulated ageing process, thus achieving a partial protective effect to delay ageing. In summary, we describe here the first discovery that age-related iron deposition and ferroptosis may be associated with auditory cortex neurodegeneration. Relieving ferroptosis might thus be a new intervention strategy for age-related hearing loss.

PMID: 32112499 [PubMed – as supplied by publisher]

Discovery of a pharmacological treatment that could “wake up” the human body’s ability to naturally regenerate lost hair cells and reverse hearing loss

Many fish, frogs, and birds possess special regeneration capacities that allow them to fully recover from hearing impairments and balance dysfunctions caused by lost hair cells.

Humans and other mammals, however, do NOT have this ability.

Sadly, our mammalian ears are vulnerable to permanent hearing loss and balance deficits.

But that could soon change…

Because new research from Jeff T. Corwin at the University of Virginia appears to have uncovered the reason for the permanent nature of hair cell loss in humans. The findings identify why certain creatures can recover from hearing damage and why humans cannot.

The most exciting part?

The team behind the research, part of Corwin’s Laboratory of Inner Ear Sensory Hair Cell Regeneration, has discovered a pharmacological treatment that could “wake up” the special supporting cells that can allow lost hair cells to regenerate in humans.

To learn more about how it works, here is a link to the study itself — which was published on February 20, 2020 in the Journal of Neuroscience.

EGF and a GSK3 Inhibitor Deplete Junctional E-cadherin and Stimulate Proliferation in the Mature Mammalian Ear.

Here is the abstract:

J Neurosci. 2020 Feb 19;:
Authors: Kozlowski MM, Rudolf MA, Corwin JT

Sensory hair cell losses underlie the vast majority of permanent hearing and balance deficits in humans, but many non-mammalian vertebrates can fully recover from hearing impairments and balance dysfunctions, because supporting cells (SCs) in their ears retain lifelong regenerative capacities that depend on proliferation and differentiation as replacement hair cells. Most SCs in vertebrate ears stop dividing during embryogenesis, and soon after birth vestibular SCs in mammals transition to lasting quiescence as they develop massively thickened circumferential F-actin bands at their E-cadherin-rich adherens junctions.

Here, we report that treatment with EGF and a GSK3 inhibitor thinned the circumferential F-actin bands throughout the sensory epithelium of cultured utricles that were isolated from adult mice of either sex. That treatment also caused decreases in E-cadherin, β-catenin, and YAP in the striola, and stimulated robust proliferation of mature, normally quiescent striolar SCs. The findings suggest that E-cadherin-rich junctions, which are not present in the SCs of the fish, amphibians, and birds which readily regenerate hair cells, are responsible in part for the mammalian ear’s vulnerability to permanent balance and hearing deficits.

SIGNIFICANCE STATEMENT

Millions of people are affected by hearing and balance deficits that arise when loud sounds, ototoxic drugs, infections, and aging cause hair cell losses. Such deficits are permanent for humans and other mammals, but non-mammals can recover hearing and balance after supporting cells regenerate replacement hair cells. Mammalian supporting cells lose the capacity to proliferate around the time they develop unique, exceptionally reinforced, E-cadherin-rich intercellular junctions. Here, we report the discovery of a pharmacological treatment that thins F-actin bands, depletes E-cadherin, and stimulates proliferation in long-quiescent supporting cells within a balance epithelium from adult mice. The findings suggest that high E-cadherin in those supporting cell junctions may be responsible, in part, for the permanence of hair cell loss in mammals.

PMID: 32079647 [PubMed – as supplied by publisher]

Additional research shows that there is a U.S. Provisional Patent Application related to the research posted here is currently pending. The application number is 62/951,996 and it was filed on December 20, 2019. The patent applicant is Jeffrey T. Corwin, and the other inventors listed include Mark Rudolf and Mikolaj Kozlowski.

Hearing Loss Treatment Report will continue to keep an eye on this promising new (potential) hearing loss treatment, which involves treatment with an EGF and a GSK3 inhibitor, and is currently being tested in mice. But considering the patent filing and strong evidence, human trials will surely follow.

Want updates? Remember to sign up for free weekly email updates, here. Especially if you want to know about new hearing loss drugs and experimental treatments as soon as possible.

Questions? Comments? Corrections? Feedback?

Send an email to michael@urgentresearch.com and say hello. This site is almost completely automated (except for occasional “exclusive” articles like this one), but there is a human behind the scenes.

rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application

https://www.mdpi.com/2077-0383/9/2/589

https://www.ncbi.nlm.nih.gov/pubmed/32098144?dopt=Abstract

Related Articles

rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application.

J Clin Med. 2020 Feb 21;9(2):

Authors: Blanc F, Mondain M, Bemelmans AP, Affortit C, Puel JL, Wang J

Abstract

Over the last decade, pioneering molecular gene therapy for inner-ear disorders have achieved experimental hearing improvements after a single local or systemic injection of adeno-associated, virus-derived vectors (rAAV for recombinant AAV) encoding an extra copy of a normal gene, or ribozymes used to modify a genome. These results hold promise for treating congenital or later-onset hearing loss resulting from monogenic disorders with gene therapy approaches in patients. In this review, we summarize the current state of rAAV-mediated inner-ear gene therapies including the choice of vectors and delivery routes, and discuss the prospects and obstacles for the future development of efficient clinical rAAV-mediated cochlear gene medicine therapy.

PMID: 32098144 [PubMed]

EGF and a GSK3 Inhibitor Deplete Junctional E-cadherin and Stimulate Proliferation in the Mature Mammalian Ear

https://www.jneurosci.org/content/early/2020/02/18/JNEUROSCI.2630-19.2020

https://www.ncbi.nlm.nih.gov/pubmed/32079647?dopt=Abstract

Related Articles

EGF and a GSK3 Inhibitor Deplete Junctional E-cadherin and Stimulate Proliferation in the Mature Mammalian Ear.

J Neurosci. 2020 Feb 19;:

Authors: Kozlowski MM, Rudolf MA, Corwin JT

Abstract

Sensory hair cell losses underlie the vast majority of permanent hearing and balance deficits in humans, but many non-mammalian vertebrates can fully recover from hearing impairments and balance dysfunctions, because supporting cells (SCs) in their ears retain lifelong regenerative capacities that depend on proliferation and differentiation as replacement hair cells. Most SCs in vertebrate ears stop dividing during embryogenesis, and soon after birth vestibular SCs in mammals transition to lasting quiescence as they develop massively thickened circumferential F-actin bands at their E-cadherin-rich adherens junctions. Here, we report that treatment with EGF and a GSK3 inhibitor thinned the circumferential F-actin bands throughout the sensory epithelium of cultured utricles that were isolated from adult mice of either sex. That treatment also caused decreases in E-cadherin, β-catenin, and YAP in the striola, and stimulated robust proliferation of mature, normally quiescent striolar SCs. The findings suggest that E-cadherin-rich junctions, which are not present in the SCs of the fish, amphibians, and birds which readily regenerate hair cells, are responsible in part for the mammalian ear’s vulnerability to permanent balance and hearing deficits.SIGNIFICANCE STATEMENTMillions of people are affected by hearing and balance deficits that arise when loud sounds, ototoxic drugs, infections, and aging cause hair cell losses. Such deficits are permanent for humans and other mammals, but non-mammals can recover hearing and balance after supporting cells regenerate replacement hair cells. Mammalian supporting cells lose the capacity to proliferate around the time they develop unique, exceptionally reinforced, E-cadherin-rich intercellular junctions. Here, we report the discovery of a pharmacological treatment that thins F-actin bands, depletes E-cadherin, and stimulates proliferation in long-quiescent supporting cells within a balance epithelium from adult mice. The findings suggest that high E-cadherin in those supporting cell junctions may be responsible, in part, for the permanence of hair cell loss in mammals.

PMID: 32079647 [PubMed – as supplied by publisher]

Role of melatonin in prevention of age-related hearing loss

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228943

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010238/

https://www.ncbi.nlm.nih.gov/pubmed/32040524?dopt=Abstract

Related Articles

Role of melatonin in prevention of age-related hearing loss.

PLoS One. 2020;15(2):e0228943

Authors: Serra LSM, Araújo JG, Vieira ALS, Silva EMD, Andrade RR, Kückelhaus SAS, Sampaio ALL

Abstract

INTRODUCTION: Age-related hearing loss (ARHL) is a consequence of aging of the auditory system. The best known mechanism of cell death in ARHL is apoptosis due to increased production of reactive oxygen species. In this context, it is hypothesized that melatonin, owing to its high antioxidant potential and its action in the mitochondria, helps prevent or delay outer hair cell dysfunction (HCD).

AIMS: To evaluate the effect of melatonin on the prevention of HCD dysfunction in the ARHL process in a susceptible murine C57BL/6J model.

METHOD: C57BL/6J animals were divided into two groups: control (CG) and melatonin (MG). The CG received a saline and ethanol solution and the MG, melatonin (10 mg/kg/day). The solutions were offered daily (50 μl) orally over a 10-month period. Distortion Product Otoacoustic Emissions (DPOAE) measurements were conducted once a month.

RESULTS: There was a decrease in DPOAE values in both groups over time and a differentiation between them from the 10th month of life onwards. At 10 months, the MG maintained higher DPOAE values than the CG at all frequencies tested.

CONCLUSION: The use of melatonin has otoprotective effects on HCD in the ARHL process in the C57BL/6J model.

PMID: 32040524 [PubMed – indexed for MEDLINE]

Exosomes mediate sensory hair cell protection in the inner ear

https://www.jci.org/articles/view/128867

https://www.ncbi.nlm.nih.gov/pubmed/32027617?dopt=Abstract

Exosomes mediate sensory hair cell protection in the inner ear.

J Clin Invest. 2020 Feb 06;:

Authors: Breglio AM, May LA, Barzik M, Welsh NC, Francis SP, Costain TQ, Wang L, Anderson DE, Petralia RS, Wang YX, Friedman TB, Wood MJ, Cunningham LL

Abstract

Hair cells are the mechanosensory receptors of the inner ear, responsible for hearing and balance. Hair cell death and consequent hearing loss are common results of treatment with ototoxic drugs, including the widely-used aminoglycoside antibiotics. Induction of heat shock proteins (HSPs) confers protection against aminoglycoside-induced hair cell death via paracrine signaling that requires extracellular HSP70 (Heat Shock 70 kDa Protein). We investigated the mechanisms underlying this non-cell-autonomous protective signaling in the inner ear. In response to heat stress, inner ear tissue releases exosomes that carry HSP70 in addition to canonical exosome markers and other proteins. Isolated exosomes from heat-shocked utricles were sufficient to improve survival of hair cells exposed to the aminoglycoside antibiotic neomycin, while inhibition or depletion of exosomes from the extracellular environment abolished the protective effect of heat shock. Hair-cell specific expression of the known HSP70 receptor, Toll-like receptor 4 (TLR4), was required for the protective effect of exosomes, and exosomal HSP70 interacted with TLR4 on hair cells. Our results indicate that exosomes are a previously undescribed mechanism of intercellular communication in the inner ear that can mediate non-autonomous hair cell survival. Exosomes may represent a novel class of nano-carriers for delivery of therapeutics against hearing loss.

PMID: 32027617 [PubMed – as supplied by publisher]

Understanding hormone and hormone therapies’ impact on the auditory system

https://onlinelibrary.wiley.com/doi/abs/10.1002/jnr.24588

https://www.ncbi.nlm.nih.gov/pubmed/32026519?dopt=Abstract

Related Articles

Understanding hormone and hormone therapies’ impact on the auditory system.

J Neurosci Res. 2020 Feb 05;:

Authors: Williamson TT, Zhu X, Pineros J, Ding B, Frisina RD

Abstract

Hormones such as estrogen, progesterone, and aldosterone all demonstrate vital roles in sustaining auditory function through either the maintenance of cochlear neurons, up/down regulation of critical molecules (i.e., IGF-1, BDNF, etc.), or generation of the endocochlear potential. With disease and/or age, hormone expression begins to decline drastically, which ultimately affects cochlear structures and the integrity of cochlear cells. The following review explores the latest findings as well as realistic outcomes for hormone therapy treatment in the auditory system. This information could serve as a potential guide for patients considering hormone therapy as a medicinal choice to alleviate the signs of onset of presbycusis-age-related hearing loss. Additional scientific investigations could also be carried out to further enhance recent findings.

PMID: 32026519 [PubMed – as supplied by publisher]

FX-322 Phase 2a Clinical Trial Update: 4 new recruitment sites… plus, changes to eligibility criteria…

Frequency Therapeutics updates official Study Record of Phase 2a clinical trial, FX-322 in Adults With Stable Sensorineural Hearing Loss.

The changes were posted to ClinicalTrials.gov on January 29, 2020 and involve: a) four new study locations, and b) adjustments to the eligibility criteria.

Interestingly, the opening of any additional U.S. sites could add new information to a past statement made by Frequency Therapeutics Chief Executive Officer, David Lucchino, who said, “We have opened all U.S. sites for our Phase 2a study of FX-322,” according to a November 18, 2019 press release.

More importantly, however, is the great opportunity these new locations could provide to any interested (and eligible) patients living in New York, Texas, Utah, or Virginia.

Clinical Trial Recruitment Locations: EXTENDED EDITION

The following four locations were added to the list of clinical trial sites:

United States, New York
Amherst, New York, United States, 14226

United States, Texas
San Antonio, Texas, United States, 78258

United States, Utah
Salt Lake City, Utah, United States, 84102

United States, Virginia
Richmond, Virginia, United States, 23235

As of February 4, 2020, these four new locations are not yet recruiting patients. However, that could change at any moment. Meanwhile, the other recruitment sites — which were posted back in October — are still actively recruiting.

The other recent changes to the FX-322 clinical trial record involve the study’s Eligibility Criteria. Changes were made to both the Inclusion and Exclusion criteria.

FX-322 Trial Eligibility: REMASTERED

Inclusion Criteria (Nov 2019 vs. Feb 2020)

BEFORE:
Established diagnosis of sensorineural hearing loss by standard audiometric measures that is stable for ≥ 6 months prior to the Screening Visit [no changes greater than 5 decibels (dB) in anyfrequency].

AFTER:
Established diagnosis of stable sensorineural hearing loss by standard audiometric measures for ≥ 6 months prior to the Screening visit (no changes in air conduction greater than 10 dB at a singlefrequency or greater than 5 dB at two contiguous frequencies from the prior audiogram to the Screening audiogram in the study ear).

Exclusion Criteria (Nov 2019 vs. Feb 2020)

BEFORE:
Any conductive hearing loss of 10 dB or more at two or more frequencies in either ear.

AFTER:
Any conductive hearing loss of greater than 15 dB at a single frequency or greater than 10 dB at two or more contiguous octave frequencies in the study ear at the Screening visit or on the prior audiogram (if the Investigator feels there is not a true conductive hearing loss, the Medical Monitor should be consulted).

That’s all for now.

Note: The next actually interesting FX-322 progress update should be arriving in June, which is when Frequency Therapeutics could be ready to report top-line data from the trial.

Want more exclusive hearing loss treatment-related updates? Then you should subscribe to the free email newsletter.

Looking for updates for other related conditions? Check out these other “Treatment Report” pages: Tinnitus, Meniere’s Disease, and Hyperacusis.

Questions, comments, concerns, feedback? Email michael@urgentresearch.com and say hello.

Prostaglandin E1 effects on CD62p and PAC-1 in patients with sudden sensorineural hearing loss

https://www.thrombosisresearch.com/article/S0049-3848(20)30032-3/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/32044505?dopt=Abstract

Related Articles

Prostaglandin E1 effects on CD62p and PAC-1 in patients with sudden sensorineural hearing loss.

Thromb Res. 2020 Jan 23;188:31-38

Authors: Xi J, Liu H, Wang X

Abstract

PERSPECTIVES: To evaluate the treatment outcome of vasodilator prostaglandin E1 (PGE1) in treating sudden sensorineural hearing loss (SSNHL) and to determine its effects on platelet activation, as reflected by changes in CD62p and PAC-1.

METHODS: We prospectively enrolled 60 patients with confirmed SSNHL and randomly divided them into two groups: the SSNHL group received regular therapy, and the SSNHL-PGE1 group received additional intravenous injection of PGE1. After 14 days of treatment, we measured clinical improvement and CD62p-positive and PAC-1-positive platelets. 30 healthy medical staff members were included as a control group.

RESULTS: The SSNHL patients had significantly higher levels of CD62p-positive or PAC-1 positive platelets than the healthy subjects. The ratios of CD62p positive or PAC-1 positive platelets significantly decreased after the two treatments. The average pure tone (PTA) hearing thresholds decreased to 26.51 ± 12.65 dB in SSNHL-PGE1 group after treatment, which was significantly lower than that of the SSNHL group (34.46 ± 10.35 dB). Patients with initial severe or profound hearing loss (PTA ≥ 71 dB) had better hearing improvement on PGE1 than on the regular treatment. Patients in the SSNHL-PGE1 treatment group had significantly lower CD62p and PAC-1 levels than those in the SSNHL group. Patients with higher initial positive CD62p and PAC-1 ratios tended to have higher potential of clinical improvement and hearing gains after PGE1 treatment. Initial CD62p and PAC-1 levels were significantly correlated with hearing thresholds in patients with SSNHL.

CONCLUSION: PGE1 application could improve treatment efficacy and suppress excessive platelet activation in patients with SSNHL.

PMID: 32044505 [PubMed – as supplied by publisher]

The role of Yamamoto new scalp acupuncture as an independent treatment for sudden sensorineural hearing loss: a case report

https://journals.sagepub.com/doi/10.1177/0964528419894594

https://www.ncbi.nlm.nih.gov/pubmed/31968987?dopt=Abstract

Related Articles

The role of Yamamoto new scalp acupuncture (YNSA) as an independent treatment for sudden sensorineural hearing loss: a case report.

Acupunct Med. 2020 Jan 22;:964528419894594

Authors: Kao TC, Yang CM

PMID: 31968987 [PubMed – as supplied by publisher]

Auditory brainstem response results demonstrate that transplantation of UC-MSCs is an efficient therapy for sensorineural hearing loss (SNHL) in pig model

https://anatomypubs.onlinelibrary.wiley.com/doi/abs/10.1002/ar.24346

https://pubmed.ncbi.nlm.nih.gov/31943852-transplantation-and-tracking-of-the-human-umbilical-cord-mesenchymal-stem-cell-labeled-with-superparamagnetic-iron-oxide-in-deaf-pigs/

Transplantation and Tracking of the Human Umbilical Cord Mesenchymal Stem Cell Labeled With Superparamagnetic Iron Oxide in Deaf Pigs

Abstract

The purpose of this study was to establish a safe and effective approach to label the human umbilical cord mesenchymal stem cells (UC-MSCs) derived from the Wharton’s Jelly with superparamagnetic iron oxide (SPIO) nanoparticles as a cell tracer. The cytotoxicity of the SPIO was screened in vitro by cytochemical experiments. The results showed the new infection protocol of SPIO-Lip2000 mixture had high efficiency and the optimal labeling concentration was a 50 μg/ml SPIO suspension. Transmission electron microscope (TEM) confirmed the distribution of the intracellular SPIO. We transplanted the labeled UC-MSCs into the sensorineural hearing loss (SNHL) minipigs at 1 week after noise exposure. Auditory brainstem response results demonstrated the transplantation of UC-MSCs was an efficient therapy for SNHL. The positive sediments in cochlear blood vessels, the bony wall of scala tympani, and spiral ganglion nerve fibers were found in the stem cell recipients’ cochlea. We did not detect iron elements in the inner/outer hair cells’ stereocilia, cuticular plate, or pillar cells from the basal to apex turns of the stem cell recipients’ cochlea. In addition, TEM found SPIO in the medulla oblongata and the cerebrum in the SNHL minipigs after stem cell transplantation. In conclusion, we established a safe and effective approach to labeled human UC-MSCs derived from Wharton’s Jelly by using SPIO nanoparticles as a cell tracer in vitro and in vivo. This protocol showed a wide promising application in stem cell therapy and tracing in vivo for experiments with large mammals. Anat Rec, 2020. © 2020 American Association for Anatomy.

AAV9-PHP.B vector drives gene expression in inner ear hair cells and could serve as a gene therapy vehicle for treatment of inner ear dysfunction in humans

https://www.ncbi.nlm.nih.gov/pubmed/31980281?dopt=Abstract

https://www.sciencedirect.com/science/article/pii/S0378595519305246?via%3Dihub

Lastly, we report here that alternate promoters, Syn and Gfap, can be used in combination with AAV9-PHP.B capsids to drive selective expression in subsets of cochlear cell types, such as neurons and supporting cells. We conclude that the AAV9-PHP.B capsid is a powerful vector for driving exogenous gene expression in pre-clinical mouse models of hearing and balance disorders and may be well-suited for further development and perhaps translation to clinical application as a gene therapy vehicle for treatment of inner ear dysfunction in humans.

Related Articles

Efficient viral transduction in mouse inner ear hair cells with utricle injection and AAV9-PHP.B.

Hear Res. 2020 Jan 13;:107882

Authors: Lee J, Nist-Lund C, Solanes P, Goldberg H, Wu J, Pan B, Schneider BL, Holt JR

Abstract

Viral delivery of exogenous coding sequences into the inner ear has the potential for therapeutic benefit for patients suffering genetic or acquired hearing loss. To devise improved strategies for viral delivery, we investigated two injection techniques, round window membrane injection or a novel utricle injection method, for their ability to safely and efficiently transduce sensory hair cells and neurons of the mouse inner ear. In addition, we evaluated three synthetic AAV vectors (Anc80L65, AAV9-PHP.B, AAV2.7m8) encoding enhanced green fluorescent protein (eGFP) and three promoters (Cmv, Synapsin, Gfap) for their ability to transduce and drive expression in desired cell types. We found the utricle injection method with AAV9-PHP.B and a Cmv promoter was the most efficient combination for driving robust eGFP expression in both inner and outer hair cells. We found eGFP expression levels rose over 3-5 days post-injection, a viral dose of 1.5 × 109 gc yielded half maximal eGFP expression and that the utricle injection method yielded transduced hair cells even when delivered as late as postnatal day 16. Sensory transduction and auditory thresholds were unaltered in injected mice relative to uninjected wild-type controls. Vestibular end organs were also transduced without affecting balance behavior. The Synapsin promoter and the Gfap promoter drove strong eGFP expression in inner ear neurons and supporting cells, respectively. We conclude the AAV9-PHP.B vector and the utricle injection method are well-suited for delivery of exogenous gene constructs into inner ears of mouse models of auditory and vestibular dysfunction.

PMID: 31980281 [PubMed – as supplied by publisher]

Possibility of using human dental pulp stem cells (DPSCs) and SHEDs as an autologous stem cell-based therapy for sensorineural hearing loss patients

https://anatomypubs.onlinelibrary.wiley.com/doi/abs/10.1002/ar.24368

https://pubmed.ncbi.nlm.nih.gov/31930687-neuronal-differentiation-of-dental-pulp-stem-cells-from-human-permanent-and-deciduous-teeth-following-coculture-with-rat-auditory-brainstem-slices/

Neuronal Differentiation of Dental Pulp Stem Cells From Human Permanent and Deciduous Teeth Following Coculture With Rat Auditory Brainstem Slices

Abstract

Sensorineural hearing loss is a common disability found worldwide which is associated with a degeneration of spiral ganglion neurons (SGN). It is a challenge to restore SGN due to the permanent degeneration and viability of SGN is requisite for patients to receive an advantage from hearing aid devices. Human dental pulp stem cells (DPSC) and stem cells from human exfoliated deciduous teeth (SHED) are self-renewing stem cells that originate from the neural crest during development. These stem cells have a high potential for neuronal differentiation. This is primarily due to their multilineage differentiation potential and their relative ease of access. Previously, we have shown the ability of these stem cell types to differentiate into spiral ganglion neuron-like cells. In this study, we induced the cells into neural precursor cells (NPC) and cocultured with auditory brainstem slice (ABS) encompassing cochlear nucleus by the Stoppini method. We also investigated their ability to differentiate after 2 weeks and 4 weeks in coculture. Neuronal differentiation of DPSC-NPC and SHED-NPC was higher expression of specific markers to SGN, TrkB, and Gata3, compared to monoculture. The cells also highly expressed synaptic vesicle protein (SV2A) and exhibited intracellular calcium oscillations. Our findings demonstrated the possibility of using DPSCs and SHEDs as an autologous stem cell-based therapy for sensorineural hearing loss patients.

Repeated Moderate Sound Exposure Causes Accumulated Trauma to Cochlear Ribbon Synapses in Mice

https://www.sciencedirect.com/science/article/abs/pii/S0306452220300075?via%3Dihub

https://pubmed.ncbi.nlm.nih.gov/31935490/

Repeated Moderate Sound Exposure Causes Accumulated Trauma to Cochlear Ribbon Synapses in Mice
Yangtuo Luo 1, Tengfei Qu 2, Qingling Song 2, Yue Qi 2, Shukui Yu 2, Shusheng Gong 2, Ke Liu 3, Xuejun Jiang 4
Affiliations expand
PMID: 31935490 DOI: 10.1016/j.neuroscience.2019.12.049

Action on Hearing Loss and Medicines Discovery Catapult team up to launch new “Hearing Medicines Discovery Syndicate”, a collaboration designed to accelerate the “much-needed development” of treatments for hearing loss and tinnitus

http://www.pharmatimes.com/news/new_fast-track_system_for_tinnitus_and_hearing_loss_1321998

New ‘fast-track’ system for tinnitus and hearing loss

Action on Hearing Loss and the Medicines Discovery Catapult have teamed up to launch a new “Hearing Medicines Discovery Syndicate”, a collaboration designed to accelerate the “much-needed development” of treatments for hearing loss and tinnitus.

The collaboration will be partnering with the National Institute for Health Research (NIHR), with academic expertise in hearing research provided University College London Hospitals BRC, Nottingham BRC and Manchester BRC, and the Cell and Gene Therapy Catapult.

Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome

https://www.nature.com/articles/s41514-019-0040-z

Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome
Mustafa N. Okur, Beatrice Mao, Risako Kimura, Scott Haraczy, Tracy Fitzgerald, Kamren Edwards-Hollingsworth, Jane Tian, Wasif Osmani, Deborah L. Croteau, Matthew W. Kelley & Vilhelm A. Bohr
npj Aging and Mechanisms of Disease volume 6, Article number: 1 (2020) Cite this article

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Novel Oral Multifunctional Antioxidant HK-2 Prevents Noise-Induced Hearing Loss and Hair Cell Loss

https://pubmed.ncbi.nlm.nih.gov/31945692-novel-oral-multifunctional-antioxidant-prevents-noise-induced-hearing-loss-and-hair-cell-loss/

https://www.sciencedirect.com/science/article/pii/S0378595519304125?via%3Dihub

Novel Oral Multifunctional Antioxidant Prevents Noise-Induced Hearing Loss and Hair Cell Loss

G D Chen 1, D M Daszynski 2, D Ding 1, H Jiang 1, T Woolman 2, K Blessing 3, P F Kador 3, R Salvi 4

PMID: 31945692 DOI: 10.1016/j.heares.2019.107880

Abstract

Oxidative stress is a major contributor to noise-induced hearing loss, the most common cause of hearing loss among military personnel and young adults. HK-2 is a potent, orally-active, multifunctional, redox-modulating drug that has been shown to protect against a wide range of neurological disorders with no observed side effects. HK-2 protected cochlear HEI-OC1 cells against various forms of experimentally-induced oxidative stressors similar to those observed during and after intense noise exposure. The mechanisms by which HK-2 protects cells is twofold, first by its ability to reduce oxidative stress generated by free radicals, and second, by its ability to complex biologically active transition metals such as Fe+2, thus reducing their availability to participate in the Fenton reaction where highly toxic hydroxyl radicals are generated. For the rat in vivo studies, HK-2 provided significant protection against noise-induced hearing loss and hair cell loss. Noise-induced hearing loss was induced by an 8-16 kHz octave band noises presented for 8 h/d for 21 days at an intensity of 95 dB SPL. In the Prevention study, HK-2 was administered orally beginning 5 days before the start of the noise and ending 10 days after the noise. Treatment with HK-2 dose-dependently reduced the amount of noise-induced hearing impairment, reflected in the cochlear compound action potential, and noise-induced hair cell loss. In a subsequent Rescue experiment in which HK-2 was administered for 10 days starting after the noise was turned off, HK-2 also significantly reduced the amount of hearing impairment, but the effect size was substantially less than in the Prevention studies. HK-2 alone did not adversely affect HEI-OC1 cell viability, nor did it cause any adverse changes in rat body weight, behavior, cochlear function or hair cell integrity. Thus, HK-2 is a novel, safe, orally-deliverable and highly effective otoprotective compound with considerable potential for preventing hearing loss from noise and other hearing disorders linked to excessive oxidative stress.

Sensorion Announces €5.6m Non-Dilutive Funding to Support SENS-401 Phase 2 Study in Sudden Sensorineural Hearing Loss; French Ministry of Armed Forces to Participate in the Study

https://www.businesswire.com/news/home/20191222005022/en/

https://www.biospace.com/article/releases/sensorion-announces-5-6m-non-dilutive-funding-to-support-sens-401-phase-2-study-in-sudden-sensorineural-hearing-loss-french-ministry-of-armed-forces-to-participate-in-the-study/

Sensorion Announces €5.6m Non-Dilutive Funding to Support SENS-401 Phase 2 Study in Sudden Sensorineural Hearing Loss; French Ministry of Armed Forces to Participate in the Study

Pipeline Therapeutics Completes $30 Million Series B Financing – Proceeds to advance PIPE-505 in hearing loss

https://www.businesswire.com/news/home/20191218005137/en/Pipeline-Therapeutics-Completes-30-Million-Series-Financing

Pipeline Therapeutics’ lead candidate, PIPE-505, is entering Phase 1b/2a testing to treat mild-to-moderate sensorineural hearing loss (SNHL) associated with cochlear synaptopathy. PIPE-505 is uniquely positioned to treat this patient population as it can have an impact on both audibility and speech intelligibility, addressing two separate pathologies associated with hearing loss.

Pipeline Therapeutics Completes $30 Million Series B Financing – Proceeds to advance PIPE-505 in hearing loss

TRPV4 and TRPV3 in cochlear hair cells (HCs) protect hearing in mice

https://www.frontiersin.org/articles/10.3389/fnmol.2019.00296/full

https://pubmed.ncbi.nlm.nih.gov/31866822-transient-receptor-potential-cation-channel-subfamily-vanilloid-4-and-3-in-the-inner-ear-protect-hearing-in-mice/

TRPV4 and TRPV3 in cochlear inner hair cells (HCs) protect hearing in mice

Transient Receptor Potential Cation Channel Subfamily Vanilloid 4 and 3 in the Inner Ear Protect Hearing in Mice

Abstract

The transient receptor potential cation channel, vanilloid type (TRPV) 3, is a member of the TRPV subfamily that is expressed predominantly in the skin, hair follicles, and gastrointestinal tract. It is also distributed in the organ of Corti of the inner ear and colocalizes with TRPV1 or TRPV4, but its role in auditory function is unknown. In the present study, we demonstrate that TRPV3 is expressed in inner hair cells (HCs) but mainly in cochlear outer HCs in mice, with expression limited to the cytoplasm and not detected in stereocilia. We compared the number of HCs as well as distortion product otoacoustic emissions (DPOAE) and auditory brainstem response (ABR) thresholds between TRPV3 knockout (V3KO) and wild-type (V3WT) mice and found that although most mutants (72.3%) had normal hearing, a significant proportion (27.7%) showed impaired hearing associated with loss of cochlear HCs. Compensatory upregulation of TRPV4 in HCs prevented HC damage and kanamycin-induced hearing loss and preserved normal auditory function in most of these mice. Thus, TRPV4 and TRPV3 in cochlear HCs protect hearing in mice; moreover, the results suggest some functional redundancy in the functions of TRPV family members. Our findings provide novel insight into the molecular basis of auditory function in mammals that can be applied to the development of strategies to mitigate hearing loss.

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