Hearing Loss Treatment Report

www.HearingLossTreatmentReport.com

Preprints

In Silico Transcriptome-based Screens Identify Epidermal Growth Factor Receptor Inhibitors as Therapeutics for Noise-induced Hearing Loss [Preprint]

CATEGORY:
Research

SCREENSHOT:
In Silico Transcriptome-based Screens Identify Epidermal Growth Factor Receptor Inhibitors as Therapeutics for Noise-induced Hearing Loss

TITLE:
In Silico Transcriptome-based Screens Identify Epidermal Growth Factor Receptor Inhibitors as Therapeutics for Noise-induced Hearing Loss

CONTENT:
bioRxiv. 2023 Jun 9:2023.06.07.544128. doi: 10.1101/2023.06.07.544128. Preprint.

ABSTRACT

Noise-Induced Hearing Loss (NIHL) represents a widespread disease for which no therapeutics have been approved by the Food and Drug Administration (FDA). Addressing the conspicuous void of efficacious in vitro or animal models for high throughput pharmacological screening, we utilized an in silico transcriptome-oriented drug screening strategy, unveiling 22 biological pathways and 64 promising small molecule candidates for NIHL protection. Afatinib and zorifertinib, both inhibitors of the Epidermal Growth Factor Receptor (EGFR), were validated for their protective efficacy against NIHL in experimental zebrafish and murine models. This protective effect was further confirmed with EGFR conditional knockout mice and EGF knockdown zebrafish, both demonstrating protection against NIHL. Molecular analysis using Western blot and kinome signaling arrays on adult mouse cochlear lysates unveiled the intricate involvement of several signaling pathways, with particular emphasis on EGFR and its downstream pathways being modulated by noise exposure and Zorifertinib treatment. Administered orally, Zorifertinib was successfully detected in the perilymph fluid of the inner ear in mice with favorable pharmacokinetic attributes. Zorifertinib, in conjunction with AZD5438 – a potent inhibitor of cyclin dependent kinase 2 – produced synergistic protection against NIHL in the zebrafish model. Collectively, our findings underscore the potential application of in silico transcriptome-based drug screening for diseases bereft of efficient screening models and posit EGFR inhibitors as promising therapeutic agents warranting clinical exploration for combatting NIHL.

HIGHLIGHTS: In silico transcriptome-based drug screens identify pathways and drugs against NIHL.EGFR signaling is activated by noise but reduced by zorifertinib in mouse cochleae.Afatinib, zorifertinib and EGFR knockout protect against NIHL in mice and zebrafish.Orally delivered zorifertinib has inner ear PK and synergizes with a CDK2 inhibitor.

PMID:37333346 | PMC:PMC10274759 | DOI:10.1101/2023.06.07.544128

SOURCE:
bioRxiv : the preprint server for biology

PUBLISHER:

PMID:
pubmed:37333346

ID:
0b58ea4968e09ff10f4e1238c494f316pubmed:37333346

DOI:
10.1101/2023.06.07.544128

DATE – PUBLISHED:
Mon, 19 Jun 2023 06:00:00 -0400

DATE – DOI:
2023-06-10T02:15:13Z

DATE – ADDED:
06/19/23 06:38AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/37333346/

LINK – DOI:
https://doi.org/10.1101/2023.06.07.544128

LINK – PUBLISHER:
http://biorxiv.org/lookup/doi/10.1101/2023.06.07.544128?utm_source=hearinglosstreatmentreport.com

IMAGE:

REFERENCE:
Hearing Loss Treatment Report, Urgent Research, 2023-06-19T10:38:27+00:00, https://www.hearinglosstreatmentreport.com.

Towards personalized auditory models: predicting individual sensorineural-hearing-loss profiles from recorded human auditory physiology [Preprint]

https://www.biorxiv.org/content/10.1101/2020.11.17.387001v1

https://www.biorxiv.org/content/10.1101/2020.11.17.387001v1?utm_source=hearinglosstreatmentreport.com

Towards personalized auditory models: predicting individual sensorineural-hearing-loss profiles from recorded human auditory physiology

Sarineh Keshishzadeh, Markus Garrett, Sarah Verhulst

doi: https://doi.org/10.1101/2020.11.17.387001

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.