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Hearing Loss: Molecular Biological Insights

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 July 2025 | Viewed by 7425

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Special Issue Editor

Dr. María Beatriz Durán-Alonso

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Guest Editor

Department of Biochemistry and Molecular Biology and Physioloy, Faculty of Medicine, Avda. Ramón y Cajal, 7, 47005 Valladolid, Spain
Interests: cochlea; inner ear; molecular mechanisms; neurodegeneration; regeneration; neuroprotection; aging; senescence

Special Issue Information

Dear Colleagues,

Disabling hearing loss is the most common sensory disorder, affecting over 5% of the world’s population and presenting alarmingly rising incidence rates. Obstacles to the development of therapeutics to treat these patients arise from the location of the cochlear tissue and the complexity that underlies the auditory function, which is regulated by a large number of genes and molecular pathways and is under the influence of environmental factors. These all act in concert to modify the severity and onset of disease; hearing problems may become apparent long after the harmful events have taken place, which further hinders the identification of the causing agents and prevents any efficacious treatment. Recent advancements in high-throughput screening approaches and single-cell transcriptomics, the development of novel tools to achieve the delivery of molecules into the inner ear, and the generation of new animal and human models of disease will all contribute to the identification of the molecular mechanisms leading to auditory disability and the elucidation of molecular targets for therapeutic strategies.

I am delighted to invite you to contribute to this Special Issue launched by the International Journal of Molecular Sciences on “Hearing Loss: Molecular Biological Insights”. The aim of this Special Issue is to provide a meeting point where scientists in the field of hearing may bring together their most recent discoveries on the molecular mechanisms leading to hearing disability as well as report on the latest advancements in molecular biology-based diagnostics and therapeutics for hearing loss. This Special Issue should help us gain an overview of the work that is currently being conducted to decipher the molecular basis of hearing and the impressive achievements that are already being reached, as well as spark the debate on the most promising leads for the development of novel therapies against this devastating disorder.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

Genetic and molecular bases of hearing loss;
Epigenetics of hearing loss;
Molecular biological techniques to study the structure and function of the auditory organ;
Multi-omic approaches for the elucidation of the molecular mechanisms underlying hearing loss;
Molecular biology of inner ear development;
Animal models and human organoid-based models to study the molecular biology of inner ear development and function;
Molecular mechanisms involved in age-related or drug-induced hearing loss;
Application of CRISPR/Cas and other molecular biology techniques to analyze the effect of altering molecular processes on inner ear development and function;
Diagnostic markers of hearing dysfunction;
Molecular pathways associated with otoprotection or inner ear cell regeneration;
Intracochlear delivery of molecular agents as a possible therapy against hearing loss.

I am looking forward to receiving your valuable contributions.

Dr. María Beatriz Durán-Alonso
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

genetics
microRNA
epigenetics
CRISPR
multi-omics
presbycusis
ototoxicity
development

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Published Papers (5 papers)

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Research

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17 pages, 4363 KiB

Open AccessArticle

Molecular Characterization of Subdomain Specification of Cochlear Duct Based on Foxg1 and Gata3

by Yongjin Gil, Jiho Ryu, Hayoung Yang, Yechan Ma, Ki-Hoan Nam, Sung-Wuk Jang and Sungbo Shim

Int. J. Mol. Sci. 2024, 25(23), 12700; https://doi.org/10.3390/ijms252312700 - 26 Nov 2024

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Abstract

The inner ear is one of the sensory organs of vertebrates and is largely composed of the vestibule, which controls balance, and the cochlea, which is responsible for hearing. In particular, a problem in cochlear development can lead to hearing loss. Although numerous studies have been conducted on genes involved in the development of the cochlea, many areas still need to be discovered regarding factors that control the patterning of the early cochlear duct. Herein, based on the dynamic expression pattern of FOXG1 in the apical and basal regions of the E13.5 cochlear duct, we identified detailed expression regions through an open-source analysis of single-cell RNA analysis data and demonstrated a clinical correlation with hearing loss. The distinct expression patterns of FOXG1 and GATA3 during the patterning process of the cochlear duct provide important clues to understanding how the fates of the apical and basal regions are divided. These results are expected to be extremely important not only for understanding the molecular mechanisms involved in the early development of the cochlear duct, but also for identifying potential genes that cause hearing loss. Full article

(This article belongs to the Special Issue Hearing Loss: Molecular Biological Insights)

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13 pages, 2128 KiB

Open AccessArticle

Neutrophil Extracellular Traps Affect Human Inner Ear Vascular Permeability

by Marijana Sekulic, Stavros Giaglis, Nina Chatelain, Daniel Bodmer and Vesna Petkovic

Int. J. Mol. Sci. 2024, 25(18), 9766; https://doi.org/10.3390/ijms25189766 - 10 Sep 2024

Cited by 1 | Viewed by 1525

Abstract

The integrity of the blood–labyrinth barrier (BLB) is essential for inner ear homeostasis, regulating the ionic composition of endolymph and perilymph and preventing harmful substance entry. Endothelial hyperpermeability, central in inflammatory and immune responses, is managed through complex intercellular communication and molecular signaling pathways. Recent studies link BLB permeability dysregulation to auditory pathologies like acoustic trauma, autoimmune inner ear diseases, and presbycusis. Polymorphonuclear granulocytes (PMNs), or neutrophils, significantly modulate vascular permeability, impacting endothelial barrier properties. Neutrophil extracellular traps (NETs) are involved in diseases with autoimmune and autoinflammatory bases. The present study evaluated the impact of NETs on a BLB cellular model using a Transwell^® setup. Our findings revealed a concentration-dependent impact of NETs on human inner ear-derived endothelial cells. In particular, endothelial permeability markers increased, as indicated by reduced transepithelial electrical resistance, enhanced dextran permeability, and downregulated junctional gene expression (ZO1, OCL, and CDH5). Changes in cytoskeletal architecture were also observed. These preliminary results pave the way for further research into the potential involvement of NETs in BLB impairment and implications for auditory disorders. Full article

(This article belongs to the Special Issue Hearing Loss: Molecular Biological Insights)

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21 pages, 8172 KiB

Open AccessArticle

Differentiation of Spiral Ganglion Neurons from Human Dental Pulp Stem Cells: A Further Step towards Autologous Auditory Nerve Recovery

by Yassine Messat, Marta Martin-Fernandez, Said Assou, Keshi Chung, Frederic Guérin, Csilla Gergely, Frederic Cuisinier and Azel Zine

Int. J. Mol. Sci. 2024, 25(16), 9115; https://doi.org/10.3390/ijms25169115 - 22 Aug 2024

Cited by 1 | Viewed by 1620

Abstract

The degeneration of spiral ganglion neurons (SGNs), which convey auditory signals from hair cells to the brain, can be a primary cause of sensorineural hearing loss (SNHL) or can occur secondary to hair cell loss. Emerging therapies for SNHL include the replacement of damaged SGNs using stem cell-derived otic neuronal progenitors (ONPs). However, the availability of renewable, accessible, and patient-matched sources of human stem cells is a prerequisite for successful replacement of the auditory nerve. In this study, we derived ONP and SGN-like cells by a reliable and reproducible stepwise guidance differentiation procedure of self-renewing human dental pulp stem cells (hDPSCs). This in vitro differentiation protocol relies on the modulation of BMP and TGFβ pathways using a free-floating 3D neurosphere method, followed by differentiation on a Geltrex-coated surface using two culture paradigms to modulate the major factors and pathways involved in early otic neurogenesis. Gene and protein expression analyses revealed efficient induction of a comprehensive panel of known ONP and SGN-like cell markers during the time course of hDPSCs differentiation. Atomic force microscopy revealed that hDPSC-derived SGN-like cells exhibit similar nanomechanical properties as their in vivo SGN counterparts. Furthermore, spiral ganglion neurons from newborn rats come in close contact with hDPSC-derived ONPs 5 days after co-culturing. Our data demonstrate the capability of hDPSCs to generate SGN-like neurons with specific lineage marker expression, bipolar morphology, and the nanomechanical characteristics of SGNs, suggesting that the neurons could be used for next-generation cochlear implants and/or inner ear cell-based strategies for SNHL. Full article

(This article belongs to the Special Issue Hearing Loss: Molecular Biological Insights)

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22 pages, 3720 KiB

Open AccessArticle

ERK1/2 Inhibition via the Oral Administration of Tizaterkib Alleviates Noise-Induced Hearing Loss While Tempering down the Immune Response

by Richard D. Lutze, Matthew A. Ingersoll, Alena Thotam, Anjali Joseph, Joshua Fernandes and Tal Teitz

Int. J. Mol. Sci. 2024, 25(12), 6305; https://doi.org/10.3390/ijms25126305 - 7 Jun 2024

Cited by 4 | Viewed by 1786

Abstract

Noise-induced hearing loss (NIHL) is a major cause of hearing impairment and is linked to dementia and mental health conditions, yet no FDA-approved drugs exist to prevent it. Downregulating the mitogen-activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL, but the molecular targets and the mechanism of protection are not fully understood. Here, we tested specifically the role of the kinases ERK1/2 in noise otoprotection using a newly developed, highly specific ERK1/2 inhibitor, tizaterkib, in preclinical animal models. Tizaterkib is currently being tested in phase 1 clinical trials for cancer treatment and has high oral bioavailability and low predicted systemic toxicity in mice and humans. In this study, we performed dose–response measurements of tizaterkib’s efficacy against permanent NIHL in adult FVB/NJ mice, and its minimum effective dose (0.5 mg/kg/bw), therapeutic index (>50), and window of opportunity (<48 h) were determined. The drug, administered orally twice daily for 3 days, 24 h after 2 h of 100 dB or 106 dB SPL noise exposure, at a dose equivalent to what is prescribed currently for humans in clinical trials, conferred an average protection of 20–25 dB SPL in both female and male mice. The drug shielded mice from the noise-induced synaptic damage which occurs following loud noise exposure. Equally interesting, tizaterkib was shown to decrease the number of CD45- and CD68-positive immune cells in the mouse cochlea following noise exposure. This study suggests that repurposing tizaterkib and the ERK1/2 kinases’ inhibition could be a promising strategy for the treatment of NIHL. Full article

(This article belongs to the Special Issue Hearing Loss: Molecular Biological Insights)

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Review

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28 pages, 1346 KiB

Open AccessReview

Gene Therapy: An Historical Overview for Familial Hearing Loss

by O’neil W. Guthrie

Int. J. Mol. Sci. 2025, 26(4), 1469; https://doi.org/10.3390/ijms26041469 - 10 Feb 2025

Viewed by 881

Abstract

Gene therapy is a promising molecular approach for the management of familial hearing loss. This type of molecular therapy is the physical manifestation of genetic determinism—the notion that individual genes cause individual phenotypes. The current composition weaves through various branches of the biomedical sciences to uncover the molecular biologic premise for genetic determinism and the impetus behind gene therapy. Consequently, it is revealed that the underlying molecular biologic premise was scaffolded on successful observations from simple biologic assays that were devoid of the complexities of human disease biology. Furthermore, modern successful gene therapies are largely driven by commercial and academic incentives at the cost of scientific rigor. This poses several perverse challenges for patients, clinicians and the public at large. Issues concerning safety, efficacy, and ethics are far from resolved despite regulatory agency approvals, the media’s bias for gene therapy and the many lucrative investor positions. Lastly, the therapeutic claims regarding gene therapy are the most ambitious claims made within the hearing sciences. Therefore, scientists, clinicians, and patients must be equipped with the tools needed to appropriately consume and appraise such claims. These and other issues are also directly addressed, with the aim of providing a realistic sense of whether current human gene therapies are ready to be positioned within our routine clinical armamentarium against hearing loss. Full article

(This article belongs to the Special Issue Hearing Loss: Molecular Biological Insights)

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