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Nature Reviews. Genetics Oct 2023Progress in deciphering the genetic architecture of human sensorineural hearing impairment (SNHI) or loss, and multidisciplinary studies of mouse models, have led to the... (Review)
Review
Progress in deciphering the genetic architecture of human sensorineural hearing impairment (SNHI) or loss, and multidisciplinary studies of mouse models, have led to the elucidation of the molecular mechanisms underlying auditory system function, primarily in the cochlea, the mammalian hearing organ. These studies have provided unparalleled insights into the pathophysiological processes involved in SNHI, paving the way for the development of inner-ear gene therapy based on gene replacement, gene augmentation or gene editing. The application of these approaches in preclinical studies over the past decade has highlighted key translational opportunities and challenges for achieving effective, safe and sustained inner-ear gene therapy to prevent or cure monogenic forms of SNHI and associated balance disorders.
Topics: Mice; Animals; Humans; Hearing Loss, Sensorineural; Hearing; Genetic Therapy; Gene Editing; Deafness; Mammals
PubMed: 37173518
DOI: 10.1038/s41576-023-00597-7 -
Signal Transduction and Targeted Therapy Apr 2022The cochlea consists of multiple types of cells, including hair cells, supporting cells and spiral ganglion neurons, and is responsible for converting mechanical forces...
The cochlea consists of multiple types of cells, including hair cells, supporting cells and spiral ganglion neurons, and is responsible for converting mechanical forces into electric signals that enable hearing. Genetic and environmental factors can result in dysfunctions of cochlear and auditory systems. In recent years, gene therapy has emerged as a promising treatment in animal deafness models. One major challenge of the gene therapy for deafness is to effectively deliver genes to specific cells of cochleae. Here, we screened and identified an AAV-ie mutant, AAV-ie-K558R, that transduces hair cells and supporting cells in the cochleae of neonatal mice with high efficiency. AAV-ie-K558R is a safe vector with no obvious deficits in the hearing system. We found that AAV-ie-K558R can partially restore the hearing loss in Prestin KO mice and, importantly, deliver Atoh1 into cochlear supporting cells to generate hair cell-like cells. Our results demonstrate the clinical potential of AAV-ie-K558R for treating the hearing loss caused by hair cell death.
Topics: Animals; Cochlea; Deafness; Genetic Therapy; Hair Cells, Auditory; Hearing Loss; Mice
PubMed: 35449181
DOI: 10.1038/s41392-022-00938-8 -
JAMA Jan 2023
Topics: Aged; Humans; Deafness; Dementia; Hearing Loss; Prevalence; United States
PubMed: 36625819
DOI: 10.1001/jama.2022.20954 -
Human Genetics Jun 2023Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6328 pathogenic missense...
Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation Database (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are "variants of uncertain significance" (VUS) due to insufficient evidence for classification. Here, we use the deep learning protein prediction algorithm, AlphaFold2, to curate structures for all DVD genes. We refine these structures with global optimization and the AMOEBA force field and use DDGun3D to predict folding free energy differences (∆∆G) for all DVD missense variants. We find that 5772 VUSs have a large, destabilizing ∆∆G that is consistent with pathogenic variants. When also filtered for CADD scores (> 25.7), we determine 3456 VUSs are likely pathogenic at a probability of 99.0%. Of the 224 genes in the DVD, 166 genes (74%) exhibit one or more missense variants predicted to cause a pathogenic change in protein folding stability. The VUSs prioritized here affect 119 patients (~ 3% of cases) sequenced by the OtoSCOPE targeted panel. Approximately half of these patients previously received an inconclusive report, and reclassification of these VUSs as pathogenic provides a new genetic diagnosis for six patients.
Topics: Humans; Proteome; Hearing Loss; Mutation, Missense; Deafness
PubMed: 37086329
DOI: 10.1007/s00439-023-02559-9 -
Proceedings of the National Academy of... Jun 2023Functional molecular characterization of the cochlea has mainly been driven by the deciphering of the genetic architecture of sensorineural deafness. As a result, the...
Functional molecular characterization of the cochlea has mainly been driven by the deciphering of the genetic architecture of sensorineural deafness. As a result, the search for curative treatments, which are sorely lacking in the hearing field, has become a potentially achievable objective, particularly cochlear gene and cell therapies. To this end, a complete inventory of cochlear cell types, with an in-depth characterization of their gene expression profiles right up to their final differentiation, is indispensable. We therefore generated a single-cell transcriptomic atlas of the mouse cochlea based on an analysis of more than 120,000 cells on postnatal day 8 (P8), during the prehearing period, P12, corresponding to hearing onset, and P20, when cochlear maturation is almost complete. By combining whole-cell and nuclear transcript analyses with extensive in situ RNA hybridization assays, we characterized the transcriptomic signatures covering nearly all cochlear cell types and developed cell type-specific markers. Three cell types were discovered; two of them contribute to the modiolus which houses the primary auditory neurons and blood vessels, and the third one consists in cells lining the scala vestibuli. The results also shed light on the molecular basis of the tonotopic gradient of the biophysical characteristics of the basilar membrane that critically underlies cochlear passive sound frequency analysis. Finally, overlooked expression of deafness genes in several cochlear cell types was also unveiled. This atlas paves the way for the deciphering of the gene regulatory networks controlling cochlear cell differentiation and maturation, essential for the development of effective targeted treatments.
Topics: Animals; Mice; Transcriptome; Cochlea; Basilar Membrane; Hearing; Deafness
PubMed: 37339214
DOI: 10.1073/pnas.2221744120 -
Deutsches Arzteblatt International Oct 2020Hearing impairment that is too severe to be adequately treated with conventional hearing aids can lead, in children, to severe developmental disturbances of hearing and... (Review)
Review
BACKGROUND
Hearing impairment that is too severe to be adequately treated with conventional hearing aids can lead, in children, to severe developmental disturbances of hearing and language, and, in adults, to communicative and social deprivation. Recent advances in medical device technology and in microsurgical techniques have led to an expansion of the indications for cochlear implantation (CI) for adults with progressive hearing loss in older age, and to a restructuring of the process of care for these patients in Germany.
METHODS
This review is based on pertinent publications retrieved by a selective search in PubMed, as well as on the CI guidelines and CI "white book" of the German Society of Otolaryngology and Head and Neck Surgery.
RESULTS
Early and accurate diagnosis is crucial for the successful auditory rehabilitation of high-grade hearing impairment. In children, a key role is played by newborn auditory screening, which is mandatory in Germany and enables the provision of a CI in the first year of life when necessary. 86% of the children receiving a CI achieve linguistic comprehension of fluently spoken sentences. For adults, positive prognostic factors for hearing after the provision of a CI include a highly motivated patient, "postlingual" onset of the hearing impairment (i.e., after the acquisition of language), and a brief duration of deafness. Auditory rehabilitation is associated with significant improvement, not just of hearing and of the comprehension of spoken language, but also of quality of life, particularly in elderly patients. For patients of any age with bilateral hearing loss, CIs should be provided on both sides, if possible. The more common complications of the procedure, with a probability of 2-4% each, are technical implant defects, dizziness, and wound-healing disturbances.
CONCLUSION
Cochlear implantation, performed in specialized centers, is a safe and reliable technique and regularly enables the successful rehabilitation of hearing in both children and adults.
Topics: Adult; Aged; Child; Cochlear Implantation; Cochlear Implants; Deafness; Germany; Humans; Infant, Newborn; Quality of Life
PubMed: 33357341
DOI: 10.3238/arztebl.2020.0690 -
Journal of the Association For Research... Feb 2023The cochlear implant (CI) is widely considered to be one of the most innovative and successful neuroprosthetic treatments developed to date. Although outcomes vary, CIs... (Review)
Review
The cochlear implant (CI) is widely considered to be one of the most innovative and successful neuroprosthetic treatments developed to date. Although outcomes vary, CIs are able to effectively improve hearing in nearly all recipients and can substantially improve speech understanding and quality of life for patients with significant hearing loss. A wealth of research has focused on underlying factors that contribute to success with a CI, and recent evidence suggests that the overall health of the cochlea could potentially play a larger role than previously recognized. This article defines and reviews attributes of cochlear health and describes procedures to evaluate cochlear health in humans and animal models in order to examine the effects of cochlear health on performance with a CI. Lastly, we describe how future biologic approaches can be used to preserve and/or enhance cochlear health in order to maximize performance for individual CI recipients.
Topics: Animals; Humans; Cochlear Implants; Quality of Life; Cochlear Implantation; Cochlea; Deafness
PubMed: 36600147
DOI: 10.1007/s10162-022-00882-y -
European Journal of Human Genetics :... Jan 2022
Topics: Deafness; Humans; Pedigree
PubMed: 34819629
DOI: 10.1038/s41431-021-01006-5 -
Ugeskrift For Laeger Dec 2023The introduction of cochlear implants (CI) for pediatric populations with deafness has changed life conditions for deaf children markedly. A new generation of children... (Review)
Review
The introduction of cochlear implants (CI) for pediatric populations with deafness has changed life conditions for deaf children markedly. A new generation of children with CI has emerged, and this review investigates how it has been documented that early intervention with CI and enrolment in family-centered auditory-verbal intervention allow children to close the language gap and develop age-equivalent language before entering school. At the school level, children keep up the language level. Most importantly children assess themselves to have levels of social well-being comparable to their peers with normal hearing.
Topics: Child; Humans; Cochlear Implantation; Deafness; Cochlear Implants
PubMed: 38078473
DOI: No ID Found -
HNO Aug 2021This article presents a case of sudden bilateral deafness in the context of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection and resultant...
This article presents a case of sudden bilateral deafness in the context of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection and resultant coronavirus disease 2019 (COVID-19). After treatment in the intensive care unit for acute respiratory distress syndrome and acute kidney failure, hearing ability had drastically changed. While hearing had been subjectively normal before the infection, deafness was now measured on the left and profound hearing loss on the right ear. The patient was treated with cochlea implants on the left and a hearing aid in the right ear. The hearing loss is most likely a complication of COVID-19.
Topics: COVID-19; Cochlear Implantation; Cochlear Implants; Deafness; Hearing Loss, Sudden; Humans; RNA, Viral; SARS-CoV-2; Speech Perception
PubMed: 34019138
DOI: 10.1007/s00106-021-01041-0