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Annual Review of Genomics and Human... Aug 2022Current estimates suggest that nearly half a billion people worldwide are affected by hearing loss. Because of the major psychological, social, economic, and health... (Review)
Review
Current estimates suggest that nearly half a billion people worldwide are affected by hearing loss. Because of the major psychological, social, economic, and health ramifications, considerable efforts have been invested in identifying the genes and molecular pathways involved in hearing loss, whether genetic or environmental, to promote prevention, improve rehabilitation, and develop therapeutics. Genomic sequencing technologies have led to the discovery of genes associated with hearing loss. Studies of the transcriptome and epigenome of the inner ear have characterized key regulators and pathways involved in the development of the inner ear and have paved the way for their use in regenerative medicine. In parallel, the immense preclinical success of using viral vectors for gene delivery in animal models of hearing loss has motivated the industry to work on translating such approaches into the clinic. Here, we review the recent advances in the genomics of auditory function and dysfunction, from patient diagnostics to epigenetics and gene therapy.
Topics: Animals; Deafness; Ear, Inner; Genetic Therapy; Genomics; Hearing Loss; Humans
PubMed: 35667089
DOI: 10.1146/annurev-genom-121321-094136 -
Advanced Science (Weinheim,... Mar 2024Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is...
Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is extensively validated in Otof-deficient mice. However, the clinical safety and efficacy of AAV-OTOF is not reported. Here, AAV-OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non-human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV-OTOF is delivered into one cochlea of a 5-year-old deaf patient and into the bilateral cochleae of an 8-year-old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure-tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5-year-old patient can be restored to the normal range at 1 month after AAV-OTOF injection, while the 8-year-old patient can hear the conversational sounds. Most importantly, the 5-year-old patient can hear and recognize speech only through the AAV-OTOF-injected ear. This study is the first to demonstrate the safety and efficacy of AAV-OTOF in patients, expands and optimizes current OTOF-related gene therapy and provides valuable information for further application of gene therapies for deafness.
Topics: Humans; Animals; Mice; Dependovirus; Hearing Loss, Sensorineural; Hearing; Deafness; Genetic Therapy
PubMed: 38189623
DOI: 10.1002/advs.202306788 -
Human Genetics Apr 2022Sensorineural hearing loss (SNHL) is a major cause of functional disability in both the developed and developing world. While hearing aids and cochlear implants provide... (Review)
Review
Sensorineural hearing loss (SNHL) is a major cause of functional disability in both the developed and developing world. While hearing aids and cochlear implants provide significant benefit to many with SNHL, neither targets the cellular and molecular dysfunction that ultimately underlies SNHL. The successful development of more targeted approaches, such as growth factor, stem cell, and gene therapies, will require a yet deeper understanding of the underlying molecular mechanisms of human hearing and deafness. Unfortunately, the human inner ear cannot be biopsied without causing significant, irreversible damage to the hearing or balance organ. Thus, much of our current understanding of the cellular and molecular biology of human deafness, and of the human auditory system more broadly, has been inferred from observational and experimental studies in animal models, each of which has its own advantages and limitations. In 2013, researchers described a protocol for the generation of inner ear organoids from pluripotent stem cells (PSCs), which could serve as scalable, high-fidelity alternatives to animal models. Here, we discuss the advantages and limitations of conventional models of the human auditory system, describe the generation and characteristics of PSC-derived inner ear organoids, and discuss several strategies and recent attempts to model hereditary deafness in vitro. Finally, we suggest and discuss several focus areas for the further, intensive characterization of inner ear organoids and discuss the translational applications of these novel models of the human inner ear.
Topics: Deafness; Ear, Inner; Hearing Loss, Sensorineural; Hearing Tests; Humans; Organoids
PubMed: 34342719
DOI: 10.1007/s00439-021-02325-9 -
Advanced Science (Weinheim,... Jun 2023The ankle-link complex (ALC) consists of USH2A, WHRN, PDZD7, and ADGRV1 and plays an important role in hair cell development. At present, its architectural organization...
The ankle-link complex (ALC) consists of USH2A, WHRN, PDZD7, and ADGRV1 and plays an important role in hair cell development. At present, its architectural organization and signaling role remain unclear. By establishing Adgrv1 Y6236fsX1 mutant mice as a model of the deafness-associated human Y6244fsX1 mutation, the authors show here that the Y6236fsX1 mutation disrupts the interaction between adhesion G protein-coupled receptor V subfamily member 1 (ADGRV1) and other ALC components, resulting in stereocilia disorganization and mechanoelectrical transduction (MET) deficits. Importantly, ADGRV1 inhibits WHRN phosphorylation through regional cAMP-PKA signaling, which in turn regulates the ubiquitination and stability of USH2A via local signaling compartmentalization, whereas ADGRV1 Y6236fsX1 does not. Yeast two-hybrid screening identified the E3 ligase WDSUB1 that binds to WHRN and regulates the ubiquitination of USH2A in a WHRN phosphorylation-dependent manner. Further FlAsH-BRET assay, NMR spectrometry, and mutagenesis analysis provided insights into the architectural organization of ALC and interaction motifs at single-residue resolution. In conclusion, the present data suggest that ALC organization and accompanying local signal transduction play important roles in regulating the stability of the ALC.
Topics: Animals; Humans; Mice; Carrier Proteins; Deafness; Extracellular Matrix Proteins; Mutation; Phosphorylation
PubMed: 37066759
DOI: 10.1002/advs.202205993 -
Cerebellum (London, England) Dec 2019Cerebellar ataxias are a clinically heterogeneous group of neurological disorders. Besides the cerebellum, several forms of hereditary ataxias or non-genetic ataxias... (Review)
Review
Cerebellar ataxias are a clinically heterogeneous group of neurological disorders. Besides the cerebellum, several forms of hereditary ataxias or non-genetic ataxias also affect other areas of the brain. Some forms of cerebellar ataxias may have cochlear and vestibular involvement and may present with deafness and symptoms or signs of vestibulopathy (dizziness, nystagmus and diplopia). Recognizing otoneurological symptoms in patients with cerebellar ataxias is mandatory, since these signs may guide a specific diagnosis, and clinicians may provide a suitable therapeutic approach. In this review, we describe and discuss the most common forms of cerebellar ataxias associated with deafness and vestibulopathy.
Topics: Animals; Cerebellar Ataxia; Cerebellar Diseases; Cerebellum; Deafness; Humans; Vestibule, Labyrinth
PubMed: 31154624
DOI: 10.1007/s12311-019-01042-4 -
Trends in Hearing 2021In children with congenital deafness, cochlear implantation (CI) prior to 12 months of age offers the opportunity to foster more typical auditory development during late... (Review)
Review
In children with congenital deafness, cochlear implantation (CI) prior to 12 months of age offers the opportunity to foster more typical auditory development during late infancy and early childhood. Recent studies have found a positive association between early implantation and expressive and receptive language outcomes, with some children able to achieve normal language skills by the time of school entry. Universal newborn hearing screening improved early detection and diagnosis of congenital hearing loss, allowing for earlier intervention, including decision-making regarding cochlear implant (CI) candidacy. It can be more challenging to confirm CI candidacy in infants; therefore, a multidisciplinary approach, including objective audiometric testing, is recommended to not only confirm the diagnosis but also to counsel families regarding expectations and long-term management. Surgeons performing CI surgery in young children should consider both the anesthetic risks of surgery in infancy and the ways in which mastoid anatomy may differ between infants and older children or adults. Multiple studies have found CI surgery in infants can be performed safely and effectively. This article reviews current evidence regarding indications for implantation in children younger than 12 months of age and discusses perioperative considerations and surgical technique.
Topics: Adolescent; Adult; Child; Child, Preschool; Cochlear Implantation; Cochlear Implants; Deafness; Hearing Loss, Sensorineural; Humans; Infant; Infant, Newborn
PubMed: 34281434
DOI: 10.1177/23312165211031751 -
The Lancet. Global Health Apr 2024
Topics: Humans; Nontuberculous Mycobacteria; Aminoglycosides; Anti-Bacterial Agents; Deafness
PubMed: 38485424
DOI: 10.1016/S2214-109X(24)00082-2 -
JAMA Otolaryngology-- Head & Neck... Oct 2020
Review
Topics: Cochlear Implants; Deafness; Health Care Costs; Humans; Speech Perception
PubMed: 32852524
DOI: 10.1001/jamaoto.2020.2285 -
Neuroscience Letters Sep 2019Hearing impairment affects 1 in 500 newborns worldwide and nearly one out of three people over the age of 65 (WHO, 2019). Hereditary hearing loss is the most common type... (Review)
Review
Hearing impairment affects 1 in 500 newborns worldwide and nearly one out of three people over the age of 65 (WHO, 2019). Hereditary hearing loss is the most common type of congenital deafness; genetic factors also affect deafness susceptibility. Gene therapies may preserve or restore natural sound perception, and have rescued deafness in multiple hereditary murine models. CRISPR-Cas9 and base editors (BEs) are newly developed gene editing technologies that can facilitate gene studies in the inner ear and provide therapeutic approaches for hearing impairment. Here, we present recent applications of gene editing in the inner ear.
Topics: Animals; CRISPR-Cas Systems; Deafness; Gene Editing; Genetic Therapy; Hearing Loss; Humans
PubMed: 31195050
DOI: 10.1016/j.neulet.2019.134326 -
Yi Chuan = Hereditas Jan 2023Hereditary deafness is one of the most common sensory disorders in humans, and exhibits high genetic heterogeneity. At present, the commonly used molecular diagnostic... (Review)
Review
Hereditary deafness is one of the most common sensory disorders in humans, and exhibits high genetic heterogeneity. At present, the commonly used molecular diagnostic methods include gene chip, Sanger sequencing, targeted enrichment sequencing, and whole-exome sequencing, with diagnosis rates reaching 33.5%-56.67%. However, there are still a considerable number of patients who can not get a timely and definitive molecular diagnosis. Furthermore, considering the economic burden on patients' families and the relatively high cost of whole-exome or whole-genome sequencing, it is vital to provide stepwise strategies combining multiple detection methods according to the phenotypes of patients. In this review, we evaluate and discuss the utility of molecular diagnosis and the application of stepwise testing strategies in hereditary deafness to provide reference for the selection of diagnostic strategies.
Topics: Humans; Deafness; Whole Genome Sequencing; Exome; Phenotype; High-Throughput Nucleotide Sequencing; Pedigree; Genetic Testing; Mutation
PubMed: 36927636
DOI: 10.16288/j.yczz.22-206