Emerging Approaches for Restoration of Hearing and Vision.

Impairments of vision and hearing are highly prevalent conditions limiting the quality of life and presenting a major socioeconomic burden. For a long time, retinal and cochlear disorders have remained intractable for causal therapies, with sensory rehabilitation limited to glasses, hearing aids, and electrical cochlear or retinal implants. Recently, the application of gene therapy and optogenetics to eye and ear has generated hope for a fundamental improvement of vision and hearing restoration. To date, one gene therapy for the restoration of vision has been approved, and ongoing clinical trials will broaden its application including gene replacement, genome editing, and regenerative approaches. Moreover, optogenetics, i.e., controlling the activity of cells by light, offers a more general alternative strategy. Over little more than a decade, optogenetic approaches have been developed and applied to better understand the function of biological systems, while protein engineers have identified and designed new opsin variants with desired physiological features. Considering potential clinical applications of optogenetics, the spotlight is on the sensory systems, particularly the eye and ear. Multiple efforts have been undertaken to restore lost or hampered function in the eye and ear. Optogenetic stimulation promises to overcome fundamental shortcomings of electrical stimulation, namely, poor spatial resolution and cellular specificity, and accordingly to deliver more detailed sensory information. This review aims to provide a comprehensive reference on current gene therapeutic and optogenetic research relevant to the restoration of hearing and vision. We will introduce gene-therapeutic approaches and discuss the biotechnological and optoelectronic aspects of optogenetic hearing and vision restoration.

Reversal of an existing hearing loss by gene activation in Spns2 mutant mice.

Hearing loss is highly heterogeneous, but one common form involves a failure to maintain the local ionic environment of the sensory hair cells reflected in a reduced endocochlear potential. We used a genetic approach to ask whether this type of pathology can be reversed, using the Spns2tm1a mouse mutant known to show this defect. By activating Spns2 gene transcription at different ages after the onset of hearing loss, we found that an existing auditory impairment can be reversed to give close to normal thresholds for an auditory brainstem response (ABR), at least at low to mid stimulus frequencies. Delaying the activation of Spns2 led to less effective recovery of ABR thresholds, suggesting that there is a critical period for intervention. Early activation of Spns2 not only led to improvement in auditory function but also to protection of sensory hair cells from secondary degeneration. The genetic approach we have used to establish that this type of hearing loss is in principle reversible could be extended to many other diseases using available mouse resources.

The Genomics of Auditory Function and Disease.

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.

Clarin-2 gene supplementation durably preserves hearing in a model of progressive hearing loss.

Hearing loss is a major health concern affecting millions of people worldwide with currently limited treatment options. In clarin-2-deficient Clrn2-/- mice, used here as a model of progressive hearing loss, we report synaptic auditory abnormalities in addition to the previously demonstrated defects of hair bundle structure and mechanoelectrical transduction. We sought an in-depth evaluation of viral-mediated gene delivery as a therapy for these hearing-impaired mice. Supplementation with either the murine Clrn2 or human CLRN2 genes preserved normal hearing in treated Clrn2-/- mice. Conversely, mutated forms of CLRN2, identified in patients with post-lingual moderate to severe hearing loss, failed to prevent hearing loss. The ectopic expression of clarin-2 successfully prevented the loss of stereocilia, maintained normal mechanoelectrical transduction, preserved inner hair cell synaptic function, and ensured near-normal hearing thresholds over time. Maximal hearing preservation was observed when Clrn2 was delivered prior to the loss of transducing stereocilia. Our findings demonstrate that gene therapy is effective for the treatment of post-lingual hearing impairment and age-related deafness associated with CLRN2 patient mutations.

Critical role of TPRN rings in the stereocilia for hearing.

Inner ear hair cells detect sound vibration through the deflection of mechanosensory stereocilia. Cytoplasmic protein TPRN has been shown to localize at the taper region of the stereocilia, and mutations in TPRN cause hereditary hearing loss through an unknown mechanism. Here, using biochemistry and dual stimulated emission depletion microscopy imaging, we show that the TPRN, together with its binding proteins CLIC5 and PTPRQ, forms concentric rings in the taper region of stereocilia. The disruption of TPRN rings, triggered by the competitive inhibition of the interaction of TPRN and CLIC5 or exogenous TPRN overexpression, leads to stereocilia degeneration and severe hearing loss. Most importantly, restoration of the TPRN rings can rescue the damaged auditory function of Tprn knockout mice by exogenously expressing TPRN at an appropriate level in HCs via promoter recombinant adeno-associated virus (AAV). In summary, our results reveal highly structured TPRN rings near the taper region of stereocilia that are crucial for stereocilia function and hearing. Also, TPRN ring restoration in stereocilia by AAV-Tprn effectively repairs damaged hearing, which lays the foundation for the clinical application of AAV-mediated gene therapy in patients with TPRN mutation.

Advances in gene therapy hold promise for treating hereditary hearing loss.

Gene therapy focuses on genetic modification to produce therapeutic effects or treat diseases by repairing or reconstructing genetic material, thus being expected to be the most promising therapeutic strategy for genetic disorders. Due to the growing attention to hearing impairment, an increasing amount of research is attempting to utilize gene therapy for hereditary hearing loss (HHL), an important monogenic disease and the most common type of congenital deafness. Several gene therapy clinical trials for HHL have recently been approved, and, additionally, CRISPR-Cas tools have been attempted for HHL treatment. Therefore, in order to further advance the development of inner ear gene therapy and promote its broad application in other forms of genetic disease, it is imperative to review the progress of gene therapy for HHL. Herein, we address three main gene therapy strategies (gene replacement, gene suppression, and gene editing), summarizing the strategy that is most appropriate for particular monogenic diseases based on different pathogenic mechanisms, and then focusing on their successful applications for HHL in preclinical trials. Finally, we elaborate on the challenges and outlooks of gene therapy for HHL.

RNA base editing therapy cures hearing loss induced by OTOF gene mutation.

Otoferlin (OTOF) gene mutations represent the primary cause of hearing impairment and deafness in auditory neuropathy. The c.2485C>T (p. Q829X) mutation variant is responsible for approximately 3% of recessive prelingual deafness cases within the Spanish population. Previous studies have used two recombinant AAV vectors to overexpress OTOF, albeit with limited efficacy. In this study, we introduce an enhanced mini-dCas13X RNA base editor (emxABE) delivered via an AAV9 variant, achieving nearly 100% transfection efficiency in inner hair cells. This approach is aimed at treating OTOFQ829X, resulting in an approximately 80% adenosine-to-inosine conversion efficiency in humanized OtofQ829X/Q829X mice. Following a single scala media injection of emxABE targeting OTOFQ829X (emxABE-T) administered during the postnatal day 0-3 period in OtofQ829X/Q829X mice, we observed OTOF expression restoration in nearly 100% of inner hair cells. Moreover, auditory function was significantly improved, reaching similar levels as in wild-type mice. This enhancement persisted for at least 7 months. We also investigated P5-P7 and P30 OtofQ829X/Q829X mice, achieving auditory function restoration through round window injection of emxABE-T. These findings not only highlight an effective therapeutic strategy for potentially addressing OTOFQ829X-induced hearing loss but also underscore emxABE as a versatile toolkit for treating other monogenic diseases characterized by premature termination codons.

Improving quality of life in the elderly: hearing loss treatment with cochlear implants.

BACKGROUND: Hearing loss impacts health-related quality of life and general well-being and was identified in a Lancet report as one of the largest potentially modifiable factors for the prevention of age-related dementia. There is a lack of robust data on how cochlear implant treatment in the elderly impacts quality of life. The primary objective was to measure the change in health utility following cochlear implantation in individuals aged ≥ 60 years. METHODS: This study uniquely prospectively recruited a large multinational sample of 100 older adults (mean age 71.7 (SD7.6) range 60-91 years) with severe to profound hearing loss. In a repeated-measures design, pre and post implant outcome measures were analysed using mixed-effect models. Health utility was assessed with the Health Utilities Index Mark III (HUI3). Subjects were divided into groups of 60-64, 65-74 and 75 + years. RESULTS: At 18 months post implant, the mean HUI3 score improved by 0.13 (95%CI: 0.07-0.18 p < 0.001). There was no statistically significant difference in the HUI3 between age groups (F[2,9228] = 0.53, p = 0.59). The De Jong Loneliness scale reduced by an average of 0.61 (95%CI: 0.25-0.97 p < 0.014) and the Lawton Instrumental Activities of Daily Living Scale improved on average (1.25, 95%CI: 0.85-1.65 p < 0.001). Hearing Handicap Inventory for the Elderly Screening reduced by an average of 8.7 (95%CI: 6.7-10.8, p < 0.001) from a significant to mild-moderate hearing handicap. Age was not a statistically significant factor for any of the other measures (p > 0.20). At baseline 90% of participants had no or mild depression and there was no change in mean depression scores after implant. Categories of Auditory perception scale showed that all subjects achieved a level of speech sound discrimination without lip reading post implantation (level 4) and at least 50% could use the telephone with a known speaker. CONCLUSIONS: Better hearing improved individuals' quality of life, ability to communicate verbally and their ability to function independently. They felt less lonely and less handicapped by their hearing loss. Benefits were independent of age group. Cochlear implants should be considered as a routine treatment option for those over 60 years with bilateral severe to profound hearing loss. TRIAL REGISTRATION: ClinicalTrials.gov ( http://www. CLINICALTRIALS: gov/ ), 7 March 2017, NCT03072862.

'The burden is very much on yourself': A qualitative study to understand the illness and treatment burden of hearing loss across the life course.

INTRODUCTION: Hearing loss is a chronic health condition that rises sharply with age. The way people respond to and cope with health conditions is influenced by their capacity to perform illness and treatment-related work. The aim was to explore the cumulative burdens of living with hearing loss and the resources mobilised to ease the burdens. METHODS: A qualitative design was used with semi-structured interviews (online or in-person) with participants recruited through audiology services and nonclinical services, such as lip-reading classes. Forty-six participants with hearing loss aged between 16 and 96 years were interviewed. An abductive approach, informed by May et al.'s burden of treatment theory, was used to analyse the data. RESULTS: The illness burden involved participants working to make sense of their hearing loss, engaging in emotional work in response to changes in sound, social interactions and identity and coping with the daily frustrations required to communicate with others. Abandonment and uncertainty characterised the treatment burden; participants engaged in emotional work to adjust to hearing technology and deal with the uncertainty of how their hearing might progress. To ameliorate the burdens, participants drew on internal resources (psychological, health literacy, cognitive) and external resources (social support, financial, information, technology). CONCLUSIONS: The workload of hearing loss appears largely devolved to the patient and is not always visible. Our work indicates the need to widen approaches in audiological care through the implementation of lifeworld-led care, family-centred care and peer support to build support for those with hearing loss. PATIENT OR PUBLIC CONTRIBUTION: We developed the project in consultation with members of the public who have lived experience of hearing loss recruited through Aston University and volunteer links to audiology services. We also consulted people more likely to be affected by hearing loss adults including adults with learning disabilities, older adults in residential care and people from South Asia (Bangladeshi, Indian and Pakistani communities). These individuals commented on the study aims, interview schedule and participant recruitment practices. One of our co-authors (expert by experience) contributed to the development and interpretation of themes and preparation of the final manuscript.

Prevalence and predictors of self-reported hearing aid use and benefit in Norway: the HUNT study.

BACKGROUND: Knowledge on hearing aid use and benefit is important to ensure appropriate and effective treatment. We aimed to assess prevalence and predictors of hearing aid use and benefit in Norway, as well as possible birth cohort changes. METHODS: We analyzed two large cross-sectional, population-based hearing surveys of 63,182 adults in 1996-1998 and 2017-2019 (the HUNT study). We used multivariable regression models to examine independent predictors of hearing aid use and benefit, including demography, hearing-related variables, known risk factors for hearing loss and birth cohort. RESULTS: The nationally weighted hearing aid use in the adult population increased from 4.2% in 1997 to 5.8% in 2018. The use among individuals with disabling hearing loss (≥ 35 dB HL) increased from 46.3% to 64.4%. Most users reported some (47%) or great (48%) help from their hearing aids. In addition to the level of hearing loss and birth cohort, factors associated with hearing aid use included lower age, tinnitus, childhood-onset hearing loss, higher education, marriage, having children, being exposed to occupational noise or impulse noise, recurrent ear infections, and head injury. In addition to the level of hearing loss, factors related to hearing aid benefit included younger age, female gender, and higher income. Being bothered by tinnitus reduced the benefit. CONCLUSION: Our study shows an increase in self-reported hearing aid usage over time in Norway, with lower adoption rates and perceived benefits observed among the elderly. The results suggest that having a spouse and children positively influences the adoption of hearing aids. These findings emphasize the necessity of customized strategies to address demographic disparities and the need for innovative enhancements in hearing rehabilitation programs.

Genetics evaluation outcomes of patients with pediatric hearing loss: 2008-2022 retrospective study.

OBJECTIVE: This study aims to explore how genetics evaluation and testing for patients with pediatric onset hearing loss affects their diagnosis and management. METHODS: Retrospective chart review was completed for patients with pediatric hearing loss that were evaluated by a genetic counselor from 2008 to 2022 with data entry into a REDCap database. Descriptive statistical analysis was completed. RESULTS: Four hundred twenty-nine patients with pediatric onset hearing loss were evaluated by genetics. Majority of patients presented with bilateral (67 %) and sensorineural (83 %) hearing loss. Genetic testing was recommended for 76 % of patients with pediatric hearing loss evaluated by a genetic counselor with 70 % completing some or all recommended tests. Overall genetic testing diagnostic rate was 34 %, with 41 % of diagnoses syndromic. Yearly trends noted an increasing number of patients evaluated, tests ordered, and subsequently an increased number of diagnoses overtime. For diagnostic results, management recommendations were made for 45 % of patients (35/78) and for 92 % of family members (72/78). This compared to total management recommendations for all patients (82/429, 19 %) and family members (110/429, 26 %). CONCLUSION: This study identified a genetic testing diagnostic rate for pediatric hearing loss of 34 % over 14 years. This study notes the beneficial outcomes of patients with hearing loss and their families meeting with a genetic counselor and the importance of collaboration with hearing loss management colleagues. It highlights the value a genetic counselor consult can add to a patient's diagnostic journey, in addition to how genetic testing impacts management for patients and their families.

[How to Support People with Hearing Impairment beyond Hearing aid Provision - A Systematic Review on Self-Management Interventions]. / Wie können Menschen mit einer Hörbehinderung über eine Hörsystemversorgung hinaus unterstützt werden?

OBJECTIVE: People with hearing handicap have to use a whole range of strategies to cope with everyday challenges - they have to self-manage their hearing impairment. While the support of self-management is well established in foreign language audiological rehabilitation programs, there are no recommendations in Germany yet. Therefore, the aim of this systematic review is first to give an overview of existing self-management interventions for people with hearing handicap and then to suggest possible applications in the German care system. METHODS: A systematic literature search was conducted on PubMed. The articles dealt with self-management interventions for people with hearing impairment. This eligibility criterion was applied to titles, abstracts, and full texts. If eligible, information on the publication, intervention, and evaluation were extracted and qualitatively summarized. The methodological quality of studies was investigated using the NIH assessment tool for interventional studies. RESULTS: 23 papers could be included and show a high heterogeneity regarding methodological quality, applied intervention, and design of evaluation. The interventions pursuing various goals include a wide range of content (e. g., communication improvement or psychosocial aspects) and have been implemented on a group-based, individual-based, or self-administered level. Despite a few studies that failed to demonstrate intervention effects, most evaluations found positive ef-fects of the intervention on hearing impairment, psychological well-being, and communication. DISCUSSION: The included studies present a high heterogeneity with regard to methodological quality, the intervention conducted, and the evaluation design. Therefore, a summary of the findings was only possible in a qualitative manner. Possibilities of adapting existing intervention programs as well as chances and limits of an implementation in the German health care system are to be discussed in the following. CONCLUSION: Overall, interventions including self-management support seem to be a profitable complement to sole technical device supply and should be further fostered in German-speaking countries as well.

Education Intervention on 'Hearing Impairment - Its Assessment and Management' among Medical Practitioners in Sikkim, India.

BACKGROUND: Health care providers must be aware of the choices in aural rehabilitation methods and assessment procedures available presently to those with hearing impairment in order to facilitate early identification and intervention and ensure quality of care to those hearing impaired individuals. The referrals from the medical fraternities for the audiological services are not uniform across India. Part of reason may be that awareness about the roles of and responsibilities of audiologist's is poor among medical practitioners. In some regions of India medical practitioners may be only grossly be aware of audiologists per se. They may not know enough to refer all individuals with hearing or balance disorders for the required audiological services. AIM: To evaluate changes in pre survey and post survey after education intervention specifically planned for medical practitioners in the state of Sikkim, India. Education intervention included awareness about hearing impairment and its assessment and management by audiologists. METHOD: A pre and post survey comparison research design with purposive convenient sampling technique was applied. Participants were medical practitioners working in geographical area of Sikkim at the time of the study. Inspection of demographic data of respondents showed that they were in their age range of 24 and 60 years and with work experience ranging 1-40 years. Participants were invited for an awareness talk which included, information about hearing loss, early identification and early intervention, tests and management of hearing loss in different age groups, need for hearing aids/cochlear implants, auditory training, and the role of an audiologist in the management of hearing loss and ways to prevent hearing loss. A pre and post awareness program responses were collected from all the participants using a customized questionnaire tool. RESULTS: Respondents exhibited, in the pre-survey questionnaire, lack of awareness in many aspects of audiology, including assessing hearing impairment, diagnosing hearing loss, and the role of an audiologist. There was an overall, statistically significant difference in the level of performance on the pre-awareness and post-awareness responses. CONCLUSION: Following an awareness campaign among the medical professionals in Sikkim, there was a considerable change in their level of awareness of hearing impairment, its assessment, and management by audiologists. The reach of the awareness campaign was significant as around 70% of subjects showed significant change in their knowledge and attitude towards hearing impairment, its management.

Novel Nanoencapsulation Technology and its Potential Role in Bile Acid-Based Targeted Gene Delivery to the Inner Ear.

Hearing loss impacts a large proportion of the global population. Damage to the inner ear, in particular the sensitive hair cells, can impact individuals for the rest of their lives. There are very limited options for interventions after damage to these cells has occurred. Targeted gene delivery may provide an effective means to trigger appropriate differentiation of progenitor cells for effective replacement of these sensitive hair cells. There are several hurdles that need to be overcome to effectively deliver these genes. Nanoencapsulation technology has previously been used for the delivery of pharmaceuticals, proteins and nucleic acids, and may provide an effective means of delivering genes to trigger appropriate differentiation. This review investigates the background of hearing loss, current advancements and pitfalls of gene delivery, and how nanoencapsulation may be useful.

A systematic review of the monogenic causes of Non-Syndromic Hearing Loss (NSHL) and discussion of Current Diagnosis and Treatment options.

Hearing impairment is one of the most widespread inheritable sensory disorder affecting at least 1 in every 1000 born. About two-third of hereditary hearing loss (HHL) disorders are non-syndromic. To provide comprehensive update of monogenic causes of non-syndromic hearing loss (NSHL), literature search has been carried out with appropriate keywords in the following databases-PubMed, Google Scholar, Cochrane library, and Science Direct. Out of 2214 papers, 271 papers were shortlisted after applying inclusion and exclusion criterion. Data extracted from selected papers include information about gene name, identified pathogenic variants, ethnicity of the patient, age of onset, gender, title, authors' name, and year of publication. Overall, pathogenic variants in 98 different genes have been associated with NSHL. These genes have important role to play during early embryonic development in ear structure formation and hearing development. Here, we also review briefly the recent information about diagnosis and treatment approaches. Understanding pathogenic genetic variants are helpful in the management of affected and may offer targeted therapies in future.

Advances in cochlear gene therapies.

PURPOSE OF REVIEW: Hearing loss is the most common sensory deficit and in young children sensorineural hearing loss is most frequently genetic in etiology. Hearing aids and cochlear implant do not restore normal hearing. There is significant research and commercial interest in directly addressing the root cause of hearing loss through gene therapies. This article provides an overview of major barriers to cochlear gene therapy and recent advances in preclinical development of precision treatments of genetic deafness. RECENT FINDINGS: Several investigators have recently described successful gene therapies in many common forms of genetic hearing loss in animal models. Elegant strategies that do not target a specific pathogenic variant, such as mini gene replacement and mutation-agnostic RNA interference (RNAi) with engineered replacement, facilitate translation of these findings to development of human therapeutics. Clinical trials for human gene therapies are in active recruitment. SUMMARY: Gene therapies for hearing loss are expected to enter clinical trials in the immediate future. To provide referral for appropriate trials and counseling regarding benefits of genetic hearing loss evaluation, specialists serving children with hearing loss such as pediatricians, geneticists, genetic counselors, and otolaryngologists should be acquainted with ongoing developments in precision therapies.

New horizons in holistic, person-centred health promotion for hearing healthcare.

Over the course of a lifetime, the risk of experiencing multiple chronic conditions (multimorbidity) increases, necessitating complex healthcare regimens. Healthcare that manages these requirements in an integrated way has been shown to be more effective than services that address specific diseases individually. One such chronic condition that often accompanies ageing is hearing loss and related symptoms, such as tinnitus. Hearing loss is not only highly prevalent in older adults but is also a leading cause of disability. Accumulating evidence demonstrates an interplay between auditory function and other aspects of health. For example, poorer cardiometabolic health profiles have been shown to increase the risk of hearing loss, which has been attributed to microvascular disruptions and neural degeneration. Additionally, hearing loss itself is associated with significantly increased odds of falling and is a potentially modifiable risk factor for cognitive decline and dementia. Such evidence warrants consideration of new possibilities-a new horizon-for hearing care to develop a holistic, person-centred approach that promotes the overall health and wellbeing of the individual, as well as for audiology to be part of an interdisciplinary healthcare service. To achieve this holistic goal, audiologists and other hearing healthcare professionals should be aware of the range of conditions associated with hearing loss and be ready to make health promoting recommendations and referrals to the appropriate health practitioners. Likewise, healthcare professionals not trained in audiology should be mindful of their patients' hearing status, screening for hearing loss or referring them to a hearing specialist as required.

Managing comorbid cognitive impairment and hearing loss in older adults: a UK survey of audiology and memory services.

BACKGROUND: midlife hearing loss is a potentially modifiable risk factor for dementia. Addressing comorbid hearing loss and cognitive impairment in services for older adults may offer opportunities to reduce dementia risk. OBJECTIVE: to explore current practice and views amongst UK professionals regarding hearing assessment and care in memory clinics and cognitive assessment and care in hearing aid clinics. METHODS: national survey study. Between July 2021 and March 2022, we distributed the online survey link via email and via QR codes at conferences to professionals working in National Health Service (NHS) memory services and audiologists working in NHS and private adult audiology services. We present descriptive statistics. RESULTS: 135 professionals working in NHS memory services and 156 audiologists (68% NHS, 32% private sector) responded. Of those working in memory services, 79% estimate that >25% of their patients have significant hearing difficulties; 98% think it useful to ask about hearing difficulties and 91% do so; 56% think it useful to perform a hearing test in clinic but only 4% do so. Of audiologists, 36% estimate that >25% of their older adult patients have significant memory problems; 90% think it useful to perform cognitive assessments, but only 4% do so. Main barriers cited are lack of training, time and resources. CONCLUSIONS: although professionals working in memory and audiology services felt addressing this comorbidity would be useful, current practice varies and does not generally address it. These results inform future research into operational solutions to integrating memory and audiology services.

Gene editing in a Myo6 semi-dominant mouse model rescues auditory function.

Myosin VI（MYO6） is an unconventional myosin that is vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments for Myo6 mutation causing hearing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate hearing loss in a Myo6WT/C442Y mouse model that recapitulated the phenotypes of human patients. The in vivo editing efficiency of the AAV-SaCas9-KKH-Myo6-g2 system on Myo6C442Y is 4.05% on average in Myo6WT/C442Y mice, which was ∼17-fold greater than editing efficiency of Myo6WT alleles. Rescue of auditory function was observed up to 5 months post AAV-SaCas9-KKH-Myo6-g2 injection in Myo6WT/C442Y mice. Meanwhile, shorter latencies of auditory brainstem response (ABR) wave I, lower distortion product otoacoustic emission (DPOAE) thresholds, increased cell survival rates, more regular hair bundle morphology, and recovery of inward calcium levels were also observed in the AAV-SaCas9-KKH-Myo6-g2-treated ears compared to untreated ears. These findings provide further reference for in vivo genome editing as a therapeutic treatment for various semi-dominant forms of hearing loss and other semi-dominant diseases.

Audiometric Outcomes of Ventilation Drainage Treatment for Otitis Media with Effusion in Children: Implications for Speech Development and Hearing Loss.

BACKGROUND Otitis media with effusion is the most commonly recognized condition in childhood. Chronic otitis media with accompanying hearing loss is particularly unfavorable in the first years of the child's life because it can not only permanently damage the structure of the middle ear, but also adversely affect speech development and intellectual abilities in the child. MATERIAL AND METHODS This study, from a single center in Poland, included 201 children (372 ears) requiring surgical treatment due to otitis media with effusion. The condition was diagnosed by an ear, nose, and throat specialist, and each patient had a hearing test performed. The control group consisted of 21 patients (42 ears) with negative outcomes following an audiological interview. RESULTS Among all of the patients enrolled in the study, a normal tympanometry result was found in 60.6% of ears, and otoemission occurred in 63.3% of ears. The average hearing threshold in the study group was 22.01 Hz in the 500 Hz frequency range, while they were 16.76 Hz, 12.72 kHz, and 14.78 kHz for the corresponding 1 kHz, 2 kHz, and 4 kHz ranges, respectively. CONCLUSIONS Ventilation drainage is an effective treatment for otitis media with effusion. The presence of genetic disease has the greatest impact on the course of otitis media. These patients most often require reinsertion of a ventilation tube.