Although numerous causative genes for hereditary hearing loss have been identified, there are no fundamental treatments for this condition. Herein, we describe a novel potential treatment for genetic hearing loss. Because mutations or deletions in the connexin (Cx) genes are common causes of profound congenital hearing loss in both humans and mice, we investigated whether gene supplementation therapy using the wild-type Cx gene could cure hearing loss. We first generated inner ear-specific connexin 30 (Cx30)-deficient mice via the transuterine transfer of Cx30-targeted short hairpin RNA (shRNA-Cx30) into otocysts. The inner ear-specific Cx30-deficient mice mimicked homozygous Cx30-deficient mice both histologically and physiologically. Subsequently, we cotransfected the shRNA-Cx30 and the wild-type Cx30 gene. The cotransfected mice exhibited Cx30 expression in the cochleae and displayed normal auditory functions. Next, we performed the transuterine transfer of the wild-type Cx30 gene into the otocysts of homozygous Cx30-deficient mice, thereby rescuing the lack of Cx30 expression in the cochleae and restoring auditory functioning. These results demonstrate that supplementation therapy with wild-type genes can restore postnatal auditory functioning. Moreover, this is the first report to show that Cx-related genetic hearing loss is treatable by in vivo gene therapy.

The stria vascularis is a nonsensory structure that is essential for auditory hair cell function by maintaining potassium concentration of the scala media. During mouse embryonic development, a subpopulation of neural crest cell-derived melanocytes migrates and incorporates into a subregion of the cochlear epithelium, forming the intermediate cell layer of the stria vascularis. The relation of this developmental process to stria vascularis function is currently unknown. In characterizing the molecular differentiation of developing peripheral auditory structures, we discovered that hepatocyte growth factor (Hgf) is expressed in the future stria vascularis of the cochlear epithelium. Its receptor tyrosine kinase, c-Met, is expressed in the cochlear epithelium and melanocyte-derived intermediate cells in the stria vascularis. Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the melanocytes into the future stria vascularis of the cochlear duct requires c-MET signaling. In addition, inactivation of either the ligand or receptor developmentally resulted in a profound hearing loss at young adult stages. These results suggest a novel connection between HGF signaling and deafness via melanocyte deficiencies. SIGNIFICANCE STATEMENT We found the roles of hepatocyte growth factor (HGF) signaling in stria vascularis development for the first time and that lack of HGF signaling in the inner ear leads to profound hearing loss in the mouse. Our findings reveal a novel mechanism that may underlie human deafness DFNB39 and DFNB97. Our findings reveal an additional example of context-dependent c-MET signaling diversity, required here for proper cellular invasion developmentally that is essential for specific aspects of auditory-related organogenesis.

Objective: To assess the feasibility of a postauricular transcortical mastoidectomy utilizing an exoscope, which offers 3D stereoscopic visualization. Study Design: Clinical capsule report. Patients: Two consecutive patients with cholesteatoma involvement in the mastoid cavity were included in the study. Intervention: After transcanal endoscopic surgery, postauricular mastoidectomy utilizing a surgical 3D exoscope was performed. Then, the cholesteatoma in the mastoid cavity was removed through the mastoidectomy opening with endoscopes. Results: The postauricular transcortical mastoidectomy utilizing a 3D exoscope was not only feasible, but importantly, the exoscope took little time to switch to and resulted in a smooth workflow. There was no cholesteatoma recurrence at 9 months. Conclusion: During endoscope-based surgery, in patients with cholesteatoma mastoid involvement, we can continue to perform the surgical procedure in a heads-up position utilizing a surgical 3D exoscope. The combination of transcanal endoscopic ear surgery and the postauricular transcortical mastoidectomy utilizing a surgical 3D exoscope is a very novel treatment strategy for cholesteatoma, and it gives us a comfortable and consistent working environment in endoscope-based ear surgery.

The otocyst, an anlage of the inner ear, presents an attractive target to study treatment strategies for genetic hearing loss and inner ear development. We have previously reported that electroporation-mediated transuterine gene transfer of Connexin30, utilizing a monophasic pulse into Connexin30^−/− mouse otocysts at embryonic day 11.5, is able to prevent putative hearing deterioration. However, it is not clear whether supplementary gene transfer can rescue significant morphological changes, caused by genetic deficits. In addition, with the transuterine gene transfer technique utilized in our previous report, the survival rate of embryos and their mothers after treatment was low, which became a serious obstacle for effective in vivo experiments. Here, we set out to elucidate the feasibility of supplementation therapy in Slc26a4 deficient mice, utilizing biphasic pulses, optimized by modifying pulse conditions. Modification of the biphasic pulse conditions during electroporation increased the survival rate. In addition, supplementation of the target gene cDNA into the otocysts of homozygous Slc24a4 knockout mice significantly prevented enlargement of the endolymphatic space in the inner ear areas; moreover, it rescued hearing and vestibular function of mice in vivo.

Background: Persistent postural-perceptual dizziness (PPPD) is a newly defined disorder characterized by functional dizziness. Due to its recent discovery, definitive treatment for PPPD has not been established; therefore, this study aimed to assess the effectiveness of virtual reality (VR)-guided, dual-task, trunk balance training for the management of PPPD using the mediVR KAGURA system.Methods: We analyzed data of patients who presented with PPPD from January 1, 2021, to February 28, 2021. The VR group included patients who underwent mediVR KAGURA-guided training for 100 tasks (10 min). Patients with PPPD who received standard treatment and rehabilitation were assigned to the control group. Equilibrium tests were performed at baseline and immediately after mediVR KAGURA-guided training to examine its effectiveness in improving static and dynamic balance. Additionally, clinical questionnaires related to balance disorders were administered at baseline and 1 week after mediVR KAGURA-guided training to examine its effects on balance-related symptoms. The primary outcome was improvements in static and dynamic balance and Niigata PPPD Questionnaire (NPQ) scores.Results: VR-guided training using mediVR KAGURA improved objective outcomes, including static and dynamic postural stability, after a single 10-min training session. Additionally, mediVR KAGURA-guided training improved scores on the Hospital Anxiety and Depression Scale and NPQ 1 week after the 10-min training session.Conclusion: VR-guided training using mediVR KAGURA represents a viable method for managing balancing ability, anxiety, and symptoms in patients with PPPD. Such training provides a safe and cost-effective solution for PPPD management. Further studies are required to evaluate the clinical efficacy of this strategy.Trial registration: Institutional Ethics Committee of Kitano Hospital, approval number: 1911003. Registered 18 December 2019,https://kitano.bvits.com/rinri/publish_document.aspx?ID=426.