Hearing loss, the most common human sensory defect worldwide, is a major public health problem. About 70% of congenital forms and 25% of adult-onset forms of deafness are of genetic origin. In total, 136 deafness genes have already been identified and there are thought to be several hundred more awaiting identification. However, there is currently no cure for sensorineural deafness. In recent years, translational research studies have shown gene therapy to be effective against inherited inner ear diseases, and the application of this technology to humans is now within reach. We provide here a comprehensive and practical overview of current advances in gene therapy for inherited deafness, with and without an associated vestibular defect. We focus on the different gene therapy approaches, considering their prospects, including the viral vector used, and the delivery route. We also discuss the clinical application of the various strategies, their strengths, weaknesses, and the challenges to be overcome.

Hearing loss affects 1.57 billion people worldwide, and projections suggest that 2.45 billion people will have hearing loss by 2050.¹ Hearing loss is the third leading cause of years lived with disability and the first leading cause of years lived with disability among people older than 70 years. The World Health Organization recently estimated that unaddressed hearing loss represents an annual worldwide cost of $980 billion, including health care, education, productivity loss, and societal costs.^2,3 In addition to constraining the ability to communicate, hearing loss is associated with delayed language among children, social isolation, altered quality of life, depression, cognitive decline, and dementia.^4-8

Neonatal gene therapy has been shown to prevent inner ear dysfunction in mouse models of Usher syndrome type I (USH1), the most common genetic cause of combined deafness-blindness and vestibular dysfunction. However, hearing onset occurs after birth in mice and in utero in humans, making it questionable how to transpose murine gene therapy outcomes to clinical settings. Here, we sought to extend the therapeutic time window in a mouse model for USH1G to periods corresponding to human neonatal stages, more suitable for intervention in patients. Mice with deletion of Ush1g ( Ush1g ^–/– ) were subjected to gene therapy after the hearing onset. The rescue of inner ear hair cell structure was evaluated by confocal imaging and electron microscopy. Hearing and vestibular function were assessed by recordings of the auditory brain stem response and vestibulo-ocular reflex and by locomotor tests. Up to P21, gene therapy significantly restored both the hearing and balance deficits in Ush1g ^–/– mice. However, beyond this age and up to P30, vestibular function was restored but not hearing. Our data show that effective gene therapy is possible in Ush1g ^–/– mice well beyond neonatal stages, implying that the therapeutic window for USH1G may be wide enough to be transposable to newborn humans.

Cochlear implantation is usually not recommended for prelingual profoundly deaf adults, although some of these patients might benefit from it. This study aims to define the candidates for cochlear implantation in this population. This retrospective study reviewed 34 prelingual profoundly deaf patients who had received a cochlear implant at 32 ± 1.7 years old (16–55), with at least 1 year of follow-up. Speech perception and quality of life were assessed before and 3, 6, and 12 months after cochlear implantation, then every year thereafter. According to the word speech intelligibility in quiet (WSI) 1 year after implantation, two groups were identified: good performer (GP) with WSI ≥ 50% (n = 15), and poor performer (PP) with WSI ≤ 40% (n = 19). At the 1 year mark, mean WSI improved by 28 ± 4.6% (−20–100) (p < 0.0001). In GP, the intelligibility for words and sentences, communication and quality of life scales improved. In PP, the communication scale improved, but not auditory performance or quality of life. GP and PP differed pre-operatively in speech production, communication abilities, and WSI in best-aided conditions. In prelingual profoundly deaf adults, a dramatic auditory performance benefit could be expected after cochlear implantation if the patients have some degree of speech intelligibility in aided conditions and have developed oral communication and speech production.

The natural history of sporadic vestibular schwannoma is unpredictable, with tumors growing, non-growing and even showing spontaneous regression in some rare cases. This retrospective study aims to describe the radiologic signs characterizing and identifying the shrinking vestibular schwannoma. Involution was considered to have occurred if tumor size had decreased by 2 mm or more on its largest diameter. All magnetic resonance imaging scans were reviewed for tumor size, internal auditory meatus size, and tumor characteristics. Volumetric measurements were performed on the first and last scan. Audiometric data were collected at the first and last visit. Fourteen patients with a confirmed spontaneous regression were included, with a mean follow-up of 5 ± 2.6 years. The mean shrinkage rate was 0.9 ± 0.59 mm/year on 2D measurements, and 0.2 ± 0.17 cm³/year on volumetric measurements, with a relative shrinkage of 40 ± 16.9%. Two remarkable radiologic features were observed: First, a festooned aspect, defined by multiple curves in the tumor outline, noticed in 12 cases (86%); second, the appearance of cerebrospinal fluid filling the internal auditory meatus, associated with an enlargement of the internal auditory meatus compared to the contralateral side, and observed in 10 out of 13 cases with internal auditory meatus invasion (77%). Those two aspects were associated in 64% of cases. These two newly reported radiologic features could help neurosurgeons, oto-neurosurgeons and neuroradiologists to identify a spontaneous vestibular schwannoma involution at first visit. This could allow any treatment to be postponed, monitoring to be more widely spaced, and patients to be reassured.