Abstract
Hearing impairment is the most frequent sensory deficit in humans of all age groups, from children (1/500) to the elderly (more than 50% of the over-75 s). Over 50% of congenital deafness are hereditary in nature. The other major causes of deafness, which also may have genetic predisposition, are aging, acoustic trauma, ototoxic drugs such as aminoglycosides, and noise exposure. Over the last two decades, the study of inherited deafness forms and related animal models has been instrumental in deciphering the molecular, cellular, and physiological mechanisms of disease. However, there is still no curative treatment for sensorineural deafness. Hearing loss is currently palliated by rehabilitation methods: conventional hearing aids, and for more severe forms, cochlear implants. Efforts are continuing to improve these devices to help users to understand speech in noisy environments and to appreciate music. However, neither approach can mediate a full recovery of hearing sensitivity and/or restoration of the native inner ear sensory epithelia. New therapeutic approaches based on gene transfer and gene editing tools are being developed in animal models. In this review, we focus on the successful restoration of auditory and vestibular functions in certain inner ear conditions, paving the way for future clinical applications.
Highlights
Hearing impairment is the most common sensory deficit in humans [1,2,3]
Permeation enhancers and controlled devices can be used to facilitate local and continuous drug transport to inner ear compartments, in particular through the semi-permeant round window. This procedure is technically simple to perform and generally of low risk, but the concentrations used are generally high and the therapeutic agent must remain in contact with the round window membrane (RWM) for a prolonged period to ensure that sufficient amounts cross the RWM; (iii) Cochleostomy: in this approach, the transgene is transferred directly to the scala media, which can be accessed via a hole drilled through the basal part of the cochlea into the cochlear endolymphatic space, near the round window [33,34,35,36,37] (Figure 4 and Table S2)
A single injection of this recombinant associated viruses (AAVs) vector pair through the round window membrane into the cochlea of Otof −/− mice led to a durable restoration of otoferlin expression in transduced inner hair cells, and a total reversal of the deafness phenotype [73]
Summary
Hearing impairment is the most common sensory deficit in humans [1,2,3]. According to the World Health Organization (WHO), disabling hearing loss affects over 5% of the world’s population (466 million people). About 140 non-syndromic hearing loss genes have been identified, causing impairments of various degrees of severity and progressivity These genes encode diverse proteins, with different functions in the inner ear, including gene regulation, ion homeostasis, synaptic transmission, and roles in auditory hair cell bundle morphology and development [7,8]. As in all therapeutic approaches, each avenue explored must be appropriate for (i) the nature of the causal agent and its defective mechanism; (ii) the target cells (auditory hair cells, supporting cells, or neurons); (iii) the degree of hearing loss and its progressivity; and (iv) the objective: preventing hearing loss, protecting or restoring function, or replacing damaged cells. We review here the therapeutic strategies in current use, and progress towards the curative treatment of hearing loss, and outline the challenges associated with in vivo gene therapy targeting the human inner ear for the treatment of human sensorineural hearing loss
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