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Adeno-associated virus (AAV)-based gene therapy is emerging as a promising treatment for deafness and vestibular deficits, due to the variety of available serotypes that offer a large range of cell targeting capabilities. Nevertheless, the tropism of these AAV serotypes for sensory inner ear cells varies greatly as the cochlea matures, presenting a significant burden for successful preclinical trials. Therefore, identifying serotypes with strong tropism for cochlear and vestibular hair cells during key stages of development in mouse inner ear, the most widely used preclinical model, is essential for advancing clinical applications. We conducted a comparative analysis of the cellular tropism and hair-cell transduction rates of four AAV serotypes in the cochlea and vestibular organs during maturation. We used AAV2, AAV8, AAV9-PHP.eB, and Anc80L65 at the embryonic, neonatal, and adult stages. Our results indicate that the cell transduction rate of these four serotypes varies with age. Notably outer hair cells were mostly targeted during the embryonic stage, inner hair cells were primarily transduced principally at the mature stage, and vestibular hair cells were the most permissive at the neonatal stage. These results provide new insights for preclinical gene therapy studies for the inner ear with potential implications for therapeutic outcomes.

Background The autosomal recessive deafness 9 (DFNB9) is caused by mutations in the otoferlin gene that accounts for 2–8% of all inherited deafness cases. In a previous study, we demonstrated that Adeno-associated virus (AAV) gene therapy restored hearing in a preclinical mouse model of profound DFNB9 deafness caused by a frameshift mutation leading to a complete loss of otoferlin expression. However, it remains to be demonstrated that it can address the full spectrum of DFNB9 deafness severity, while also restoring central auditory processing essential for speech understanding. Methods Using homologous recombination in mouse embryonic stem cells, we created a knock-in mouse model carrying the E1799del otoferlin mutation, which mirrors the human E1804del variant linked to DFNB9 deafness, characterized by moderate-to-profound deafness during febrile episodes in affected individuals. A mixture of male and female mice was used at P2, P8, and P30. Some were followed for up to 4 months for longevity monitoring and behavioral tests. Results The mouse model exhibits abnormal otoferlin distribution, failure of synaptic transmission in inner hair cells, and profound hearing loss, all of which is restored to normal through AAV gene therapy. Notably, we conduct objective behavioral testing to provide the first evidence that gene therapy administered to the cochlea, which is part of the peripheral auditory system, can restore frequency discrimination, indicating the recovery of central auditory processing. This is achieved even when treatment is administered late at the end of the critical period. Conclusions These findings indicate that gene therapy can address the entire spectrum of DFNB9 hearing loss, and that profound deafness during critical period may not impede the restoration of central auditory processing. Plain language summary We investigated gene therapy, a technique that introduces a healthy copy of a gene to restore normal cell function, as a potential treatment for an unusual form of inherited deafness caused by mutations in the otoferlin gene. These mutations result in the production of a defective protein, leading to hearing loss during fever episodes. We developed and studied a mouse model with the same genetic alteration observed in affected individuals and discovered that the deafness resulted from the abnormal protein distribution in the inner ear. We use gene therapy to correct this mislocalization and restored normal hearing. Our findings indicate that gene therapy may be an effective approach for treating all forms of otoferlin-related hearing loss. Benamer et al. develop a knock-in mouse model carrying the E1799del otoferlin mutation to study the atypical DFNB9 variant form of deafness. They show the mouse model exhibits abnormal otoferlin distribution, failure of synaptic transmission in inner hair cells, and profound hearing loss, all of which can be restored with AAV gene therapy.

In the mammalian cochlea, sensory hair cells are crucial for the transduction of acoustic stimuli into electrical signals, which are then relayed to the central auditory pathway via spiral ganglion neuron (SGN) afferent dendrites. The SGN output is directly modulated by inhibitory cholinergic axodendritic synapses from the efferent fibers originating in the superior olivary complex. When the adult cochlea is subjected to noxious stimuli or aging, the efferent system undergoes major rewiring, such that it reestablishes direct axosomatic contacts with the inner hair cells (IHCs), which occur only transiently during prehearing stages of development. The trigger, origin, and degree of efferent plasticity in the cochlea remains largely unknown. Using functional and morphological approaches, we demonstrate that efferent plasticity in the adult cochlea occurs as a direct consequence of mechanoelectrical transducer current dysfunction. We also show that, different from prehearing stages of development, the lateral olivocochlear - but not the medial olivocochlear - efferent fibers are those that form the axosomatic synapses with the IHCs. The study also demonstrates that in vivo restoration of IHC function using AAV-Myo7a rescue reestablishes the synaptic profile of adult IHCs and improves hearing, highlighting the potential of using gene-replacement therapy for progressive hearing loss.