Peripheral gene therapy for restoring hearing and central auditory processing in two mouse models of progressive and profound deafness – HearAgain

Deafness is a major public health concern, with a prevalence of congenital deafness of around 1 in 700 newborns, and ~80% of these cases attributable to genetic causes. Unfortunately, there is currently no cure available for hearing loss. However, gene therapy, specifically using adeno-associated virus (AAV)-mediated gene therapy, has recently emerged as a promising therapeutic option. Particularly noteworthy are the encouraging results from several ongoing clinical trials aimed at treating patients with DFNB9 hereditary auditory synaptopathy. AAV-mediated gene therapy for hereditary deafness is increasingly considered a reliable curative treatment option. However, despite the success observed in DFNB9 patients, many challenges must be addressed before its application can be widely extended to humans. Indeed, restoration of hearing in preclinical models is generally assessed by means of auditory evoked potential recordings in the brainstem, and sometimes by assessing reflex behaviours in response to sound stimuli, which does not represent a measure of final sound perception but only of the functioning of the peripheral auditory system. It is therefore crucial to demonstrate, before application in humans, that gene therapy can also fully restore central auditory processing to normal sound perception. Furthermore, it is also important to assess the impact of developmental processes in the auditory system in the case of late therapy taking place after potentially critical periods for the maturation of neural networks processing sound information. The aim of this project is to use for the first time state-of-the-art tools (biphotonic imaging, neuronal population analysis, perceptual measurements) set up by the coordinator to assess the central and perceptual effects of gene therapy carried out in murine preclinical models.
The project involves two models of hearing loss established by the partner team: i) A model defective for the ribbon synapse (primarily the ribeye protein), associated with various forms of severe to profound auditory synaptopathy.
ii) A model for DFNB16 resulting from a mutation in the stereocilin encoding gene, affecting outer hair cell function.
The project aims to establish and evaluate gene therapy for each of these two models. Gene therapy will be administered in separate groups at two stages of mouse development: before the onset of hearing, enabling assessment of the maximum level of hearing restored through gene therapy, and after the onset of hearing during the first critical periods of sound exposure. It will also assess whether the absence of normal sound exposure affects the outcome of restoration at the perceptual level and in the central auditory system.
Our objective is to convincingly establish to what extent peripheral therapy can restore the normal perception of sound signals, thereby strengthening the basis for clinical application.

This project involves two teams at the Institut de l'Audition who have already established preliminary results validating the envisaged approach, and whose complementary expertise will enable the very first preclinical evaluation of the impact of gene therapies for auditory restoration at the perceptual level. The project will also establish the bases for two new therapeutic solutions for congenital hearing loss affecting a significant number of patients.