Time window for gene therapy to restore normal hearing in preclinical models of human deafness and balance disorders – TIME-TO-EAR

Mammal’s hearing and balance functions rely on highly specialized sensory organs in the inner ear, the cochlea and the vestibule, the hearing and the balance organs, respectively.
Deafness and balance defects are the most prevalent inherited sensory disorders in humans. Roughly 1 in 700 newborns are clinically deaf. About 80% of the congenital deafness cases have a genetic cause, with 30% of those cases associated with balance defects.
To date, there is currently no curative therapeutic approach for deafness and balance impairment. However, in recent years, adeno-associated viruses (AAVs) have emerged as a promising vector for gene therapy. Although AAV-based gene therapy has shown promise in pre-clinical and clinical trials for various inherited disorders, it has not yet been used for treating hearing loss. It is worth noting that there are currently over 136 known genes associated with inner ear defects, and potentially up to 500 genes remain to be identified, underscoring the potential of gene therapy as a treatment for deafness and balance defect. In addition, the inner ear of humans is anatomically suitable for in vivo gene therapy, thanks to its isolated fluid-filled compartments that allow for local application with minimal risk of dissemination. During the last decade, we focused our efforts on the development of AAV gene therapy for restoring hearing and balance in mouse model for human inner ear defects. We were able to restore both hearing and balance in newborn mouse models for the Usher1G and IIIA syndromes. Recently, we reported the first proof-of-principle that AAV gene therapy can restore normal hearing in otherwise profoundly deaf DFNB9 mouse model, raising hopes for future gene therapy trials in DFNB9 patients. Though, despite the abovementioned successes, there are still many challenges to overcome for gene therapy before it can be applied to human deafness. Firstly, the onset of hearing occurs postnatally in mice and in utero in humans, making it difficult to literally transpose murine therapeutic time windows to the clinical setting in human patients. This implies that to be able to do so, gene therapy should be delivered to the inner ear of near adult mice. However, the transduction rate of auditory sensory cells by AAVs decreases drastically with age, emphasizes the crucial need to explore and identify novel variant AAVs that exhibit a strong tropism for mature hair cells. Secondly, does peripheral gene therapy restore normal central auditory perception? Indeed, there is a critical period (CP) of plasticity, during which the central auditory circuits progressively lose their ability to encode new specific acoustic cues properly, which may be detrimental to the recovery of complete auditory perception after hearing restoration. These developmental processes and their impact on gene therapy outcomes remain largely unknown.
The objective of this project is to fill this gap by using therapy to “turn on” the hearing and balance in mouse models for human inner ear defect, at several time points during the CP of central nervous system maturation and assess the level of the hearing auditory perception brought by gene therapy.
We will investigate three mouse models for human deafness, including DFNB9, DFNB16 and Usher syndrome of type IG (USH1G).
There are three chief steps to take to achieve these goals:
? STEP 1. Identify /or engineer AAV serotypes with a strong tropism for adult mouse inner ear hair cell
? STEP 2. Investigate the therapeutic time window allowing hearing and balance restoration
? STEP3. Evaluate the recovery of central auditory processing and of auditory performance

The primary objective of this project is to develop gene therapies to restore hearing and balance in mouse models for human inner ear defects, that can ultimately be applied to patients.