Preclinical insights into how spontaneous glutamate release from inner hair cells shapes gene therapy outcomes in auditory synaptopathy // Preclinical insights into how spontaneous glutamate release from inner hair cells shapes gene therapy outcomes in au

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Hearing relies on the specialized sensory organ of the inner ear, the cochlea, which orchestrates the coordinated activity of sensory cells. The outer hair cells (OHCs) amplify incoming sound and enhance frequency selectivity, whereas the inner hair cells (IHCs) convert sound wave into electrical signals and release glutamate onto auditory neurons to initiate signal transmission to the brain. Dysfunction of sensory hair cells leads to hearing loss, ranging from mild to profound deafness. This represents the most widespread human sensory deficits, affecting approximately 70 million Europeans and 430 million people worldwide (www.who.int/pbd/deafness/en/). Beyond communication barriers, hearing loss has major social and economic consequences (>€200 billion/year in Europe) and profoundly impacts of life, including social isolation, depression, and cognitive decline. Genetic factors are a major contributor to hearing loss, particularly in congenital and early-onset cases. Approximately 80% of congenital hearing loss is attributed to genetic causes. To date, over 156 deafness genes have been identified as being associated with hearing loss.
Current treatments like hearing aids and cochlear implants remain suboptimal, as they do not correct the genetic cause, while gene therapy offers a curative alternative. Preclinical studies in Otof-/- mice, a model of DFNB9 auditory synaptopathy, have shown robust hearing restoration even in adult animal models (i.e., 5–10 years in humans). Early clinical results confirm functional recovery in children with DFNB9 deafness.
Remarkably, our recent findings show that Otof-/- mice recover hearing after gene therapy administered at six weeks, beyond the presumed critical period of auditory plasticity, suggesting a broader therapeutic window. Based on these results, we hypothesize that the spontaneous activity of spiral ganglion neurons, driven by spontaneous glutamate release from IHCs, may help extend the effective period for DFNB9 gene therapy.

The goal of this Ph.D. project is to test this hypothesis through comparative analysis of two mouse models addressing two fundamental questions:
1. What is the upper limit of the optimal therapeutic window in the DFNB9 mouse model beyond which gene therapy no longer produces effective hearing recovery?
2. Is this therapeutic window conserved across other forms of genetic auditory synaptopathies involving dysfunction at the synapse between IHCs and primary auditory neurons?

The Ph.D student will define the upper age limit for gene therapy efficacy in two mouse models: Otof-/- (DFNB9), which retain spontaneous but lack evoked release, and Vglut3-/- (DFNA25), which lack both. Treatments will be given at P30, P40, and P60, ages paralleling human adolescence. Outcomes will be assessed through transgene expression, cochlear protein distribution, hearing restoration, and cortical sound processing with behavioral and psychometric tests. This comparative approach will clarify how spontaneous IHC activity shapes auditory plasticity and whether extended therapeutic windows are a general feature of auditory synaptopathies, thereby providing greater flexibility for clinical translation.
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Début de la thèse : 01/10/2026

Public funding alone (i.e. government, region, European, international organization research grant)

Concours pour un contrat doctoral

Sorbonne Université SIS (Sciences, Ingénierie, Santé)

394 Physiologie, physiopathologie et thérapeutique

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