# Dual AAV gene therapy achieves recovery of hearing and auditory processing in a DFNB16 mouse model

## TL;DR

A gene therapy using dual AAV vectors successfully restored hearing and auditory processing in mice with DFNB16, a common cause of genetic deafness.

## Contribution

This is the first proof that gene therapy can restore both peripheral and central auditory functions in a DFNB16 mouse model.

## Key findings

- Dual AAV-mediated Strc gene delivery restored stereocilin expression and OHC bundle architecture.
- Treated mice showed near-normal hearing thresholds and frequency discrimination up to 100 days post-treatment.
- The therapy demonstrated translational potential for treating human genetic deafness.

## Abstract

DFNB16, the second most common genetic cause of hearing loss, is caused by mutations of the STRC gene encoding stereocilin, a protein essential for the effective functioning of outer hair cells (OHCs) as cochlear amplifiers. Strc
−/− mice, which lack stereocilin, display severe to profound deafness and constitute a relevant preclinical model for DFNB16.

Using Strc−/− mice, we developed a gene therapy strategy based on the use of dual AAV9‐PHP.eB vectors to deliver the full‐length Strc cDNA. Therapeutic efficacy was assessed by evaluating stereocilin expression, OHC bundle architecture, and their attachment to the tectorial membrane, together with functional recovery using distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABR) measurements and Go/No‐Go behavioral testing with psychometric analysis.

Dual‐AAV–mediated Strc gene delivery restored stereocilin expression, OHC bundle architecture and their attachment to the tectorial membrane, leading to the recovery of cochlear amplification and hearing to near normal thresholds, as confirmed by distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements. Behavioural assessment showed that treated Strc
−/− mice regained normal frequency discrimination, indicating a restoration of higher‐order auditory processing, up to 100 days post‐treatment.

These findings provide the first proof‐of‐principle that peripheral gene therapy can restore OHC function, cochlear amplification and central auditory perception in a DFNB16 model.

Dual AAV‐mediated gene delivery restored peripheral hearing in a DFNB16 preclinical mouse model.The same treatment also restored central auditory processing.AAV‐mediated gene therapy represents a promising curative strategy for DFNB16.These results reinforce the translational potential for treating human genetic deafness.

Dual AAV‐mediated gene delivery restored peripheral hearing in a DFNB16 preclinical mouse model.

The same treatment also restored central auditory processing.

AAV‐mediated gene therapy represents a promising curative strategy for DFNB16.

These results reinforce the translational potential for treating human genetic deafness.

DFNB16 is among the most prevalent forms of congenital deafness, caused by mutations in the Stereocilin gene. Although no treatment currently exists, gene therapy represents a promising curative approach. Here, we demonstrate that AAV‐mediated gene delivery in a DFNB16 mouse model restored both peripheral hearing and central auditory processing.