Cochlear gene therapy restores hearing and auditory processing in an atypical DFNB9 mouse model.

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Otolaryngology

Background:

• Autosomal recessive deafness 9 (DFNB9) is caused by otoferlin gene mutations, accounting for 2-8% of inherited deafness.
• Previous studies showed Adeno-associated virus (AAV) gene therapy restored hearing in a profound DFNB9 mouse model.
• The efficacy of AAV gene therapy across the full spectrum of DFNB9 severity and its impact on central auditory processing remained to be demonstrated.

Purpose of the Study:

• To create and characterize a novel mouse model for DFNB9 deafness.
• To evaluate the efficacy of AAV gene therapy in this model, focusing on hearing restoration and central auditory processing.
• To determine if late-stage gene therapy administration can restore auditory function.

Main Methods:

• Created a knock-in mouse model with the otoferlin E1799del mutation using homologous recombination.
• Administered AAV gene therapy to the cochlea of mice at various developmental stages.
• Conducted behavioral tests and auditory assessments up to 4 months post-treatment.

Main Results:

• The mouse model displayed otoferlin mislocalization, impaired synaptic transmission, and profound hearing loss.
• AAV gene therapy successfully normalized otoferlin distribution and synaptic function, restoring hearing.
• Objective behavioral testing demonstrated that cochlear gene therapy restored frequency discrimination, indicating recovery of central auditory processing, even with late treatment.

Conclusions:

• AAV gene therapy is effective for the entire spectrum of DFNB9 hearing loss.
• Restoration of central auditory processing is achievable even after profound deafness during the critical period.
• These findings support AAV gene therapy as a potential treatment for DFNB9 deafness.