Gene Therapy Increases Auditory Cortex Activation and Supports Development in Children with Hearing Loss Due to OTOF Gene Mutation

Hearing is a critical sense for children to explore the world and for their development. However, some children are born with profound hearing loss due to genetic factors. One such condition is autosomal recessive hearing loss type 9, or DFNB9, caused by mutations in the OTOF (Otoferlin) gene. DFNB9 is typically characterized by congenital or pre-lingual, bilateral, profound hearing loss. While hearing aids and cochlear implants are currently the primary approaches for these individuals, in recent years, gene therapy has begun to show great potential as a treatment targeting the underlying cause of the disease.

One of the latest developments in this promising field is a study published in the journal Nature Human Behaviour (Zhang, J. et al., 2025), which examined the changes in the auditory cortex and cognitive development following gene therapy in children diagnosed with DFNB9. Researchers aimed to understand what happens in the brain during the transition from auditory deprivation to recovery in this unique patient group, using objective neuroimaging tools.

Study Details: Who Participated, What Was Done?

The study included ten children (five girls, five boys) with a confirmed diagnosis of biallelic (mutations in both genes) OTOF gene mutations. All children received gene therapy via an adeno-associated virus carrying the human OTOF transgene (AAV1-hOTOF).

Various methods were used to monitor changes in their brains and their development before treatment (T0) and at specific post-treatment intervals (T1: 4-6 weeks, T2: 13 weeks, and T3: 26 weeks):

• Functional Near-Infrared Spectroscopy (fNIRS) and Electroencephalography (EEG): These methods were used to observe changes in the children's neural responses to sound and in their brain maps.

• Griffiths Mental Development Scales (GMDS) and Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV): These standardized tests were used to assess the children's cognitive development levels.

  
  

Promising Findings: Revival in the Auditory Cortex and Developmental Advances

The study revealed remarkable improvements in the children following gene therapy:

• Increased Activation in the Auditory Cortex: As early as 4 weeks post-surgery, children who received the treatment showed a significant increase in activation in key brain regions associated with auditory functions, such as the Sylvian parieto-temporal area (SPT) and part of the anterior temporal lobe (ATL), when listening to music or speech. This indicates that their brains began to respond more strongly to auditory stimuli.

• Positive Changes in Brain Rhythms: In resting-state EEG measurements, a significant increase in beta band power (brain activity in the 13-30 Hz frequency range) was detected after gene therapy, reaching its peak at the 13th week (T2).

• Improvement in Auditory Discrimination: Researchers clearly identified Mismatch Negativity (MMN) responses—a key electrophysiological marker showing the brain's ability to distinguish stimuli with different acoustic properties—as early as 4 weeks post-treatment. By week 13, all patients exhibited MMN waves, especially in the frontal regions of the brain.

• Advances in Cognitive Development: Most importantly, significant increases were observed in the children's total developmental quotient and intelligence quotient scores at 13 (T2) and 26 (T3) weeks compared to the pre-treatment period. This suggests that gene therapy may positively affect not only hearing but also overall cognitive development.

• Correlational Findings: In patients who received bilateral gene therapy, a positive correlation was found between the GMDS hearing and speech scores and both the resting-state EEG beta band power and the ERP (event-related potential) amplitudes in response to both standard and deviant stimuli.

  
  

What Do These Findings Mean?

The results of this groundbreaking study provide preliminary evidence that gene therapy can lead to the formation of neural activity similar to a normal auditory pattern in children with congenital hearing loss. The researchers emphasize that the first three months post-surgery may be a critical phase for rapid cortical development. These findings once again underscore the importance of early hearing screening and early interventions like gene therapy.

Limitations and Future Perspectives

The researchers noted that the study's sample size was small due to the rarity of DFNB9. Future research would benefit from including comparisons with patients who have received cochlear implants, having larger sample sizes, and providing longer-term follow-up data. Additionally, it would be meaningful to determine the link between auditory recovery, its effect on speech development, and cortical reorganization (e.g., using functional MRI or brain region traceability analyses).

Conclusion

This research is a significant step in understanding the potential and effects of gene therapy for hearing loss caused by OTOF gene mutations. The preliminary evidence presented offers hope that this innovative treatment approach can not only improve auditory functions but also support the overall cognitive development of children. Such advancements in audiology and genetics hold the potential to enhance the quality of life for individuals with hearing loss in the future.

Reference: Zhang, J. et al. (2025). Preliminary evidence for enhanced auditory cortex activation and mental development after gene therapy in children with autosomal recessive deafness 9. Nat. Hum. Behav. https://doi.org/10.1038/s41562-025-02184-8