Gene Therapy Boosts Auditory Cortex Activation in Children with OTOF-Related Hearing Loss

Hearing is a critical sense for children to explore the world and develop. However, some children may be born with profound hearing loss due to genetic factors. One such condition is autosomal recessive hearing loss type 9 — that is, DFNB9 — caused by mutations in the OTOF (otoferlin) gene. DFNB9 is characterized by bilateral, profound hearing loss that usually begins congenitally or in the prelingual period. Although 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 cause of the disease.

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

Details of the Study: Who Took Part, and What Was Done?

The study included ten children (five girls, five boys) with confirmed biallelic (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 the children's brains before treatment (T0) and at specific periods after treatment (T1: weeks 4–6, T2: week 13, and T3: week 26):

• Functional Near-Infrared Spectroscopy (fNIRS) and Electroencephalography (EEG): With these methods, changes in the children's neural responses to sound and in their brain maps were observed.
• Griffiths Mental Development Scales (GMDS) and the Wechsler Intelligence Scale for Children (WISC-IV): With these standard tests, the children's levels of mental development were assessed.

Promising Findings: Reactivation in the Auditory Cortex and Advances in Development

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

1. Increased Activation in the Auditory Cortex: While listening to music or speech, the treated children showed a marked increase in activation — as early as week 4 after surgery — in the Sylvian parieto-temporal area (SPT) and part of the anterior temporal lobe (ATL), regions important for auditory functions.
2. Positive Changes in Brain Rhythms: In resting-state EEG measurements, a significant increase in power was found particularly in the beta band (13–30 Hz) after gene therapy, reaching its highest level at week 13 (T2).
3. Improvement in Auditory Discrimination Ability: Mismatch Negativity (MMN) responses, which indicate the ability to distinguish stimuli with different acoustic properties, were clearly identified as early as 4 weeks after treatment. By week 13, all patients showed MMN waves.
4. Advances in Mental Development: Significant increases were observed in the children's total developmental quotient and intelligence quotient scores at weeks 13 (T2) and 26 (T3) compared with before treatment.
5. Correlational Findings: In patients who received bilateral gene therapy, a positive correlation was found between GMDS hearing and speech scores and EEG beta-band power and ERP amplitudes.

What Do These Findings Mean?

The results of this groundbreaking study provide preliminary evidence that gene therapy can lead to neural activity resembling a normal auditory pattern in children with congenital hearing loss. The researchers emphasize that the first three months after surgery in particular may be a critical stage for rapid cortical development. These findings once again demonstrate the importance of early hearing screening and early intervention.

Limitations and Future Perspectives

Because DFNB9 is a rare condition, the study's sample size was noted to be small. It would be beneficial for future research to include comparisons with patients receiving cochlear implants, to have larger sample sizes, and to provide longer-term follow-up data.

Conclusion

This research is an important step in understanding the potential of gene therapy in hearing loss due to OTOF gene mutations. The preliminary evidence presented gives hope that this innovative approach may not only improve auditory functions but also support children's overall mental development.