A pivotal study published in Nature Medicine marks a major milestone in the treatment of congenital deafness caused by mutations in the OTOF gene. In a recent single-arm trial, a team of researchers successfully restored bilateral hearing in five pediatric patients using a novel adeno-associated virus (AAV)-based gene therapy. The study, which builds on previous unilateral trials, demonstrates the potential of precision medicine to change lives—and transform clinical approaches to hereditary sensory disorders.

The therapy targets autosomal recessive deafness 9 (DFNB9), a condition caused by biallelic mutations in OTOF, the gene responsible for encoding otoferlin—a key protein in synaptic transmission between sensory hair cells and the auditory nerve. Individuals with this mutation are typically born profoundly deaf, with pure-tone average thresholds near 100–110 dB. Traditional hearing aids or cochlear implants offer limited results in such cases.

Using an AAV1 vector to deliver a functional copy of the OTOF gene directly to the cochlea, researchers treated both ears of five children aged between 1 and 5 years. Within 13 to 26 weeks, all five showed substantial hearing recovery. Audiometric results revealed improvements in auditory thresholds, speech recognition in quiet environments, and even early indications of spatial hearing and music perception in some subjects.

“This study shows that bilateral delivery of AAV-hOTOF can restore clinically meaningful hearing in children with DFNB9, which was previously considered untreatable,” said lead researcher Dr. Yilai Shu. “It’s a strong proof-of-concept for the therapeutic use of gene therapy in sensory systems.”

The trial also reported a favorable safety profile, with no dose-limiting toxicity or serious adverse events. All 36 reported adverse events were mild to moderate in intensity, making the treatment promising not only for efficacy but also for long-term tolerability.

Importantly, these findings were followed by an expanded cohort study involving 10 additional participants aged 1.5 to 23.9 years. Published in Nature Medicine in July 2025, this phase further confirmed the effectiveness of the therapy, with younger patients (especially those aged 5–8) demonstrating the most dramatic gains—sometimes approaching normal hearing levels within a month. Older participants also showed significant improvements, highlighting the therapy’s broad therapeutic window.

For molecular biologists and researchers in gene therapy, this represents a powerful example of bench-to-bedside translation. It underscores the value of viral vector design, delivery strategies, and target specificity in human gene therapy applications. For healthcare professionals in diagnostics and pediatric medicine, it opens the door to new early-intervention strategies for hereditary hearing loss.

Source:

Wang W, Chai R, Shu Y, et al. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nature Medicine. 2024; https://doi.org/10.1038/s41591-024-03023-5