OTOF Gene Therapy Successfully Improves Hearing in Clinical Trial
A gene therapy for OTOF-related deafness successfully restores hearing in patients, with improvements seen within weeks.
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A new study in Nature Medicine reports that gene therapy can restore partial hearing in individuals with a genetic form of deafness caused by mutations in the OTOF gene. The research, which involved scientists at Karolinska Institutet and several hospitals and universities in China, assessed the therapy’s safety and efficacy in ten patients aged between 1 and 24 years.
Treating otoferlin deficiency
All participants in the trial had congenital deafness or severe hearing impairment resulting from mutations in OTOF, the gene responsible for producing the protein otoferlin. Otoferlin is critical for transmitting sound signals from the inner ear to the brain. Its absence or malfunction disrupts auditory communication at the synapse between hair cells and auditory neurons.
Otoferlin
Otoferlin is a protein required for the proper function of synapses in the auditory system. It helps transmit electrical signals from inner ear hair cells to auditory nerves.
Adeno-associated virus (AAV)
AAV is a type of viral vector commonly used in gene therapy to deliver DNA to cells.
Researchers delivered a functional version of the OTOF gene to patients’ inner ears using a single injection of a synthetic adeno-associated virus (AAV). This was administered via the round window, a membrane at the base of the cochlea. The treatment was designed to prompt cells in the cochlea to produce otoferlin, restoring the flow of auditory signals.
Improvements seen within weeks
Most participants experienced hearing improvement within one month. By 6 months, all 10 had shown measurable gains. On average, the volume at which participants could detect sound improved from 106 decibels to 52 decibels. The most substantial benefits were seen in younger patients, particularly those aged between five and eight years.
“This is a huge step forward in the genetic treatment of deafness, one that can be life-changing for children and adults.”
Dr. Maoli Duan.
Although children appeared to benefit the most, the therapy also showed promising results in older individuals. A seven-year-old patient was able to engage in daily conversations with her mother four months after treatment, indicating that early intervention may lead to more robust outcomes.
Monitoring safety and long-term impact
No serious adverse events were recorded during the 6 –12 months of follow-up. The most common side effect was a temporary drop in neutrophil levels, a type of white blood cell. Researchers will continue to monitor patients to evaluate the long-term stability of the treatment's effects.
The study extends previous gene therapy work, which had mainly involved younger children, by including teenagers and adults. The researchers hope to expand gene therapy approaches to target other genetic causes of deafness, such as GJB2 and TMC1. These genes are more prevalent but may be more complex to treat.
Reference: Qi J, Zhang L, Lu L, et al. AAV gene therapy for autosomal recessive deafness 9: a single-arm trial. Nat Med. 2025. doi: 10.1038/s41591-025-03773-w
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