Gene Therapy Breakthrough Restores Hearing in Genetic Deafness: Long-Term Success in OTOF-Related Cases

A one-time gene therapy targeting the OTOF gene has restored hearing in most participants in a multicenter clinical trial for a rare form of inherited deafness, with benefits lasting up to 2.5 years, according to new findings published in Nature.

The therapy, developed to treat autosomal recessive deafness 9 (DFNB9) caused by mutations in the OTOF gene, improved hearing in 90% of the 12 patients who received the treatment. Three of those patients achieved normal hearing sensitivity, enabling natural acoustic hearing.

Patients aged 18 and younger showed the strongest gains in both hearing and speech recognition. While adults also experienced improvements, the effect was less pronounced in older participants.

According to Zheng-Yi Chen, DPhil, corresponding author of the study and associate scientist at Mass Eye and Ear, a member of the Mass General Brigham healthcare system, the results were remarkable. “It’s remarkable to see patients go from complete deafness to being able to hear,” Chen said. “For many patients, that also means the ability to develop and use speech.”

The OTOF gene provides instructions for making otoferlin, a protein essential for transmitting sound signals from the inner ear to the brain. Mutations in this gene prevent the protein from functioning, leading to profound deafness from birth. In this trial, a single administration of the gene therapy successfully delivered a functional copy of the OTOF gene to the inner ear.

The study represents the largest clinical trial of gene therapy for inherited hearing loss to date and the longest follow-up reported so far. Researchers noted that the findings reinforce earlier trials showing gene therapy can treat certain forms of genetic deafness and may guide future research and care strategies.

Worldwide, about 430 million people live with disabling hearing loss, including 34 million children, according to the World Health Organization. Genetic factors account for up to 60% of congenital hearing loss, with OTOF mutations responsible for an estimated 2% to 8% of those genetic cases.

Researchers said the platform used in this therapy could be adapted to target other genes linked to deafness. Work is already underway to modify the approach for mutations in the GJB2 gene, the most common cause of genetic hearing loss.