An experimental gene therapy for a rare form of genetic deafness has successfully restored hearing in children and adults, with improvements lasting for at least 2.5 years, according to a study published April 22 in Nature.

The study, co-led by Harvard Medical School investigators at Massachusetts Eye and Ear and researchers at the Eye & ENT Hospital of Fudan University in China, corrected mutations in the OTOF gene, one of about 200 genes whose mutations are known to cause deafness from birth.

Patients 18 years old and younger saw the strongest gains in hearing and ability to recognize speech. Adults receiving the therapy also saw improvements, though the effect was smaller.

Overall, 90 percent of recipients saw their hearing improve, with half reaching normal levels by the study’s end at 2.5 years.

“How well it worked is really amazing,” said Zheng-Yi Chen, co-senior author of the paper and HMS associate professor of otolaryngology head and neck surgery at Mass Eye and Ear. “After two and a half years, more than half of them reached a normal level. They can hear a whisper. At that level, it’s better than mine.”

Worldwide, about 430 million people are affected by hearing loss serious enough to require rehabilitation, including 34 million children, according to the World Health Organization.

Sixty percent of deafness in newborns has genetic causes, with mutation in the OTOF gene responsible for between 2 percent and 8 percent of cases. Babies with the OTOF mutation are completely deaf at birth, which affects speech acquisition and can hinder cognitive development unless children are given a cochlear implant at a young age.

At the time the results were published, there were no drugs approved to treat OTOF mutations or any other form of congenital deafness.

The next day, on April 23, the FDA announced approval of an OTOF gene therapy from a different team. Boston Children’s Hospital is one of the sites participating in clinical trials of that therapy, designed for children and developed by Regeneron, as well as other gene therapies for hearing loss. A. Eliot Shearer, HMS associate professor of otolaryngology head and neck surgery at Boston Children’s, is a principal investigator on those trials.

“The success of OTOF gene therapy marks a paradigm shift in treating hearing loss,” said Yilai Shu, co-senior author with Chen on the Nature study, a professor at the Eye & ENT Hospital of Fudan University, and a former HMS postdoctoral fellow in Chen’s lab.

The trials provide proof that personalized gene therapy approaches can be developed for congenital deafness caused by different gene mutations, he said.

Though the OTOF gene mutation is responsible for a relatively small proportion of inherited deafness, Chen, Shu, and colleagues said the platform developed in their work can be modified to correct other genes implicated in deafness. They are already adapting it to treat deafness due to mutations in the GJB2 gene, the most common cause of genetic hearing loss.

An expanded trial

This study, which enrolled 42 participants ranging in age from 9 months to 32 years across eight sites in China, is the largest clinical trial of a gene therapy for inherited hearing loss to date and the longest follow-up reported so far.

The work builds on research published in 2024 that piloted the therapy among a small number of children. Those trials resulted in improvements rapid enough to surprise researchers and thrill parents, who saw their children go from completely deaf to responding to voices within just weeks.

“As follow-up time goes on, these children continue to bring us ongoing surprises,” said Shu. “They progress from responding to sounds, to imitating speech, to speaking in short sentences, and then to reciting poems and even singing. They always fill us with joy and encouragement.”

This most recent trial included three adults, two of whom showed hearing recovery, though less than what was seen in younger participants.

“It is very encouraging to see meaningful improvements in some adult patients,” Chen said. “It suggests there may be more flexibility in the human auditory system than we expected.”

The therapy targets a condition called DFNB9, caused by the OTOF mutation. OTOF encodes the otoferlin protein, active in a snail-shaped structure in the inner ear called the cochlea. There, sound waves are translated into electric signals that, with the help of otoferlin, are conveyed to nerves and the brain. Without properly functioning otoferlin, electric pulses generated in the ear never make it to the brain.

Researchers said DFNB9 was an attractive target for therapy because it is caused by a mutation in a single gene, simplifying the repair. In addition, though the mutation disrupts signaling between the ear and the brain, cochlear cells are undamaged and ready to perform once the connection is restored.

To treat the condition, the team injects a neutralized virus carrying a normal copy of OTOF into the fluid of the inner ear. The virus travels to the cochlea and expresses the OTOF gene in cochlear hair cells. That jump-starts production of normal otoferlin and restores the connection between the cochlea and nerves leading to the brain.

Promising results

Among trial participants who responded to treatment, some reported hearing sound in as little as two weeks. Improvement was rapid over the first six weeks, plateauing around 26 weeks, with hearing recovery maintained through 2.5 years.

Though half achieved normal levels of hearing by that point, many of those who didn’t nonetheless saw significant improvement, Chen said, though hearing aids or other assistance might be required for day-to-day functioning.

That the effect endured so long is important, Chen said, because early lab experiments in mice saw the effect fade over time. Another key finding, he said, was that the treatment is safe, causing no serious adverse events among participants and no dose-related toxicity among groups that received three different doses.

While research will continue, Chen said that the team, whose work is supported by the Chinese and Shanghai governments and Fudan University, is beginning to explore regulatory requirements for the treatment to be approved for use in the clinic. That effort will begin in China. The hope is that expansion to other countries, including the United States, will follow.

The scientists will continue to follow study participants through five years, said Chen, who also holds the Ines and Fredrick Yeatts Chair in Otolaryngology at Mass Eye and Ear. Several outstanding questions remain, including why 10 percent of participants didn’t respond to treatment and why adults didn’t respond as well as youth.

“We have been working in this field for decades and there was nothing, nothing, nothing,” Chen said. “Then the treatment came out, worked really well, and now more trials are coming. We’re looking forward to what the future will bring for patients.”

Article originally appeared on Harvard Medical School