Four decades have passed since cochlear implants gave infants born deaf the ability to hear. Now, gene therapy promises to restore natural hearing for those born with a rare form of deafness, and the discovery could lead to similar treatments for more common types of hearing loss.

The treatment, which targets a mutation in the otoferlin (OTOF) gene, has been effective in most of the tested children. The rare mutation causes hearing loss in an estimated 20-50 babies born in the US each year.

“You hear the stories about parents who, for the first time, have to be quiet after they put their child to bed at night: That’s a ritual that a lot of people take for granted,” said Jonathon Whitton, PhD, global head of auditory programs for Regeneron in Tarrytown, New York, that is developing its treatment, DB-OTO.

The results of the first clinical trials of the approach were published in 2022, and since then, five groups of researchers — including from pharmaceutical companies and academic labs in the US, China, and France — have worked on drugs targeting the gene. Two newcomers to the space — Chinese manufacturers — registered trials in 2023 and 2024 that have not yet started.

Regeneron plans to file for FDA approval of its treatment by the end of the year. If it succeeds, the US would be the first country to approve a gene therapy for hearing loss, said Zheng-Yi Chen, DPhil, an associate scientist at Massachusetts Eye and Ear in Boston and a clinical trial collaborator with Eye & ENT Hospital of Fudan University in Shanghai, China.

“This is the first time hearing loss has actually been reversed by any intervention outside of devices,” Chen said. “It’s just truly remarkable.”

Deafness linked to OTOF mutations is a type of auditory neuropathy, a spectrum of disorders in which the inner ear can detect sound but struggles sending that information to the brain.

Many forms of deafness involve the death of hair cells in the inner ear, which help transmit sound to the brain. But with OTOF-related deafness, the hair cells have not degenerated, said Lawrence R. Lustig, MD, chair of the Department of Otolaryngology-Head and Neck Surgery at Columbia University in New York City and an investigator of a clinical trial run by Regeneron.

“The inner ear is normal and waiting for this molecular switch to be turned back on, and gene therapy allows us to do that,” Lustig said.

The FDA has already selected Regeneron’s DB-OTO for an expedited approval process for products that fulfill “a major national priority,” ensuring a decision on its application within 2 months of filing.

Soon after seeing positive results from clinical trials of DB-OTO starting in 2023, the company fast-tracked development and began working “very collaboratively with regulators to understand what that path should look like,” Whitton said.

In the first trial of the treatment, 3 of 12 children with profound hearing loss “started having normal hearing sensitivity,” Whitton said. Of the remaining, six children improved to moderate hearing range, one had no improvement, and two had some improvements after 24 weeks.

Regeneron was not the first group to demonstrate results of gene therapy for OTOF-related hearing loss. In December 2022, a child in China became the first-ever recipient of such treatment during a clinical trial led by Fudan University and Massachusetts Eye and Ear. In October 2023, Eli Lilly-owned Akouos gave its gene therapy to a child in the US for the first time. Other trials led by the Chinese firm Otovia Therapeutics and French biotech company Sensorion have also reported positive preliminary results in 2025.

“You put all the data together, I think the pattern becomes very clear. After treatment, it takes them about a month to get there. It’s very, very rapid,” said Fan-Gang Zeng, PhD, director of the Center for Hearing Research in the School of Medicine at the University of California, Irvine, who is participating in Otovia’s research.

‘The Perfect Model’

At least 150 genes are linked to hearing loss. The OTOF gene, however, is different because of its “unusually high safety profile,” said Daniel I. Choo, MD, an otolaryngologist and surgeon at the University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center in Cincinnati.

With other gene therapies, the viral vector that delivers the treatment could leak from the target organ, turning on elsewhere in the body. But “this otoferlin gene is only turned on inside the cochlea, so even if you injected it through an IV and it ended up in your foot, there’s no way to turn it on down there,” Choo said.

For Chen, “the next critical question is, how many of those different types of deafness can still be treatable after birth? That’s one thing I constantly have to wonder about, that’s already keeping me up at night,” he said. “Otoferlin is one of the best examples, but it will be hard to match.”

Lustig said several groups of researchers are working on therapies for other more common forms of genetic deafness, including those caused by mutations in the GJB2 gene, which affect proteins needed for ear cell communication and survival. Those research efforts have yet to be made public, he said.

GJB2 abnormalities cause about 15%-20% of genetic deafness cases in the US and are among the most challenging to address. This genetic mutation involves a variety of cells throughout the inner ear that usually cause hair cell degeneration early in childhood, Lustig said.

Chen’s group is working on combining cell regeneration with gene therapy, aiming to first restore inner ear cells that have died or degenerated before applying gene treatment.

Decisions Facing Clinicians

Researchers do not know why about 10% of children with deafness who participated across all OTOF gene clinical trials did not respond to gene therapy.

Across the trials, participants on average started with 100 dB hearing level, defined as profound hearing loss. After 1 month of treatment, children’s hearing decreased to 50 dB, or moderate hearing loss, Zeng said. He is investigating why some children show no effects.

“I’m scratching my head,” Zeng said. “I’ve personally looked at data from the left and right ear, their gene mutation types, anything that allows us to predict” outcomes, and he has yet to find any clues.

Other challenges remain. The therapy is delivered inside a virus, which could later in life elicit an immune response if patients receive gene therapy in their other ear, said Alan G. Cheng, MD, a surgeon-scientist at the Stanford Ear Institute and Lucile Packard Children’s Hospital in California.

How long gene therapy lasts is another unknown, while cochlear implants are “supposed to last a lifetime,” Cheng said. “No one wants to have to update a gene every few years because they expire.”

Chen, who helped conduct the clinical trial in China that included the first child to receive the gene therapy, said hearing improvements have not waned for that patient. Patients typically show improvements for 3-6 months after treatment before plateauing, while some continue improving for up to 1 year.

The promising early results have sparked growing interest among families affected by hearing loss, and many patients have asked about the therapy since the first reports of successful treatment back in 2023, Cheng said. However, only a small subset of these patients has the OTOF mutation.

Cheng said he is surprised by the level of interest among caregivers, who he thought might hesitate to let their children be “test subjects” and undergo surgery for a fairly investigational drug.

“Families are very open to having a surgery to put a gene in, and some might actually choose this over a cochlear implant,” Cheng said.

Research on how the OTOF gene therapy compares with traditional cochlear implants may be catching the eye of some of those caregivers. An investigation published in JAMA Neurology in July compared 72 patients aged 1-18 years who were randomized to receive OTOF gene therapy, cochlear implants, or both treatments in opposite ears.

Compared to children with cochlear implants only, those treated with gene therapy performed better at speech detection in noisy settings and in music perception.

But choosing gene therapy involves risk. The optimal age to acquire language is between birth and age 3, with learning becoming significantly harder after age 7, said Choo, who is the site principal investigator for Eli Lily’s upcoming clinical trial at Cincinnati Children’s Hospital.

Children can still receive a cochlear implant if gene therapy does not work. But assessing whether the therapy works in a child can take up to 18 months, complicating the decision to choose between gene therapy or a cochlear implant.

A delay in hearing improvement may affect brain development. For a 2-year-old in their prime language learning window, “that ticking clock starts calculating in the back of your head,” Choo said.

“The cochlear implant is still the best standard of care right now,” Choo said. “We can tell parents, ‘this is what your kid will do in 3, 6, 9, 12 months post-implant.’ We don’t have those predictable outcomes yet for gene therapy, and for some kids, it doesn’t work at all.”

Sarah Amandolare is a freelance journalist living in New York City.