Gene therapy improves hearing in 90% of patients with inherited deafness in largest trial of its kind

In the largest and longest trial of its kind, 90% of people who received an experimental gene therapy for congenital deafness showed marked improvements in their hearing over the next several years.

The trial, which involved 42 people and was conducted across eight sites in China, mostly involved children but also included three adults, two of whom responded well to the therapy. All of the participants started out with complete hearing loss. Although the children's hearing improved more than the adults' did, the trial results still suggest adults could benefit from the treatment. The trial was described Wednesday (April 22) in the journal Nature.

"In some patients, their recovery is so good, they reach completely normal [hearing]," said study co-author Zheng-Yi Chen, an associate scientist at the Eaton-Peabody Laboratories at Mass Eye and Ear and an associate professor at Harvard Medical School. "It would be like a completely blind patient having 20-20 vision back," Chen told Live Science.

These improvements in hearing appear to progress over time and then plateau and stabilize by around the one-year mark, Chen said. By now, 10 of the trial participants have been monitored for at least two years, and of those, all can hear normal-volume conversation — around 50 to 60 decibels — and five can hear whispers, he said.

Four of the 42 patients didn't show any improvements in their hearing after the treatment, and it's still unclear why. But given the therapy spurred improvement in most patients and that the improvement lasted a long time, Chen is excited for the next steps.

"I really foresee, in the next few years, that there'll be many different trials coming up for different types of genetic hearing loss," said Chen, who is a co-founder of Salubritas Therapeutics, a company developing regenerative therapies for sensory disorders. "We're just the beginning; we're really at a turning point in history."

Repairing the inner ear

About 1.5 in 1,000 children are born with hearing loss, though the exact prevalence varies by country. Up to 8% of these congenital hearing loss cases are caused by various loss-of-function mutations in the OTOF gene, which carries instructions for a protein called otoferlin.

This protein is critical to the ear's inner hair cells, which translate vibrations into signals that the brain can interpret. If a person carries two mutant copies of the OTOF gene — one from each parent — they'll have severe to profound hearing loss. People with severe hearing loss cannot hear normal-volume speech but can hear some loud sounds; those with profound hearing loss cannot hear speech spoken at any volume and can hear only very loud sounds, if any. (Deaf people mostly have profound hearing loss, which implies very little or no hearing, according to the World Health Organization.)

As such, speech development is often severely impacted in people with OTOF-related deafness, unless they're fitted with a cochlear implant at a young age. Cochlear implants are very effective at improving hearing, Chen said, "but it comes with a limitation in that it's mechanical, so the sound is very different." People's voices can sound a bit like Donald Duck's, and the nuances of music are very difficult to perceive, he noted. And as with any device, the implants experience wear and tear and require maintenance.

By contrast, the new gene therapy would likely be a one-and-done treatment and correct the underlying issue causing deafness: the defective OTOF gene. Using harmless viruses as delivery vehicles, the therapy distributes working copies of OTOF into the inner ear, thus restoring the hair cells' function.

In previous trials with 11 children, the therapy was both safe and effective, with most of the kids showing robust improvements in their hearing. However, those trials were only months long, raising questions about how long the improvements last and whether any side effects could show up down the line. The trial runners also wondered if the treatment could work for older patients.

"These are the three main questions: the duration, the safety and the patient population," Chen said. "The current study really addresses those."

The new trial included 39 children and teens, ages 9 months to 18 years, and three adults in their 20s and 30s. Most got the gene therapy in just one ear, as many currently or previously had a cochlear implant in the other ear. Six participants got the treatment in both ears.

No serious side effects were seen in any of the patients, although some experienced temporary upticks or declines in specific types of immune cells. A handful had mild vertigo, and one had some inflammation of the inner ear.

For most of the 38 participants who responded to the treatment, their hearing started to improve within weeks and then continued to increase over time. The team has two years of data on 15 of the treated ears, 100% of which can detect conversational speech and 60% can detect whispers.

Generally, participants under 18 had greater improvement than adults. Interestingly, one factor that seemed tied to the degree of hearing recovery was the condition of the participants' outer hair cells, which are different from inner hair cells. These cells act as amplifiers, increasing the motion of the eardrum in response to sound, Chen explained. In people who have had hearing loss for a long time, these cells' function may degrade, and that may affect how much hearing they can regain through the therapy, he suggested. But this idea warrants more study.

The participants whose hearing improved also gained better speech perception. In turn, being able to better hear speech enabled some participants to better produce speech themselves, with some learning to speak for the first time. The standout example was an 11-year-old girl with no history of using cochlear implants.

Following therapy, "she managed to develop some rudimentary capacity to speak, and she can say simple words," Chen said. "We want to know, with more rehabilitation down the road, what else can we do to help her."

Next steps

The team is now exploring whether it's feasible to give patients multiple doses of the therapy and if that boosts outcomes. Future trials could run even longer than this one, to see how well the improvements hold, and they could investigate why some patients don't respond to the treatment, Chen said.

Early tests hint that this gene therapy or others like it could be superior to cochlear implants in some respects — for instance, by enabling better music perception and speech detection in noisy environments. However, "I think the implant will remain the major treatment option for a long time to come," Chen noted, and some patients may not be good candidates for gene therapy.

Once a gene therapy is approved, this will become a choice for patients and their caregivers to weigh, in part because it's likely not possible to get gene therapy on an ear that previously had a cochlear implant installed, he said. That's because the installation physically damages the inner ear cells to some degree, although less-damaging surgical techniques are now being developed, he said.

Anecdotally, the children with one cochlear implant who had their second ear treated tended to prefer switching off their implants once their hearing improved, Chen added. "Often, they just don't wear the cochlear; they don't want to wear the cochlear. They just leave the other ear that was treated with gene therapy," he said.

This experimental therapy will now be tested in further trials and continue to move through China's drug approval process. Chen hopes it will someday be approved in the U.S., as well. That would likely require additional trials in the United States, as the Food and Drug Administration (FDA) often asks for extra data before approving therapies that have been cleared in other countries, he noted.

Meanwhile, Chen anticipates that a treatment made by Regeneron Pharmaceuticals could be the first gene therapy for deafness to earn approval from the FDA. Regeneron announced its intention to file for approval in 2025 and a decision is expected within a year, although the exact timing is unknown, Chen said.

"That'll be a major event for the field," he said.

Editor's note: Since this article was published, Regeneron's gene therapy for OTOF-related hearing loss has been approved by the FDA.