In the largest and longest trial of its kind, 90% of people who received an experimental gene therapy for congenital hearing loss showed significant improvement in their hearing over the next few years.
The trial involved 42 participants and was conducted at eight centers in China, primarily children, but also three adults, two of whom responded well to treatment. All participants initially had complete hearing loss. Although children’s hearing improved more than adults, the trial results still suggest that adults may also benefit from treatment. The study was published in the journal Nature on Wednesday (April 22).
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These hearing improvements appear to progress over time, then level off and stabilize after about a year, Chen said. To date, 10 of the trial participants have been monitored for at least two years, and all of them can hear conversations at normal volume (about 50 to 60 decibels), and five can hear whispers, he said.
Four of the 42 patients did not see any improvement in their hearing after treatment, but the reason is still unclear. But given that the treatment accelerated improvement in most patients and that improvement lasted for a long time, Chen is excited about next steps.
“I really expect that in the next few years, we’ll see a lot of different trials for different types of inherited hearing loss,” said Chen, co-founder of Salbritas Therapeutics, a company that develops regenerative therapies for sensory disorders. “We are only at the beginning. We are at a turning point in history.”
inner ear repair
Approximately 1.5 in 1,000 children are born with hearing loss, although the exact prevalence varies by country. Up to 8% of these congenital hearing losses are caused by various loss-of-function mutations in the OTOF gene, which carries instructions for a protein called otoferlin.
This protein is important for the inner hair cells of the ear, which convert vibrations into signals that the brain can interpret. If a person has two mutated copies of the OTOF gene (one from each parent), they will have severe to profound hearing loss. People with severe hearing loss cannot hear speech at normal volumes, but they can hear some loud sounds. People with severe hearing loss cannot hear speech at any volume and can only hear very loud sounds. (According to the World Health Organization, most deaf people have profound hearing loss, meaning they have little or no hearing ability.)
Therefore, people with OTOF-related hearing loss often have their language development severely affected unless they receive a cochlear implant at an early age. While cochlear implants are very effective in improving hearing, “they have the limitation that they sound very different because they are mechanical,” Chen said. He pointed out that a person’s voice can sometimes sound a little like Donald Duck’s voice, and it’s very difficult to recognize the nuances in music. Also, like any device, implants wear out and require maintenance.
In contrast, the new gene therapy would likely be a one-time treatment that would correct the defect in the OTOF gene, the underlying problem that causes hearing loss. This therapy uses a harmless virus as a delivery vehicle to distribute a working copy of OTOF to the inner ear and restore hair cell function.
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In a previous trial of 11 children, the therapy was safe and effective, with most children seeing significant improvements in hearing. However, these trials lasted only a few months, raising questions about how long the improvements would last and whether side effects would appear in the future. Trial participants also wondered whether the treatment would be effective in older patients.
“There are three main issues: duration, safety, and patient volume,” Chen said. “The current study addresses exactly those questions.”
The new trial involved 39 children and teens ranging from 9 months to 18 years old and three adults in their 20s and 30s. Most people received gene therapy in only one ear because most had a current or previous cochlear implant in the other ear. Six participants received bilateral treatment.
None of the patients had serious side effects, but some experienced a temporary increase or decrease in certain types of immune cells. A few people had mild dizziness, and another had inflammation in the inner ear.
Of the 38 participants who responded to treatment, most hearing began to improve within a few weeks and continued to improve over time. The team has two years of data on 15 of the treated ears, 100% of which can detect speech sounds and 60% of which can detect whispers.
In general, participants under 18 years of age showed greater improvement than adults. Interestingly, one factor that appeared to be related to the degree of hearing recovery was the status of the participants’ outer hair cells, which was different from the inner hair cells. These cells act as amplifiers, increasing the movement of the eardrum in response to sound, Chen explained. In people with long-term hearing loss, these cells may become less functional, which could affect how much hearing can be restored with treatment, he suggested. However, this idea requires further research.
Participants whose hearing improved also improved their speech recognition. Additionally, by being able to hear audio better, participants were able to vocalize themselves better, with some learning to speak for the first time. A notable example was an 11-year-old girl with no history of cochlear implant use.
After treatment, “she managed to develop rudimentary conversational skills and was able to say simple words,” Chen said. “We want to know what else we can do to help her as she progresses further into her rehabilitation.”
next step
The research team is currently investigating whether it is possible to give patients multiple doses of this treatment and whether this would increase the effectiveness of the treatment. Future clinical trials may run longer than this one to see how long the improvements last, and may investigate why some patients don’t respond to treatment, Chen said.
Early tests suggest that this gene therapy and others like it may be better than cochlear implants in some ways, such as improving music recognition and speech detection in noisy environments. However, “I think implants will continue to be a major treatment option for a long time to come,” Chen said, noting that some patients may not be good candidates for gene therapy.
If gene therapy were approved, it would be an option for patients and their caregivers to consider, in part because it would probably not be possible to receive gene therapy in an ear that previously had a cochlear implant, he said. That’s because the device does some physical damage to inner ear cells, he said, but less damaging surgical techniques have now been developed.
Anecdotally, Chen added, children with a cochlear implant in one ear and treatment in the other tend to prefer to turn off the implant once their hearing improves. “In many cases, they just don’t put the cochlea on, they don’t want to put the cochlea on. They just leave the other ear that was treated with gene therapy,” he says.
This experimental treatment will now be tested in further trials and continues through China’s drug approval process. Chen hopes it will be approved in the United States someday. That would likely require additional testing in the U.S., he noted, since the Food and Drug Administration often requires additional data before approving treatments approved in other countries.
Meanwhile, Chen predicts that a treatment developed by Regeneron Pharmaceuticals could become the first gene therapy for hearing loss to be approved by the FDA. Regeneron has announced its intention to apply for approval in 2025, and Chen said a decision is expected within a year, although the exact timing is unclear.
“It’s going to be a big deal for the sector,” he said.
This article is for informational purposes only and does not provide medical advice.
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