Researchers are testing an approach that involves replacing a mutated gene in the inner ears of children with severe hearing loss.
Two companies have launched clinical trials to see if they can restore hearing to children with a rare type of genetic deafness.
Akouos and Decibel Therapeutics, both based in Boston, are testing experimental therapies in children with severe hearing loss due to variations in a gene called OTOF. A third firm, Sensorion, in France, is gearing up to begin a similar trial in Europe. The companies are all aiming to deliver functioning copies of this gene to the inner ear. The approach is known as gene therapy. It’s designed to be given once and have lasting effects.
Genetic causes account for 50 to 60 percent of hearing loss in babies, and up to 8 percent of those cases are due to mutations in the OTOF gene. About 20,000 people across the United States, United Kingdom, Germany, France, Spain, and Italy are thought to be affected. People with alterations in this gene lack a key protein needed for hearing called otoferlin.
“We want to restore physiological hearing on all frequencies so these babies can hear early on, they can learn to speak, and they can interact with their environment with having the full spectrum and range of sound,” says Vassili Valayannopoulos, vice president and head of clinical research and development at Decibel Therapeutics.
Hearing is a complex process that involves thousands of sensory hair cells in the inner ear. When sound waves hit these cells, they vibrate and release a chemical messenger called a neurotransmitter. This chemical initiates an electrical signal in the auditory nerve that’s sent to the part of the brain that interprets sound. Otoferlin is like a switch that controls the release of this neurotransmitter, Valayannopoulos says.
“If this switch is broken, the sound hits these cells and the chemical is not released,” he says. “If you fix the switch, you restore this whole circuit.” The companies think that delivering working copies of OTOF to hair cells will prompt the production of the otoferlin protein and enable hearing.
Getting the genes to these cells requires making a small incision behind the ear and infusing the therapy into the cochlea, the spiral-shaped part of the inner ear. This is also where cochlear implants are placed. These devices stimulate the auditory nerve using electrodes. They allow some people to receive and process sounds, but do not provide natural hearing. The sound can be robotic or tinny, and the devices are not good at conveying the complexity of music or distinguishing speech from background noise.
“Gene therapy is attractive because it might lead to a more normal ability to understand speech and appreciate things like music and more complex soundscapes,” says Manohar Bance, an ear surgeon at Cambridge University Hospitals in the UK and chief investigator for the Decibel trial.
Akouos CEO Manny Simons wrote, “At the individual level, hearing loss can have a profound impact on cognitive development and psychiatric health.” (The company did not make a representative available for an interview.)
Because cochlear implants can damage the delicate hair cells of the inner ear, the companies running the current trials are seeking children who don’t have these devices. Decibel Therapeutics is enrolling up to 22 children in the US, UK, and Spain and will follow them for five years. Akouos plans to include up to 14 participants at hospitals in the US and Taiwan, and that study will last for two years. Representatives from both companies declined to say whether any participants have been given the gene therapy yet.
Gene therapy has worked in experiments with deaf mice that lack the otoferlin protein. Scientists are able to confirm hearing recovery by placing electrodes on the animals’ heads and playing sounds into their ears. The electrodes measure whether the brain is responding to the sounds. The same kind of test will be done on trial participants to learn whether the gene therapy allows them to hear.
This isn’t the first time researchers have attempted to use gene therapy for hearing loss. The Swiss pharmaceutical company Novartis launched a trial in 2014 for adults with severe hearing loss due to the damage of their sensory hair cells. Over time, aging and exposure to loud noises can damage these cells, and once they die, the body can’t replace them. They don’t regrow, like skin cells or the ones that line the gut.
The Novartis trial aimed to deliver a gene to change the supporting cells around the damaged ones into new hair cells. But the company suspended the study in 2019 when researchers found that participants had no meaningful increase in hearing.
“It turns out that regrowing hair cells is tough,” says Lawrence Lustig, a hearing loss expert at Columbia University who was an investigator on the Novartis trial. Since many of the participants were older and already had profound hearing loss, Lustig says they probably had few supporting cells that could be turned into hair cells. (Lustig is also one of the investigators for the Decibel trial.)
While the Novartis trial was happening, Lustig and others were working on ways to restore hearing in genetic forms of hearing loss. In 2019, Lustig and his collaborators showed that OTOF gene therapy could be used to restore hearing in mice lacking the otoferlin protein. A separate group in Germany published similar findings in 2021, showing that the results could be reproduced.
“For any gene therapy to work, your target cell has to be alive and not dead,” says Jeffrey Holt, a professor of otolaryngology and neurology at Harvard Medical School, who studies gene therapy for deafness but isn’t involved with the current trials. Many genetic mutations linked to deafness cause the hair cells in the inner ear to die, but OTOF mutations leave these cells intact. “That bodes well for this strategy,” he says.
While the trials are open to participants up to age 18, Holt says it may be best to give the gene therapy earlier in life. “The auditory system goes through a maturation process, and if you deliver this at a stage after that system has already matured in the absence of sound, we don’t really know how it’s going to handle that new input of information,” he says. This is why adults have a harder time learning a new language than children do. Children’s brains are highly plastic—meaning they can easily form new connections and learn new things.
Doctors recommend cochlear implant surgery before age 3 so that children can learn sounds when their language skills are developing, although older people can still benefit from the devices.
While the current trials are for a rare type of deafness, researchers with the companies think other genetic mutations that cause deafness could be addressed with gene therapy.
But not everyone thinks deafness needs medical interventions. Jaipreet Virdi, a historian of medicine, technology, and disability at the University of Delaware who is deaf, says that gene therapy is an extension of the debate that began in the 1990s over cochlear implants, which some Deaf people view as a threat to the Deaf community. They argue that implanting Deaf children before they have a chance to acquire language denies them autonomy and access to Deaf culture. “Erasure before choice is presented—to an individual, not their parents—is problematic,” Virdi says.
Wyatte Hall, a psychologist and public health researcher at the University of Rochester who studies language acquisition’s role in deaf people’s health and is deaf himself, says hearing parents with a child who is deaf may see medical interventions or technology as a way to help their child fit into the world as they know it. But Hall says Deaf people contribute to the richness of society. “As long as deaf people has been around on the earth, people have always been trying to fix us,” he says. “The fact that we’re still here suggests that there is still some kind of inherent evolutionary value in us, and our differences contribute to the world we all live in.”
He’s not necessarily opposed to cochlear implants and gene therapy, but he doesn’t think parents should limit access to sign language in favor of a medical-only approach. When working with families of Deaf children, he emphasizes a “both” approach—using technology and sign language. “If gene therapy or technology doesn’t work,” Hall says, “sign language is there as a developmental safeguard.”