Gene Therapies Break Through Against Genetic Hearing Loss in Children

Earlier this year, Regeneron revealed that its gene therapy DB-OTOF elicited “dramatic” hearing improvement in two young children with profound genetic deafness, sparking excitement in a formerly barren field. And Regeneron is not alone.

Akouos, a subsidiary of Eli Lilly, is testing its AK-OTOF gene therapy in a study that is open to children of all ages, including newborns. Early results have been positive, with an 11-year-old patient going from profound deafness in both ears to mild-to-moderate hearing loss in the treated ear.

Meanwhile, researchers at Fudan University in Shanghai and Mass Eye and Ear have treated six children aged 3 to 11 years with genetic hearing loss, with their AAV1-hOTOF therapy. Five children regained hearing in both ears, could identify sounds and gained speech, and two could appreciate music, Genetic Engineering & Biotechnology Newsreported.

While each of these treatments is unique, all focus on reversing deficiencies in otoferlin, a protein that is expressed in the inner hair cells of the ear. The experimental gene therapies use a functioning copy of the gene that stimulates otoferlin production, often leading to near-normal hearing in one or both of the patients’ ears.

“These are very exciting treatments still in the experimental stage, but definitely something that I think could change how we treat patients with this specific genetic mutation,” said Nandini Govil, a pediatric otolaryngologist and director of the hearing loss program at Children’s Healthcare of Atlanta. Children’s is not directly involved in any of the clinical trials. “I think gene therapy is one of the things that will be a big game-changer,” she told BioSpace.

Positive Early Signs

Otoferlin is responsible for transmitting sound information to the auditory nerve. A genetic mutation present in 1% to 8% of all cases of genetic hearing loss prevents the ear from producing otoferlin, even if the rest of the ear develops normally.

“We thought that this is an opportunity where if we could develop a technology to deliver a functional copy of otoferlin to that cell type, these kids might go from no hearing to maybe really good hearing,” Jonathon Whitton, executive director and head of Regeneron’s Auditory Global Program, told BioSpace. “That, in our minds, was almost miraculous.”

So far, treating otoferlin deficiency has been one of the most successful gene therapy approaches, noted Zheng-Yi Chen, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear. “[These are patients] without any hearing or speech capacity restored to almost normal.”

The aforementioned clinical trials all involved different ways of injecting a functioning copy of the otoferlin gene into patients’ inner ears. Chen’s study in Shanghai and at Mass Eye and Ear used bilateral injections after previously testing the treatment in one ear. Meanwhile, Akouos and Regeneron are trialing their therapies in one ear in the interest of safety and understanding efficacy, Whitton explained.

In these trials, the children began to detect some sounds within a few weeks of treatment. Within months, all showed normal levels of hearing in the treated ears. The children could detect sounds, develop speech recognition and determine from which direction a sound was coming.

Six months after receiving Regeneron’s DB-OTO therapy, one child responded to speech sounds in normal hearing range. “This is astounding—we went from no responses at the maximum presentation levels, which are sounds as loud as a chainsaw, to responding to sounds as soft as whispers, in about six months,” Whitton said.

‘Therapeutic White Space’

Whitton and Chen agree that the field of hearing loss lacks drug or biological therapies. It took many years of work to move the gene therapies to clinical trials because there was no precedent, they said.

“The hearing field is what some people call a therapeutic white space—there’s no therapeutics there now,” Whitton said. “Everything you do is kind of doing it for the first time.”

The only approved treatments for hearing loss are hearing aids and cochlear implants, Chen said. Cochlear implants are beneficial, but the resulting sounds can be mechanical and lack nuance; for instance, a person may be unable to hear speech in a noisy environment or detect where sound is coming from.

Developing a method of delivering the gene therapy without precedent was a challenge. “There’s not a roadmap to do that already,” Whitton said. Whitton and colleagues worked with pediatric otolaryngologists and other surgeons to develop a method similar to cochlear implantation.

“The idea behind using this approach was the same clinicians [and] same surgeons who are normally involved in implantations are going to be same surgeons involved in delivering the next generation of therapies to these patients,” Whitton explained. “We want to use a procedure they are all comfortable with across all age [groups].”

Adults Could Benefit, Too

The currently running otoferlin gene therapy trials are first-in-human pediatric Phase I/II trials, geared toward treating children as early as possible in their lives, Whitton and Chen said. But adults with this genetic mutation could benefit from otoferlin gene therapy, too.

Gene therapy could restore an adult’s hearing to the same level as in children, Chen said. But to what extent can speech ability be restored? He noted there were doubts about whether an older child could gain speech after recovering hearing but cited an 11-year-old child from his clinical trial who gained some rudimentary speech after treatment and can say single words.

“This shows there is plasticity in the brain; maybe we can push the boundary further. Maybe people who are much older can benefit from some kind of speech recovery,” Chen said. “We don’t know to what extent we can do that, but that’s what we’re going to find out.”

Much work remains to be done. All of the ongoing trials are still enrolling patients, who will be followed for several years to monitor progress. It’s important to note that this is not a cure, Chen stressed.

“I won’t use the word ‘cured’ or say they’re completely cured,” he said. “They’re probably not too far from that, but we need to follow up for a longer time. This is really a historic moment and we’re just so thrilled for everyone involved.”