Across two clinical trials, gene therapy restores hearing in children deaf since birth: #ASGCT24

BALTIMORE — Ten out of 11 children who were born deaf can now hear after receiving a gene therapy from a Shanghai biotech, according to new results shared Thursday.

The children who recovered their hearing are also showing improvements in their ability to speak. Some are saying the words “mama” and “baba” — Chinese for “mom” and “dad” — for the first time, said Yilai Shu of Fudan University in Shanghai, who led the early-stage clinical study.

At the American Society of Gene & Cell Therapy annual meeting Thursday morning, Shu also shared a video of a young child who received the hearing loss gene therapy dancing to music — something they were unable to do before.

“The families really get touched. They get tears,” Shu told Endpoints News before his presentation.

Four children have been part of the study for over a year and have shown durable improvements in their hearing, Shu said.

The treatment is one of several experimental gene therapies that have led to hearing restoration in children with a rare mutation who were born deaf. Researchers hope that the promising clinical results will spark more gene therapy research for additional forms of genetic deafness.

Shu’s study uses a therapy from Shanghai Refreshgene Therapeutics and was conducted in collaboration with Harvard Medical School.

On Wednesday, Columbia University’s otolaryngology department chair Lawrence Lustig shared that two children who had received a similar gene therapy developed by Regeneron had their hearing restored to the normal range by six months.

“Everybody was very — not pessimistic — but guarded about how things would go,” Lustig said. “If you can take somebody from a cochlear implant candidate into ‘OK, I can use a hearing aid,’ even for a period of time, that to me would have been a home run.”

“Nobody was expecting hearing in the normal range. Nobody,” he continued.

Eli Lilly is also developing a gene therapy for this rare form of deafness, reporting that the treatment restored hearing in the first child dosed in January.

Otoferlin

The children in the trials have a mutated version of a gene that encodes for otoferlin, an important protein in the ear’s sound-sensing hair cells for signaling to the brain. The genetic hearing impairment that these companies have developed therapies for is exceedingly rare. Lustig estimated there are 20 to 50 patients per year in the US born with the mutation.

The gene therapies, which are injected into the inner ear, use a viral vector known as an AAV to deliver a functional version of the gene.

One patient in the Shanghai Refreshgene trial did not regain hearing following the therapy. Shu said during his presentation that his team does not know why the patient did not benefit from gene therapy, but noted that they suspect the child may have neutralizing antibodies to the viral vector.

Six of the children in Shu’s study received the therapy in one ear, while five received it in both ears.

The five children who received the treatment in both ears have also experienced improvements in their ability to locate the source of a sound, which is harder to do with just one hearing ear. All in all, the Shanghai group has dosed 12 patients in total, Shu said.

Regeneron has dosed just the two patients so far, Lustig said. The company hopes to enroll a total of 22 patients and then use the study to apply for FDA approval late next year. Regeneron is also developing a second gene therapy for a more prevalent form of deafness called GJB2-related hearing loss.

Recruiting rare disease patients

Recruiting for the studies in the US is not easy, because there are so few patients with the otoferlin mutation. Lustig said his team is recruiting “as aggressively as possible” and “advertising like crazy.”

Even so, the disease is an ideal model for showing gene therapy can work for hearing loss. Unlike other forms of genetic hearing loss, the inner ear hair cells in these children are well-preserved. And when these hair cells die, they don’t regenerate.

“These kids really are quite rare, but there’s a reason why we’re all going after this model,” Lustig said. “Because you have very little degeneration, if any, if you can intervene early enough.

“No one’s going to make a gazillion dollars on otoferlin deafness with 20 to 50 people in the US. But what it is going to do is spark funding into the field and drive research and R&D into gene therapy for more common forms of genetic deafness,” he said.

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