Gene Therapy Study Shows Restored Hearing and Speech in Children Born Deaf Who Were Treated in Both Ears

A novel gene therapy targeting a form of hereditary deafness has restored hearing in five children who were treated in both ears. The children were also able to perceive speech better and gained the ability to locate and determine the position of sounds. The study, the world’s first clinical trial of gene therapy in both ears (bilaterally), shows additional benefits over the results of the first phase of this study, published earlier this year, in which children were treated in one ear. The research was led by scientists at Mass Eye and Ear (a member of the Mass General Brigham health system) and Fudan University Eye & ENT Hospital in Shanghai. The results were published in Nature Medicine.

Benefits of Gene Therapy

“The results of these studies are amazing,” said study co-author Zheng-Yi Chen, DPhil, associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear. “We continue to see dramatic improvement in the hearing ability of the treated children, and the new study shows additional benefits of gene therapy when applied to both ears, including the ability to localize sound sources and improvements in speech recognition in noisy environments.”

The researchers noted that their team’s goal has always been to treat children in both ears to give them the ability to perceive sound in three dimensions—a skill that is important for communication and everyday tasks such as driving. “Restoring hearing in both ears of children born deaf can maximize the benefits of hearing restoration,” said the study’s senior author, Dr. Yilai Shu, PhD, professor and director of the Diagnosis and Treatment Center for Genetic Hearing Loss at Fudan University Eye and ENT Hospital in Shanghai. “These new findings show that this approach is promising and warrants larger international studies.”

More than 430 million people worldwide are affected by disabling hearing loss, including about 26 million with congenital deafness. Up to 60 percent of childhood deafness is caused by genetic factors. Children with DFNB9 are born with mutations in the OTOF gene that prevent the production of the functional otoferlin protein, which is necessary for the auditory and neural mechanisms underlying hearing.

This study is the first clinical trial to use bilateral ear gene therapy to treat DFNB9. The research presents an interim analysis of a single-arm study involving five children with DFNB9 who were observed over a period of 13 or 26 weeks at the Eye & ENT Hospital of Fudan University in Shanghai, China. Shu injected functioning copies of the human OTOF transgene, carried by an adeno-associated virus (AAV), into the patients’ inner ears using a special, minimally invasive procedure. The first case of bilateral treatment was performed in July 2023. During the follow-up period, 36 adverse events were observed, but no dose-limiting toxicity or serious events occurred. All five children showed restoration of hearing in both ears, with dramatic improvements in speech perception and sound localization. Two of the children gained the ability to perceive music, a more complex auditory signal, and were observed dancing to music in videos recorded for the study.

Helping People Regain their Hearing

In 2022, this research team conducted the world’s first gene therapy for DFNB9 in a study involving six patients in China who were treated in one ear. This study, whose results were published in The Lancet in January 2024, showed that five out of six children achieved improvements in hearing and speech. Shu first presented the data at the 30th Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) in Brussels, Belgium, in October 2023, becoming the first person worldwide to present clinical data on the restoration of hearing through gene therapy. “These results confirm the efficacy of the treatment we previously reported and represent an important step forward in gene therapy for genetic hearing loss,” Shu said. Shu trained as a postdoctoral fellow at Mass Eye and Ear under Chen for four years, and their collaboration has continued for more than a decade since his return to Shanghai.

“Our study clearly supports the treatment of children with DFNB9 in both ears, and we hope that this study can be expanded and that this approach can also be considered for deafness due to other genes or non-genetic causes,” added Chen, who is also an associate professor of otolaryngology and head and neck surgery at Harvard Medical School. “Our ultimate goal is to help people regain their hearing, regardless of how their hearing loss was caused.” Currently, there are no drugs available to treat hereditary deafness, which has created an opportunity for novel interventions such as gene therapies.

Longer Follow-up Period Required

The Gene and Cell Therapy Institute at Mass General Brigham helps translate scientific discoveries from researchers into initial clinical trials in humans. Chen and his colleagues are working with the institute to develop platforms and vectors with Good Manufacturing Practice standards that would allow his team to more easily test this therapeutic approach with other genes in the future.

The authors note that further work is needed to further investigate and refine the therapy. The bilateral study requires more consideration than the unilateral (one-sided) study, as surgery on both ears in a single procedure doubles the operating time. In addition, injecting double doses of AAVs into the body is likely to result in a stronger immune response and a higher potential for side effects. Looking ahead, more patients and a longer follow-up period are needed, and continued analysis of gene therapies and cochlear implants in larger randomized trials will be of great value.