Gene therapy trial restores hearing in both ears of children who were born deaf

A new gene therapy designed to target a form of inherited deafness has restored hearing function in five children who were treated in both ears. Children also experienced better speech perception and gained the ability to localize and determine the position of sound.

The study, the world’s first clinical trial of gene therapy administered to both ears (bilaterally), shows benefits beyond those observed in the first phase of this trial, published earlier this year, when children were treated in a ear

The research was led by investigators from the Mass Eye and Ear and Eye & ENT Hospital of Fudan University in Shanghai, and the findings were published in Nature Medicine.

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

The researchers noted that their team’s goal was always to treat children in both ears to achieve the ability to hear sound in three dimensions, an important skill for communication and common everyday tasks like driving.

“Restoring hearing in both ears of children who are born deaf can maximize the benefits of hearing recovery,” said lead study author Yilai Shu MD, Ph.D., professor, director of the Genetic Loss Diagnosis and Treatment Center. of Hearing connected with the Eye. & ENT Hospital of Fudan University in Shanghai, “These new results show that this approach holds great promise and warrants larger international trials.”

Over 430 million people worldwide are affected by disabling hearing loss, of which approximately 26 million are congenital deafness. Up to 60% 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 protein otoferlin, which is necessary for the auditory and neural mechanisms underlying hearing.

This new study is the first clinical trial using bilateral ear gene therapy to treat DFNB9. The new research presents an interim analysis of a single-arm trial of five children with DFNB9 who were observed over a 13-week or 26-week period at Fudan University Eye & ENT Hospital in Shanghai, China. Shu injected functional copies of the human OTOF transgene carried by adeno-associated virus (AAV) into patients’ inner ears through a specialized, minimally invasive surgery.

The first case of bilateral treatment was performed in July 2023. During follow-up, 36 adverse events were observed, but there were no dose-limiting toxicities or serious events. All five children showed recovery of hearing in both ears, with dramatic improvements in speech perception and sound localization. Two of the children acquired an ability to appreciate music, a more complex auditory signal, and were observed dancing to music in videos captured for the study. The trial remains ongoing with participants continuing to be monitored.

In 2022, this research team delivered the world’s first gene therapy for DFNB9 as part of a trial of six patients in China treated in one ear. That trial, the results of which were published in Lancet in January 2024, showed that five out of six children gained improvements in hearing and speech. Shu first presented the data at the 30th Annual Congress of the European Society for Gene and Cell Therapy (ESGCT) in Brussels, Belgium in October 2023, becoming the first in the world to report clinical data on the use of gene therapy for restore hearing.

“These results confirm the efficacy of the treatment we previously reported and represent a major step forward in gene therapy for genetic hearing loss,” Shu said. Shu trained under Chen for four years as a postdoctoral fellow at Mass Eye and Ear, with their collaboration continuing for more than a decade since he returned to Shanghai.

“Our study strongly supports treating children with DFNB9 in both ears, and our hope is that this test can be expanded and this approach can also be looked at for deafness caused by other genes or non-genetic causes,” added Chen, who is also an associate. professor of Otolaryngology – 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 left room for new interventions such as gene therapies.

Mass General Brigham’s Gene and Cell Therapy Institute is helping to translate scientific discoveries made by researchers into first-in-human clinical trials. Chen and his colleagues are working with the Institute to develop platforms and vectors with good manufacturing practice standards that would enable his team to more easily test this therapeutic approach with other genes in the future.

The authors note that more work is needed to further study and improve the therapy. The bilateral study requires more consideration compared to the unilateral (one-ear) study, as operations on both ears double the surgical time. Furthermore, by injecting double doses of AAVs into the body, the immune response is likely to be stronger and the potential for adverse effects may be greater.

Looking forward, more patients as well as a longer duration of follow-up are needed, and continued analysis of gene therapies and cochlear implants in larger randomized trials will be valuable.

Provided by Mass Eye and Ear