Five children born with inherited deafness have gained hearing in both ears following a groundbreaking gene therapy trial, marking the world's first clinical study to administer bilateral ear treatment for genetic hearing loss. The children, aged between one and 11 years, all had DFNB9, a condition caused by mutations in the OTOF gene that prevents production of the otoferlin protein essential for hearing.
The study, led by investigators from Mass Eye and Ear and Eye & ENT Hospital of Fudan University in Shanghai, represents a significant advancement over previous single-ear treatments. Results were published June 5th in Nature Medicine, demonstrating that bilateral treatment provides additional benefits beyond what was observed when children were treated in one ear.
Dramatic Hearing Recovery Achieved
All five children showed hearing recovery in both ears within weeks of treatment, with remarkable improvements in speech perception and sound localization abilities. Two children gained the ability to appreciate music and were observed dancing to music in videos captured for the study. Video footage shows a two-year-old boy responding to his name three weeks after treatment and dancing to music after 13 weeks, having shown no response to either before receiving the injections.
"Restoring hearing in both ears of children who are born deaf can maximize the benefits of hearing recovery," said lead study author Dr. Yilai Shu, professor and director of Diagnosis and Treatment Center of Genetic Hearing Loss at Eye & ENT Hospital of Fudan University in Shanghai. "These new results show this approach holds great promise and warrant larger international trials."
The therapy involves injecting functioning copies of the human OTOF transgene carried by adeno-associated virus (AAV) into the inner ears through specialized, minimally invasive surgery. The first bilateral treatment case was conducted in July 2023.
Building on Previous Success
This research builds on the team's earlier work from 2022, when they delivered the first gene therapy in the world for DFNB9 as part of a trial treating six patients in one ear. That trial, with results published in The Lancet in January 2024, showed five of six children gained improvements in hearing and speech.
"These results confirm the efficacy of the treatment that we previously reported on and represent a major step in gene therapy for genetic hearing loss," said Shu, who initially presented clinical data on using gene therapy to restore hearing at the 30th annual congress of European Society of Gene and Cell Therapy in Brussels, Belgium in October 2023.
Addressing Significant Medical Need
Over 430 million people worldwide are affected by disabling hearing loss, with congenital deafness constituting about 26 million cases. Up to 60 percent of childhood deafness is caused by genetic factors, and children with DFNB9 account for 2-8% of all congenital hearing loss cases.
Currently, no drugs are available to treat hereditary deafness, creating significant opportunity for novel interventions like gene therapies. The bilateral approach is particularly important because it enables three-dimensional hearing, a capability essential for communication and daily tasks such as participating in group conversations and being aware of traffic when crossing roads.
Safety Profile and Future Directions
The interim analysis examined five children observed over either 13-week or 26-week periods. During follow-up, 36 adverse events were observed, but no dose-limiting toxicity or serious events occurred. However, researchers note that bilateral treatment requires additional consideration compared to single-ear approaches, as operations in both ears double surgical time and potentially increase immune response risks.
"Our study strongly supports treating children with DFNB9 in both ears, and our hope is this trial can expand and this approach can also be looked at for deafness caused by other genes or non-genetic causes," said Dr. Zheng-Yi Chen, a scientist at Massachusetts Eye and Ear who co-led the trial. "Our ultimate goal is to help people regain hearing no matter how their hearing loss was caused."
The researchers emphasize that larger randomized trials with longer follow-up periods are necessary to fully assess the therapy's benefits and risks. Mass General Brigham's Gene and Cell Therapy Institute is working with Chen's team to develop platforms and vectors with good manufacturing practice standards to enable testing of this therapeutic approach with other genes in the future.
