New gene therapy trial shows restored hearing and speech in children born deaf, treated in both ears

"The results from these studies are astounding," said study co-senior author Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear. "We continue to see the hearing ability of treated children dramatically progress and the new study shows added benefits of the gene therapy when administrated to both ears, including the ability for sound source localization and improvements in speech recognition in noisy environments."

The researchers noted their team's goal was always to treat children in both ears to achieve the ability to hear sound in three dimensions, a capability important for communication and common daily tasks such as 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, PhD, professor, director of Diagnosis and Treatment Center of Genetic Hearing Loss affiliated with the Eye & ENT Hospital of Fudan University in Shanghai, "These new results show this approach holds great promise and warrant larger international trials."

Over 430 million people around the world are affected by disabling hearing loss, of which congenital deafness constitutes about 26 million of them. 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 functioning otoferlin protein, which is necessary for the auditory and neural mechanisms underlying hearing.

This new study is the first clinical trial to use bilateral ear gene therapy for treating DFNB9. The new research presents an interim analysis of a single-arm trial of five children with DFNB9 who were observed over either a 13-week or 26-week period at the Eye & ENT Hospital of Fudan University in Shanghai, China. Shu injected functioning copies of the human OTOF transgene carried by adeno-associated virus (AAV) into the inner ears of patients through a specialized, minimally invasive surgery. The first case of bilateral treatment was conducted in July 2023. During follow-up, 36 adverse events were observed, but no dose-limiting toxicity or serious events occurred. All five children showed hearing recovery in both ears, with dramatic improvements in speech perception and sound localization. Two of the children gained 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 first gene therapy in the world for DFNB9 as part of a trial of six patients in China treated in one ear. That trial, which had results published in The Lancet in January 2024, showed five of six children gained improvements in hearing and speech. Shu initially presented the data at the 30th annual congress of European Society of Gene and Cell Therapy (ESGCT) in Brussels, Belgium in October 2023, becoming the first in the world to report clinical data on using gene therapy to restore hearing.

"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. 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 this trial can expand 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 hearing no matter how their hearing loss was caused."

Currently, there are no drugs available to treat hereditary deafness, which has made room for novel interventions like 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 refine the therapy. The bilateral study requires more consideration compared to the unilateral (one-ear) study as operations in both ears, in the course of one surgery, doubles 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 could be greater. Looking ahead, more patients as well as a longer follow-up duration are necessary, and continued analysis of gene therapies and cochlear implants in larger randomized trials will be valuable.