Gene therapy trial shows restoration of hearing in children born deaf

Summary: A new gene therapy has restored hearing in both ears of five children with hereditary deafness, improving their hearing function, speech perception and ability to localize sound.

Relations:

1. The gene therapy improved speech perception and the children’s ability to localize sound, and some even gained the ability to appreciate music.
2. Treatment of both ears led to better results compared to treatment of one ear, indicating potential for more complete hearing recovery.
3. This study marks the first clinical trial using bilateral ear gene therapy for DFNB9, demonstrating the efficacy of the therapy and paving the way for larger international trials.

A new gene therapy designed to target an inherited form of deafness restored hearing function in five children who were treated in both ears.

Improving children’s hearing and speech

Children also experienced better speech perception and gained the ability to localize and determine the position of sound. The study, a clinical trial that administered a gene therapy in both ears (bilaterally), shows additional benefits than those seen 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 Mass Eye and Ear (a member of the Mass General Brigham health care system) and Fudan University Eye & ENT Hospital in Shanghai, and the findings were published June 5 in Nature Medicine.

“The results from these studies are surprising,” says 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.”

Treatment of both ears

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,” says lead study author Yilai Shu, MD, PhD, professor, director of the Genetic Hearing Loss Diagnosis and Treatment Center. related to Eye & ENT. Fudan University Hospital in Shanghai, “These new results show that this approach holds great promise and warrants larger international trials.”

Further reading: Gene therapy restores hearing in children with hereditary deafness

Impact of hearing loss

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

Bilateral ear gene therapy

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 human copies OTOF adeno-associated virus (AAV)-carried transgene into patients’ inner ears through 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.

Gene therapy for DFNB9

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, whose results were published in of Lancet in January 2024, showed that five out of six children had 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,” says 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 that this test can be expanded and this approach can be looked at for deafness caused by other genes or non-genetic causes,” added Chen, of 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, during one operation, double the operation 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.

Featured Image: Yilai Shu, MD, PhD, communicates with a new patient at Fudan University Eye & ENT Hospital in Shanghai, China. Photo: Eye & ENT Hospital of Fudan University