Doctor examines ear drum of little girl
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A trial conducted by researchers in the U.S. and China has shown that a new gene therapy for children born with autosomal deafness caused by the OTOF gene restored hearing function when both ears were treated. The five children in the study, reported today in Nature Medicine, also showed better speech perception and the ability localize and determine the position of sound in their environment.

The new research, which the investigators say is the first clinical trial to administer a gene therapy to both ears simultaneously, builds on data from the first phase of this trial in which patients were treated in only one ear. The research is led by a team from Mass Eye and Ear (a member of the Mass General Brigham healthcare system) and Eye & ENT Hospital of Fudan University in Shanghai, China.

Finding successful bilateral (both ears) therapies to restore hearing for children with autosomal deafness is important as it provides the ability to hear sounds in three dimensions, a vital capability for comprehending sounds and their sources to allow for better communication and to safely perform 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, a professor and 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.”

The trial is focused on children with a genetic form of deafness called autosomal recessive deafness 9 (DFNB9) which is caused by the OTOF gene. In this form of deafness, the OTOF gene prevents production of the protein otoferlin which is vital for the auditory and neural mechanisms that underlie hearing.

The data shows an interim analysis of the data from a single-arm trial of five children with DFNB9. In the study, Shu injected an adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene into the inner ears of the subjects. The progress of the patients was observed over either a 13-week or 26-week period.

All five of the children with autosomal deafness showed dramatic improvements in speech perception, and sound localization and two of the five showed the ability to enjoy music, which is a much more complex auditory signal. Observations of these patients is ongoing as the trial continues.

“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 of the 2022 study which treated subjects with the therapy in only one ear and published in The Lancet in January.

“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 Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear. “Our ultimate goal is to help people regain hearing no matter how their hearing loss was caused.”

During follow-up, the researchers noted a total of 36 adverse events, but there were no dose-limiting toxicity or serious side effects related to them. The team noted that the simultaneous injection of two AAVs into the body will likely provoke a stronger immune response, increasing the possibility of adverse events. Further study of this gene therapy will include a larger patient cohort, along with longer duration of follow-up of treated patients.

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