A novel gene therapy designed to target a form of inherited deafness caused by mutations in the OTOF gene restored hearing function in all five children who were treated in both ears. The clinical trial in Shanghai, China, led by investigators from Mass Eye and Ear, and from Eye & ENT Hospital of Fudan University Shanghai, also showed that children treated using the AAV1-hOTOF gene therapy gained the ability to determine locations that sounds came from and experienced improved speech perception in noisy environments.
The trial is the first to provide gene therapy for this form of inherited deafness to children in both ears (bilaterally), and the newly reported results demonstrated additional benefits to those observed in the first phase of the trial, published earlier this year, when children were treated in one ear. The researchers say they hope to expand their work internationally. The trial is ongoing with longer follow-ups to confirm the safety and efficacy findings.
“The results from these studies are astounding,” said 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.”
Chen is co-senior author of the team’s published report in Nature Medicine, titled “Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results.”
More than 5% of the world’s population—about 430 million people, including 34 million children—are affected by disabling hearing loss, the authors wrote, citing WHO figures. “There are about 26 million people with congenital hearing loss, of which 60% is attributed to genetic factors,” they added.
Children with autosomal recessive deafness 9 (DFNB9) are born with mutations in the OTOF gene that prevent the production of functional otoferlin, a protein that is necessary for the auditory and neural mechanisms underlying hearing. “DFNB9 is characterized by congenital or prelingual, severe-to-complete bilateral hearing loss and accounts for 2–8% of hereditary deafness,” the investigators noted.
An adeno-associated virus (AAV) serotype 1 vector carrying human OTOF transgene (AAV1-hOTOF) coding the human functional otoferlin protein had previously been shown to be effective and safe in mouse models and in nonhuman primates. In 2022, the research team delivered the world’s first gene therapy DFNB9, as part of a trial involving six patients in China who were treated in one ear. The results of that study, published in January 2024, showed that five of the six children gained improvements in hearing and speech. Yilai Shu MD, PhD, professor, director of the Diagnosis and Treatment Center of Genetic Hearing Loss affiliated with the Eye & ENT Hospital of Fudan University in Shanghai, initially presented the data at the 30th Annual Congress of European Society of Gene and Cell Therapy (ESGCT) in Brussels, in October 2023, representing the first in the world to report clinical data on using gene therapy to restore hearing.
The new study described in Nature Medicine is the first clinical trial to use bilateral ear gene therapy for treating DFNB9. The researchers noted that their team’s goal always was to treat children in both ears to achieve the ability to hear sound in three dimensions “The ability to localize sound source, determining the position of a sound source in three dimensions, is important for speech communication and daily safety such as driving,” they pointed out. “Restoring hearing in both ears of children who are born deaf can maximize the benefits of hearing recovery,” added Shu, who is also the lead study author.
During treatment 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. “These new results show this approach holds great promise and warrants larger international trials,” said Shu. “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.”
The authors concluded, “Our results show that AAV1-hOTOF binaural gene therapy for patients with DFNB9 is feasible, safe, and efficacious. The study expands the scope of DFNB9 treatment, potentially improving clinical intervention for hereditary deafness and promoting clinical transformation of gene therapy for hereditary deafness caused by other deafness genes.”
The authors noted 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 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. The authors acknowledged, “This trial is limited by the small patient numbers and the relatively short follow-up period. The trial is ongoing; long-term follow-up visits and more patients are needed for further investigation … In the future, investigation of gene therapy and cochlear implant in a larger randomized trial needs to be explored.”
