**Shanghai, China** – A novel gene therapy targeting inherited deafness caused by OTOF gene mutations successfully restored hearing in five children treated in both ears. Led by Mass Eye and Ear and Eye & ENT Hospital of Fudan University Shanghai, the trial demonstrated significant improvements in hearing, sound localization, and speech perception. PackGene Biotech provided the AAV CDMO service for this research.

Breakthrough Gene Therapy Restores Hearing in Children with Inherited Deafness

This trial is the first to administer gene therapy bilaterally for this form of deafness in children. Researchers aim to expand this work internationally.

“The results are astounding,” said Zheng-Yi Chen, DPhil, of Mass Eye and Ear. “We see dramatic progress in the hearing ability of treated children, with added benefits in sound source localization and speech recognition.”

More than 5% of the world’s population, including 34 million children, are affected by disabling hearing loss. DFNB9, caused by OTOF gene mutations, prevents the production of otoferlin, a protein necessary for hearing.

An AAV1 vector carrying the human OTOF transgene had shown effectiveness in animal models. In 2022, the team delivered the first DFNB9 gene therapy in a trial with six patients in China treated in one ear. Results published in January 2024 showed significant improvements in hearing and speech for five children. Yilai Shu, MD, PhD, of Fudan University presented the data at the ESGCT Congress in October 2023.

The current study in *Nature Medicine* is the first to use bilateral ear gene therapy for DFNB9. Shu emphasized the importance of bilateral hearing restoration for maximizing recovery benefits.

The interim analysis involved five children treated with AAV1-hOTOF gene therapy and observed over 13 or 26 weeks at Fudan University. Shu performed the minimally invasive surgery, injecting functional copies of the OTOF transgene into the patients’ inner ears. The first bilateral treatment was in July 2023, resulting in bilateral hearing restoration and improved auditory and speech function.

During follow-up, 36 adverse events were observed, but no serious events occurred. All five children showed dramatic improvements in speech perception and sound localization. Two children even appreciated music, demonstrated by their dancing in study videos. The trial is ongoing with participants continuing to be monitored. “These results show this approach holds great promise and warrants larger international trials,” said Shu. “These confirm the efficacy of the treatment and represent a major step in gene therapy for genetic hearing loss.”

The authors concluded that AAV1-hOTOF binaural gene therapy for DFNB9 is feasible, safe, and efficacious, promoting the clinical transformation of gene therapy for other hereditary deafness genes.

Chen added, “Our study supports treating children with DFNB9 in both ears. Our ultimate goal is to help people regain hearing regardless of the cause.” Chen is also an associate professor at Harvard Medical School.

Further research is needed to refine the therapy, considering the doubled surgical time and potential for stronger immune responses when treating both ears. More patients and longer follow-up durations are necessary. The authors acknowledged, “This trial is limited by small patient numbers and short follow-up. Long-term follow-up visits and more patients are needed for further investigation… Future investigation of gene therapy and cochlear implants in larger randomized trials is necessary.”

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