Gene therapy applied to both ears in children with DFNB9 shows enhanced outcomes, including improved sound localization and hearing in noisy settings

KEY POINTS

BOSTON (June 5, 2024) — A breakthrough gene therapy targeting a genetic form of deafness has demonstrated restored hearing function in five children treated in both ears. These children exhibited significant improvements in speech recognition and could now discern the location of sounds. This bilateral gene therapy—administered to the ears on both sides—is the first of its kind in clinical practice and has shown additional benefits compared to an earlier phase that only treated one ear. The collaborative research, conducted by investigators from Mass Eye and Ear, part of Mass General Brigham’s healthcare network, and the Eye & ENT Hospital of Fudan University in Shanghai, was published on June 5th in Nature Medicine.

“These are extraordinary findings,” said Zheng-Yi Chen, DPhil, study co-senior author and associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear. “We’ve observed remarkable improvements in the children’s auditory capabilities, and this latest study underscores the added advantage of treating both ears for better sound localization and enhanced speech comprehension in challenging environments.”

The research team had always envisioned treating both ears to give children the ability to hear sounds more naturally in three dimensions—an essential trait for everyday tasks such as communication and driving.

“By restoring hearing in both ears, we significantly enhance the benefits of recovery,” said lead study author Yilai Shu, MD, PhD, professor and director of the Diagnostic and Treatment Center for Genetic Hearing Loss at Eye & ENT Hospital of Fudan University. “These promising results strongly support the need for more extensive international trials.”

Globally, over 430 million individuals suffer from profound hearing loss, 26 million of whom have congenital deafness. Genetic causes account for up to 60% of childhood deafness. DFNB9, a genetic form of hearing impairment, is caused by mutations in the OTOF gene, leading to insufficient production of otoferlin, a protein crucial for auditory and neural processes.

This study represents the first clinical trial utilizing bilateral gene therapy to treat DFNB9. It offers an interim assessment of five children observed for either 13 or 26 weeks at the Eye & ENT Hospital of Fudan University. Shu delivered functioning OTOF genes via adeno-associated virus (AAV) into both inner ears of the patients through a minimally invasive procedure. The first bilateral treatment took place in July 2023. Although 36 adverse events were recorded in the follow-up period, no serious toxicity or dose-limiting complications were reported. All five children showed hearing restoration in both ears, with notable improvements in detecting speech and localizing sounds. Two children even developed a newfound appreciation of music and were observed dancing to it in videos. The trial remains ongoing as participants continue to be monitored.

Previously, in 2022, this research team successfully introduced the world’s first gene therapy for DFNB9 by treating one ear in six children from China. That trial, published in The Lancet in January 2024, demonstrated hearing and speech improvement in five out of six participants. Shu initially disclosed the results during the European Society of Gene and Cell Therapy’s 30th Congress in Brussels in October 2023, marking the first-ever report of gene therapy restoring hearing.

“These latest results validate the earlier findings and signify a crucial advancement in gene therapy for hereditary hearing loss,” said Shu. A former postdoctoral fellow under Chen at Mass Eye and Ear, Shu has maintained a decade-long collaboration with Chen since returning to Shanghai.

“Our study supports treating both ears for children with DFNB9 and opens a door to consider this approach for other genetic or non-genetic hearing impairments,” added Chen, who also serves as an associate professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School. “Our ultimate mission is to restore hearing, regardless of the cause of hearing loss.”

Currently, there is no pharmaceutical solution for inherited deafness, leaving an avenue for pioneering therapies such as gene therapies.

Mass General Brigham’s Gene and Cell Therapy Institute is instrumental in translating scientific breakthroughs into clinical trials. Chen and colleagues are working closely with the institute to develop manufacturing platforms and vectors that meet regulatory standards, facilitating the expansion of such therapies to target other genes in the future.

The researchers emphasize that further investigation is necessary to optimize the therapy. Bilateral gene therapy poses more complexity compared to its unilateral counterpart, as surgery on both ears doubles the operational time. The immune system might also react more intensely due to the higher viral load from administering double doses of AAVs, leading to a potentially heightened risk of adverse reactions. Looking ahead, larger patient groups and longer follow-up periods will be essential. Comparisons with cochlear implants in broader randomized trials will also provide valuable insights.

Note: Kaiyu Gao is employed by Shanghai Refreshgene Therapeutics Co., Ltd. Zheng-Yi Chen is a co-founder of Salubritas Therapeutics. No other authors have identified any conflicts of interest.

Funding: This research was supported by the National Natural Science Foundation of China, China’s National Key R&D Program, several Shanghai-based institutions including the Science and Technology Commission and Municipal Health Commission, Fudan University, and Shanghai Refreshgene Therapeutics Co., Ltd. Zheng-Yi Chen received additional funding from the Ines and Fredrick Yeatts Fund.

Reference: Wang, H., et al. “Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results.” Nature Medicine. DOI: 10.1038/s41591-024-03023-5.

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About Mass Eye and Ear

Founded in 1824, Massachusetts Eye and Ear is an international leader in healthcare and research specializing in ophthalmology and otolaryngology (ENT). A teaching hospital of Harvard Medical School and part of Mass General Brigham, the institution offers advanced treatment for conditions involving the eyes, ears, nose, throat, head, and neck. Home to the globe's largest group of hearing and vision researchers, Mass Eye and Ear scientists are determined to unravel the root causes of sensory ailments and pioneer novel treatments. In U.S. News & World Report’s 2023–2024 rankings, Mass Eye and Ear claimed the #4 spot for Ophthalmology and #7 for ENT care. For more information, visit the Focus blog, or follow them on Instagram, Twitter, and Facebook.

Journal:

Nature Medicine

DOI:

10.1038/s41591-024-03023-5

Study Design:

Randomized controlled/clinical trial

Research Area:

People

Article Title:

Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results

Article Publication Date:

June 5, 2024

COI Disclosure:

Kaiyu Gao works at Shanghai Refreshgene Therapeutics Co., Ltd., while Zheng-Yi Chen is a co-founder of Salubritas Therapeutics. All other contributors disclose no conflicts of interest.