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Gene Therapy Restores Hearing in Small Trial for Kids With Hereditary Deafness

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Five out of six children with a type of hereditary hearing loss have shown improvement in their hearing and speech recognition after treatment with an experimental gene therapy. This is the first gene therapy trial for children with this type of hearing loss.

Tackling hereditary hearing loss

Hearing loss affects over 1.5 billion people worldwide, while approximately 60% of childhood hearing loss cases are genetic in origin.

There are many causes of hereditary deafness. In the current study, the researchers focused on an autosomal recessive form called DFNB9, caused by mutations in a gene called otoferlin (OTOF). The otoferlin protein transmits sound signals from the ear to the brain. In DFNB9, mutations in the OTOF gene result in the production of faulty otoferlin.

Though the cause of the condition is well known, there are no drugs currently available to treat this hereditary deafness. As a result, researchers are now turning to cell and gene therapies.

The current study, published in The Lancet, is the result of a collaboration between Mass Eye and Ear and Fudan University in Shanghai, China.

“If children are unable to hear, their brains can develop abnormally without intervention,” said Dr. Zheng-Yi Chen, an associate scientist in the Eaton–Peabody Laboratories at Mass Eye and Ear and a co-senior author of the study. “The results from this study are truly remarkable. We saw the hearing ability of children improve dramatically week by week, as well as the regaining of their speech.”

Gene therapy trialed in a small number of patients

The gene therapy assessed in this study utilizes an adeno-associated virus (AAV). The virus introduces a healthy version of the OTOF gene into the inner ears of patients and is administered as a single injection during a surgical procedure.

The researchers recruited 6 children into the study with total deafness, defined as an average auditory brainstem response (ABR) threshold of over 95 decibels. This tests how well sound signals move from the ear to the brain stem, estimating the threshold of hearing sensitivity.

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After the gene therapy procedure, the children were monitored for 26 weeks at the Eye & ENT Hospital of Fudan University, China. After this period, 5 of the 6 children demonstrated hearing recovery with 40–57 decibel reductions in ABR testing. The children also showed improvements in their speech perception and an improved ability to conduct normal conversation.

Notably, the researchers observed 48 adverse events, though the majority (96%) were low grade and the remainder were transitory with no long-term effects.

Further trials needed to validate effects

Overall, the study provides evidence for the safety and effectiveness of gene therapies in treating DFNB9, demonstrates the potential of these therapies for other forms of genetic hearing loss and increases our understanding of the safety of these inner ear procedures.

The study also sheds light on the use of dual AAVs that carry two copies of a gene, as AAVs typically have a gene size limit. As OTOF exceeds that limit, the use of a similar dual viral vector could hold promise for other large genes.

“We are the first to initiate the clinical trial of OTOF gene therapy. It is thrilling that our team translated the work from basic research in an animal model of DFNB9 to hearing restoration in children with DFNB9,” said co-senior author Professor Yilai Shu of the Eye & ENT Hospital of Fudan University. “I am truly excited about our future work on other forms of genetic hearing loss to bring treatments to more patients.”

The researchers plan to expand the trial to a larger group of participants, as just six participants took part in the study, as well as track their long-term outcomes.

“Not since cochlear implants were invented 60 years ago, has there been an effective treatment for deafness,” said Chen. “This is a huge milestone that symbolizes a new era in the fight against all types of hearing loss.”

Reference: Lv J, Wang H, Cheng X, et al. AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial. The Lancet. 2024;0(0). doi: 10.1016/S0140-6736(23)02874-X

This article is a rework of a press release issued by Mass Eye and Ear. Material has been edited for length and content.