Gene therapy restores hearing in children with hereditary deafness

A new study co-led by researchers at Mass Eye and Ear, part of Mass General Brigham, demonstrated the effectiveness of gene therapy in restoring hearing function to children with hereditary deafness.

In a trial of six children conducted at the Eye & ENT Hospital of Fudan University in Shanghai, China, researchers found the new gene therapy to be an effective treatment for patients with a specific form of autosomal recessive deafness caused by OTOF mutations. (otoferlin), called DFNB9.

With its first patient treated in December 2022, this research represents the first human clinical trial to deliver gene therapy to treat this disease, with the largest number of patients treated and longest follow-up to date. Their results were published on January 24 in The Lancet.

“If children are unable to hear, their brains can develop abnormally without intervention,” said Zheng-Yi Chen, DPhil, associate scientist at Eaton-Peabody Laboratories at Mass Eye and Ear and associate professor of otolaryngology. laryngology and head and neck surgery at university. Harvard Medical School. “The results of this study are truly remarkable. We saw the children’s hearing ability improve significantly from week to week, as well as their speech recovery.”

Hearing loss affects more than 1.5 billion people worldwide, of whom approximately 26 million have congenital deafness. For hearing loss in children, more than 60% has a genetic cause.

DFNB9, for example, is an inherited disease caused by mutations in the OTOF gene and the inability to produce a functional otoferlin protein, which is necessary for the transmission of sound signals from the ear to the brain.

There are currently no FDA-approved drugs to combat hereditary deafness, which has opened the door to new solutions such as gene therapies.

To test this new treatment, six children with DFNB9 were observed over a period of 26 weeks at the Eye & ENT Hospital of Fudan University. Mass Eye and Ear collaborators used an adeno-associated virus (AAV) carrying a version of the human OTOF gene to carefully introduce the gene into patients’ inner ears through a special surgical procedure. Different doses of the single injection of the viral vector were used.

All six children in the study had total hearing loss, as indicated by an average auditory brainstem response (ABR) threshold above 95 decibels. After 26 weeks, five children demonstrated hearing recovery, showing a reduction of 40 to 57 decibels on ABR tests, dramatic improvements in speech perception, and restored ability to conduct a normal conversation. Overall, no dose-limiting toxicities were observed. During patient follow-up, 48 adverse events were observed, a significant majority (96%) of which were low grade, the remainder being transient and without long-term impact.

Trial results will also be presented Feb. 3 at the annual meeting of the Association for Otolaryngology Research.

This study provides evidence for the safety and effectiveness of gene therapies in the treatment of DFNB9, as well as their potential for other forms of genetic hearing loss. Additionally, the results contribute to an understanding of the safety of AAV insertion into the human inner ear.

Regarding the use of AAVs, the success of a double-AAV vector carrying two pieces of the OTOF gene is remarkable. Typically, AAVs have a gene size limit, and so for a gene like OTOF that exceeds this limit, making a dual viral vector opens the door to using AAV with other large genes that are generally too large for the vector.

“We are the first to initiate the OTOF gene therapy clinical trial. It is exciting that our team has translated the work from basic research in the animal model of DFNB9 to hearing restoration in children with DFNB9,” said lead study author Yilai Shu, MD, of Fudan University Eye and ENT Hospital at Fudan University.

Shu previously worked as a postdoctoral researcher in Chen’s lab at Mass Eye and Ear. “I’m really 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 sample and follow their results over a longer period of time.

“Since the invention of cochlear implants 60 years ago, there has been no effective treatment for deafness,” Chen said. “This is an important milestone that symbolizes a new era in the fight against all types of hearing loss.”