Gene therapy restores hearing in deaf children

Researchers from China and the US have demonstrated the effectiveness of gene therapy towards restoring hearing function for children suffering from hereditary deafness, having conducted the first known human clinical trial for treating this condition with gene therapy. Their results have been published in The Lancet.

Hearing loss affects more than 1.5 billion people worldwide, with congenital deafness making up about 26 million of those individuals. For hearing loss in children, more than 60% stem from genetic reasons. DFNB9, for example, is a specific form of autosomal recessive deafness caused by mutations of the OTOF gene and a failure to produce a functioning otoferlin protein, which is necessary for the transmission of the sound signals from the ear to the brain. There are currently no FDA-approved drugs to help with hereditary deafness.

“If children are unable to hear, their brains can develop abnormally without intervention,” noted Zheng-Yi Chen, an associate scientist at Mass Eye and Ear (a teaching hospital of Harvard Medical School).

In order to test the gene therapy drug RRG-003, six children with DFNB9 were observed over a 26-week period at the Eye and ENT Hospital of Fudan University (FDEENT), while the researchers utilised an adeno-associated virus (AAV) to ‘carry’ a version of the human OTOF gene into the inner ears of the patients through a special surgical procedure. Testing in animals had shown that the OTOF gene exceeded the loading capacity of a single AAV, so the research team utilised a dual-vector delivery system, with two AAV vectors carrying the OTOF gene.

“To put it simply, if one car isn’t powerful enough to move the cargo, we need two cars to move together,” said team leader Professor Shu Yilai, from FDEENT.

All six children in the study had total deafness, as indicated by an average auditory brainstem response (ABR) threshold of over 95 decibels. After 26 weeks, five children demonstrated hearing recovery, showing a 40- to 57-decibel reduction in ABR testing, dramatic improvements in speech perception and the restored ability to conduct normal conversation. And while 48 adverse events were observed during patient follow-up, a significant majority (96%) were low grade and the rest were transitory with no long-term impact.

“The results from this study are truly remarkable,” Chen said. “We saw the hearing ability of children improve dramatically week by week, as well as the regaining of their speech.”

The study provides evidence towards the safety and effectiveness of gene therapies in treating DFNB9, as well as their potential for other forms of genetic hearing loss, with Chen describing the breakthrough as a “huge milestone” on par with the invention of the cochlear implant 60 years ago. The researchers now plan to expand the trial to a larger sample size and to track outcomes over a longer timeline.

The results also contribute to an understanding of the safety of AAV insertion into the inner ear, with the success of the dual AAV vector carrying two pieces of the OTOF gene opening the door for AAVs’ use with other large genes.

“It is thrilling that our team translated the work from basic research in animal model of DFNB9 to hearing restoration in children with DFNB9,” Shu concluded. “I am truly excited about our future work on other forms of genetic hearing loss to bring treatments to more patients.”

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