In a groundbreaking achievement, scientists have used gene therapy to successfully restore hearing in children diagnosed with a hereditary form of deafness. “There’s no sound I don’t like,” said 11-year-old Aissam Dam, who recently received the treatment, during an interview published in The New York Times earlier this week. “They’re all good.”

While Dam’s treatment was conducted as part of an FDA-approved clinical trial at the Children’s Hospital of Philadelphia, it is one of five being conducted in the United States, China, and Europe. Although there are a multitude of genes known to cause hearing loss, all five studies focus on a specific gene known as otoferlin (OTOF), which codes a protein in the inner ear that transmits sound to the brain. 

“Genetic diseases are caused by changes in genes that prevent proteins in cells from functioning properly,” explained Jieyu Qi, lead author of one of the trials in China recently published in Advanced Science. “Gene therapy, in simple terms, repairs the gene that has been damaged so that cells can regain lost function.”

As in Dam’s case, Qi and his team were able to use gene therapy to replace the mutated OTOF gene with a healthy version in a five-year-old and eight-year-old boy with OTOF mutations, restoring normal cell function and their ability to hear.

“There are currently no biological treatments on the market for any form of hearing loss,” commented Jeffrey Holt, a professor of otolaryngology at Harvard Medical school, who was not involved in the studies. “This is a milestone and bodes well for the development of treatments that may benefit other forms of hearing loss.”

Delivering healthy genes

Gene therapies have been in development for several decades, with over 40 studies having documented the successful restoration of hearing in animal models. Each has honed in on a specific mutation among a pool of genes related to deafness.

“It’s been a long time coming,” said Margaret Kenna, an otolaryngologist at Boston Children’s Hospital and professor of otolaryngology at Harvard Medical School, in a New York Times interview. Kenna is also an investigator on the trial being run by Eli Lilly. “For decades people have been saying, ‘When is this going to work? I didn’t think gene therapy would begin in my practice lifetime. But here it is.”

The technology uses an inactivated adenovirus to safely deliver healthy copies of a gene to the affected cells. Adenoviruses are easy to manipulate in the lab, where the harmful viral genes are removed or disabled and the therapeutic genes are inserted. The modified adenovirus is also engineered to be unable to replicate and cause an active viral infection.

The virus is then delivered to the patient, typically through injection, where it enters the target cells by binding to specific receptors on their surface. Once inside, the virus is broken down and the DNA is released and carried to the cell’s nucleus where the cell’s machinery then uses it to produce the healthy versions of the defective proteins.

Two patients get their hearing back

In their exploratory trial, Qi and his colleagues first evaluated the therapy in mouse models before testing it in two young patients. The children’s hearing baseline was determined through two well-known auditory tests that gauge the functioning of hair cells in the inner ear, also known as the cochlea.

“[Their] hearing was almost completely lost, but the [auditory] results showed that [the] outer hair cells were still functional, suggesting a potentially intact cochlear structure,” the scientists wrote in their paper. Gene therapy has the capability to restore cell function but cannot repair a damaged organ.

Within one month following treatment, the five-year-old patient’s hearing in the treated ear was restored to normal range, and the eight-year-old patient demonstrated the ability to perceive conversational sounds. Notably, the five-year-old patient could only recognize speech through the ear that had received the injection.

“[Our gene therapy] efficiently introduced target genes into cochlear cells, and repaired the damaged cells caused by gene mutation so that the cells […] can recover to normal,” said Qi. 

This is a vast improvement compared to the only other available treatment for this form of deafness: cochlear implants, which help mimic the function of a healthy inner ear by sending sound directly to the hearing nerve. These allows patients to hear, but not at an optimal level.

“The human ear can hear the continuous frequency of sounds in the range of 200-20,000 Hz, “explained Qi. “Patients with cochlear implants can only hear part of the continuous frequency, and the hearing resolution in noisy environment is affected.”

The implants also make recruiting trial participants challenging as they sometimes alter the inner ear, making it difficult to say with certainty whether the gene therapy worked. For this reason, children with implants had to be excluded.

The gene therapy is intended for use in infants and small children because sound is important for our brain’s development. However, initial testing was done in older, eligible patients for safety reasons. Receiving gene therapy later in life may restore hearing to normal levels but our brain’s ability to interpret and understand sound, specifically speech, occurs inside a narrow learning window that normally happens between the ages of two and three. Older patients will certainly benefit, but their spoken language skills may be limited.

A long road ahead

While the results are significant, Qi says he’s unsure how long the therapeutic effect will last. Earlier research has shown that the effects of gene therapy can be maintained for several years However, long-term observations are necessary to be able to make this claim for current trial patients.

Though still early days, the optimism surrounding the five ongoing trials is palpable. Qi says that more patients under the age of 10 are being recruited for their ongoing trials to explore and optimize the treatment window as well as monitor how long the effects persist and the long-term safety of the adenovirus vector.

Building on the success with older children, the US Food and Drug Administration (FDA) has granted permission to expand trials to include younger children. Results from additional trials run in China and Europe are expected to be published in the coming weeks, and another will begin next month.

Holt pointed out that while all are important, these studies are just a drop in the bucket when it comes to the number of genetic hearing disorders that still await treatment. OTOF-related deafness is an extremely rare form of deafness, affecting roughly 200,000 people worldwide.

“While, these preliminary results are encouraging for patients with OTOF hearing loss, there are over a hundred genes that carry mutations known to cause hearing loss,” said Holt. “There is still a lot of work to do to help millions of patients around the world with genetic and acquired forms of hearing loss.” 

Undoubtedly, the foundations laid here will serve as a launching point for future endeavors aimed at restoring hearing for millions of people.

This article was also contributed to by Shrish Roy

Reference:  Yilai Shu, Lei Xu, Xia Gao, Huawei Li, Renjie Chai, et al., AAV-Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness, Advanced Science (2024). DOI: 10.1002/advs.202306788

Feature image credit: Damon Hall on Unsplash