A single arm clinical trial involving researchers at the Karolinska Institutet, together with colleagues at hospitals and universities in China, has shown that gene therapy can improve hearing in adults as well as in children with congenital deafness or severe hearing impairment due to mutations in the otoferlin gene (OTOF). The study results showed that hearing improved in all ten patients—aged 1.5 years to 23.9 years—who were treated using the adeno-associated virus (AAV)-OTOF gene therapy, and that the treatment was well tolerated.
The newly reported data add to previous findings from reports over the last year from trials of gene therapy for deafness due to OTOF mutations. In February 2025 Regeneron reported what it described as clinically meaningful hearing improvements for most children treated with its DBO-OTO gene therapy in the Phase I/II CHORD study. In 2024 Mass Eye and Ear researchers and their colleagues in China reported that children with autosomal recessive deafness (DFNB9) caused by the OTOF gene experienced hearing function restoration when both ears were treated simultaneously with OTOF gene therapy.
Commenting on the newly reported study including adult patients, Maoli Duan, MD, PhD, consultant and docent at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Sweden, said, “This is a huge step forward in the genetic treatment of deafness, one that can be life-changing for children and adults.” Duan is co-corresponding author of the researchers’ published paper in Nature Medicine, titled “AAV gene therapy for autosomal recessive deafness 9: a single-arm trial.” In their paper the team stated, “In conclusion, we found that a single injection of AAV-OTOF is well tolerated and safe, effectively improving hearing in DFNB9 patients of various ages.”
Gene therapy can treat or even prevent disease by altering genetic materials in living cells, the authors explained. “One specific approach involves gene replacement—a process that delivers normal genes to produce functional proteins for the treatment of diseases caused by missing or faulty genes.” OTOF is a gene that is responsible for producing otoferlin, a protein that is important for transmitting sound signals from the ear to the brain. Mutations in OTOF can cause severe-to-profound congenital deafness. And while gene therapy for congenital deafness has shown promising results in children, there is a lack of data in older populations, the researchers continued. “To our knowledge, a multicenter clinical trial of gene therapy for deafness involving adult participants has not been reported previously.”
Duan et al. administered a gene therapy that used a synthetic adeno-associated virus (AAV) to deliver a functional version of the OTOF gene to the inner ear via a single injection through a membrane at the base of the cochlea called the round window. “We used an adeno-associated virus serotype, Anc80L65 (AAV-Anc80L65)-mediated OTOF gene delivery vector,” they explained. The primary endpoints for the study were safety and tolerability within five years, and secondary endpoints assessed auditory function. All ten patients had at least six months of follow up.
The study findings showed that the effect of gene therapy was rapid, and the majority of the patients recovered some hearing after just one month. “Importantly, the present gene therapy is able to improve hearing rapidly with the first month of drug delivery, albeit to various degrees, in all ten participants, including one older adolescent and one adult,” the team stated.
A six-month follow up showed considerable hearing improvement in all participants, the average volume of perceptible sound improving from 106 decibels to 52. The younger patients, especially those between the ages of five and eight, responded best to the treatment. “An age-dependent therapeutic effect was observed, with optimal outcomes in five- to eight-year-olds,” the authors continued.
One of the participants, a seven-year-old girl, quickly recovered almost all her hearing and was able to hold daily conversations with her mother four months afterwards. The therapy also proved effective in adults. “These preliminary results show that AAV-OTOF was safe and well tolerated in patients ranging from toddlerhood to adulthood,” the investigators stated.
“Smaller studies in China have previously shown positive results in children, but this is the first time that the method has been tested in teenagers and adults, too,” said Duan. “Hearing was greatly improved in many of the participants, which can have a profound effect on their life quality. We will now be following these patients to see how lasting the effect is.”
The results also showed that the treatment was safe and well-tolerated. The most common adverse reaction was a reduction in the number of neutrophils, a type of white blood cell. No serious adverse reactions were reported in the follow-up period of 6 to 12 months.
In conclusion, the authors noted, “The present result has not only expanded the therapeutic window to include adolescents and adults, but also indicated an optimal age range of five [to] eight years for the therapy. Future larger trials are needed to validate these findings.” The reported trial remains ongoing, the team also pointed out, “…and requires extended follow-up to confirm the long-term safety and efficacy.”
“OTOF is just the beginning,” added Duan. “We and other researchers are expanding our work to other, more common genes that cause deafness, such as GJB2 and TMC1. These are more complicated to treat, but animal studies have so far returned promising results. We are confident that patients with different kinds of genetic deafness will one day be able to receive treatment.”
The study was conducted in collaboration with a number of institutions, including Zhongda Hospital, Southeast University, China, and was financed by several Chinese research programs and Otovia Therapeutics, which developed the gene therapy and employs many of the researchers involved in the study.
