Last year brought multiple advances in the gene therapy for inherited hearing loss field. In January 2024, positive results were reported in two pioneering human trials. The larger of the two studies showed hearing recovery and improvements in speech recognition in five out of six children with DFNB9 (a form of autosomal recessive deafness caused by mutations in OTOF, the otoferlin gene). In addition, Akouos (a wholly owned subsidiary of Eli Lilly and Company) announced positive initial clinical results in one patient from its Phase I/II AK-OTOF-101 gene therapy study. In February of this year, 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.
There is no doubt that the field has momentum. However, despite the enthusiasm over the recent results in children, there has been a lack of data in older populations.
Now, five sites in China tested a single-arm trial of adeno-associated virus (AAV)-OTOF gene therapy in ten participants with autosomal recessive deafness 9 aged 1.5 to 23.9 years. The results showed that hearing improved in all ten patients who were treated, and that the treatment was well tolerated.
This work is published in Nature Medicine in the article, “AAV gene therapy for autosomal recessive deafness 9: a single-arm trial.”
“This is a huge step forward in the genetic treatment of deafness, one that can be life-changing for children and adults,” notes Maoli Duan, MD, PhD, consultant and docent at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet in Sweden.
The researchers administered a gene therapy that used a synthetic AAV (the Anc80L65 capsid) to deliver a functional version of the OTOF gene to the inner ear. This was done via a single injection through a membrane at the base of the cochlea called the round window.
The study findings suggest that 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.
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 six to twelve months.
“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.”
“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.”
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