Gene therapy partially restores hearing in children with congenital deafness

A group of Chinese researchers have published the results of a clinical trial of gene therapy for a form of hereditary deafness. A normal gene was delivered to patients' inner ear cochlea using an adeno-associated virus. The therapy did not cause any serious side effects, but did restore some hearing in the children. The researchers hope that the approach could be used for patients with other forms of hereditary deafness.

Mutations in some genes can lead to nonsyndromic deafness — partial or complete hearing loss without any other clinical manifestations. Most of these disorders (about 80%) are inherited in an autosomal recessive manner — that is, regardless of gender and with the possibility of compensating for the function of the damaged gene with the only “healthy” one, if there is one (this is similar to living with a single kidney).

The forms of non-syndromic deafness do not have separate names, but are simply referred to by number - depending on the order in which they were discovered. Each of them is associated with one gene.

Autosomal recessive deafness 9, in particular, is associated with a mutation in the gene of the protein otoferlin ( OTOF , Fig. 1, see otoferlin ). This name and designation of the gene is due to the fact that it was discovered by classical methods - a targeted search for a locus associated with cases of hereditary deafness. The gene was "lucky" to be discovered before the invention of whole-genome search methods - therefore, it does not have an uninformative name of letters and numbers, which is assigned to the gene when reading the entire genome, but a beautiful name reflecting the clinical picture of the disease caused by its mutation. It turns out that autosomal recessive deafness 9 has been known for quite a long time - including in the context of its genetic association.

Otoferlin belongs to a large family of proteins that ensure the fusion of membrane vesicles, which store neurotransmitters, with the cell membrane. Its normal function is necessary for the unusual synapses of the cochlea in the inner ear.

In the organ of Corti of the cochlea, the nerve fibers of the auditory nerve do not perceive sound vibrations directly: this function is performed by hair cells, vibrating under the action of a sound wave and responding to it with an electrical signal (Fig. 2). But there is no direct electrical contact between them and the fibers of the auditory nerve - therefore, the transmission of excitation is carried out due to the neurotransmitter glutamate, prepared in advance by hair cells in membrane vesicles. Otoferlin is necessary so that when the hair cells are electrically excited, the vesicles "open" in time and release glutamate into the synaptic cleft, where it will be felt by receptors on the fibers of the auditory nerve (Fig. 3).

A mutation in the otoferlin gene leads to protein inactivation and the inability of hair cells to release the neurotransmitter. Therefore, the disease is clinically manifested as auditory nerve neuropathy. Instrumental studies show the viability of hair cells: they continue to generate an electrical potential in response to sound, and their vibrations can be recorded as a sound from the cochlea ( otoacoustic emission ). But an attempt to measure the auditory evoked potentials of the brainstem shows that the signal along the auditory nerve either does not reach the brain at all, or is sharply weakened (in the latter case, the patient retains poor hearing - he can hear a scream near the auricle).

It turns out that all the structures of the inner ear in this form of hereditary deafness are, in principle, intact - and it is enough to deliver a normal otoferlin gene to the hair cells so that a functional protein is synthesized from it. Then it will ensure the fusion of vesicles with the membrane, the synaptic cleft will be filled with a neurotransmitter in response to sound, and the patient will gain hearing.

Such manipulation can be carried out in an already formed organism, and not only in a zygote, thanks to the adeno-associated virus . Its principle of action resembles the Sputnik V vaccination: the vaccine adenovirus "forces" muscle cells to synthesize the S-protein of the virus, and the adeno-associated virus, into which the normal otoferlin gene is introduced, can "force" hair cells to synthesize normal otoferlin.

Of course, an injection of such an adenovirus should not be done in the deltoid muscle, but in the cochlea of the inner ear. Fortunately, ENT doctors can perform such an intervention relatively safely - surgical access to the inner ear has been worked out due to the many interventions performed on cochlear implantation . Since the cochlea itself is a bone structure, the needle is inserted into it through the membrane of the round window.

Let me remind you that the cochlea of the inner ear (the outer walls of which are represented by bone tissue) has two windows covered with soft membranes. The oval window is struck by the stapes - one of the bones of the middle ear, mechanically transmitting sound to the cochlea. Accordingly, it is impossible to make an injection through the membrane of the oval window.

But there is also a round window, free of additional bones. The task of the membrane that covers it is to provide free space for the movement of the liquid that fills the cochlea: after all, it is incompressible, like any liquid, and without a free membrane we would not hear quiet sounds, and the first loud one would destroy the cochlea due to water hammer.

Evolutionarily, the round window membrane was formed for this purpose. But, as we see, it came in handy for an injection...

An adeno-associated virus carrying the normal otoferlin gene was created in 2024. At the same time, it was tested on several children - up to 6 patients from 1 to 11 years old. The treatment led to them being able to communicate at the level of a normal conversation - which is already an achievement! However, this is too narrow an age group for a clinical trial. We did not know whether the "therapeutic" virus works on teenagers or infants - and after all, a patient can get to an audiologist at this age.

A recent article in Nature Medicine describes the first full-scale clinical trial of gene therapy with an adeno-associated virus carrying the normal otoferlin gene. “Full-scale” is a relative term here. The pathology in question is an orphan disease, like many other gene diseases. Therefore, the study included only 10 patients and 13 ears. Why such a discrepancy? The fact is that most patients receive an injection in only one ear, and only a few in both. This reduces the risk of complications if the patient has residual hearing.

The study was also non-comparative, meaning there was no control group. Given the nature of the intervention, this is justified: injecting a placebo into the cochlea would have carried unacceptably high risks for the patient relative to the benefits. However, this is the first study to cover the entire spectrum of pediatric patients, from infants to adolescents.

If we take the "average temperature in the hospital" - the average values for all patients, then we get a rather encouraging picture. Before treatment, patients on average heard sounds only starting from 106 decibels - this is the volume of a jackhammer or an airplane engine. By the end of treatment, patients on average heard sounds starting from 52 decibels - and this is already loud speech or the noise of a vacuum cleaner. That is, it was possible to talk to a virtual average child after such treatment.

Unfortunately, the success rate varied from patient to patient. The best result was achieved by a seven-year-old girl, who responded to the therapy with almost complete hearing restoration. Overall, the effect was best in the 5-8 age group. Teenagers and children aged 1-2 responded worse to the treatment. Young children were a particular puzzle for the researchers: it is generally believed that in early childhood the body's compensatory capabilities are almost unlimited. The researchers tested various hypotheses, including hydraulic damage to the infant cochlea by the volume of injected fluid, but they were unable to find a satisfactory explanation.

There were no serious side effects during treatment or for six months after. Of the minor ones, there was a decrease in the level of neutrophils in the blood, which remained a change in the laboratory indicator, which did not significantly affect the lives of the little patients.

The effect of the therapy was relative, but its manifestation itself represents a significant breakthrough. This is the first demonstration of the effectiveness and safety of gene therapy for structures of the cochlea — and a great reserve for the future treatment of other forms of deafness. In a press release on the article, the researchers expressed hope that they will be able to use these developments to treat more common forms of hereditary deafness — for example, those associated with the GJB2 and TMC1 genes. So far, according to the researchers, attempts have been made to treat these forms only in laboratory animals, so it is too early to talk about custom-made adeno-associated viruses instead of hearing aids. But who knows — maybe they will write about this soon too...

Source: Jieyu Qi, Liyan Zhang, Ling Lu, Fangzhi Tan, Cheng Cheng, Yicheng Lu, Wenxiu Dong, Yinyi Zhou, Xiaolong Fu, Lulu Jiang, Chang Tan, Shanzhong Zhang, Sijie Sun, Huaien Song, Maoli Duan, Dingjun Zha, Yu Sun, Xia Gao, Lei Xu, Fan-Gang Zeng & Renjie Chai. AAV gene therapy for autosomal recessive deafness 9: a single-arm trial // Nature Medicine . 2025. DOI: 10.1038/s41591-025-03773-w.

Georgy Kurakin