Congenital deafness and the OTOF gene: gene therapy works

A form of congenital deafness present from birth will perhaps be treatable by intervening directly on the gene responsible. This is the proposal put forward in a new study published in Nature Medicine and conducted by researchers from various international institutions, including: Southeast University, Beijing Institute of Technology, Nantong University (China), Karolinska Institute (Sweden) and the University of California (USA). The team conducted a gene therapy trial on ten people affected by a rare hereditary from of hearing loss, and improvements were seen in all participants after just a few weeks.

Congenital hearing loss and the OTOF gene: what causes it

The research, which follows and integrates the results of a similar trial published in 2024, concerns individuals with mutations in the OTOF gene, responsible for the production of otoferlin: a protein essential for transmitting sound signals from the sensory cells in the inner ear to the auditory nerve. When the gene is altered, otoferlin doesn't function correctly and the signal generated by the inner ear cells can not be effectively transmitted. This can result in severe or profound congenital hearing loss.

It is the very presence of this well-known genetic defect that has made this type of deafness a particularly promising candidate for gene therapy: instead of merely amplifying the sound, as hearing aids do, or bypassing certain structures in the ear with cochlear implants, the aim here is to try to restore the altered biological mechanism.

How gene therapy for hearing loss works

The international researchers involved in the study used a viral vector, a modified virus made non-pathogenic, belonging to the family of adeno-associated viruses (AAVs): its role is to transport into the cells of the inner ear a functioning copy of the OTOF gene. All by means of a single injection in the inner ear.

The idea underlying gene therapy for hearing loss is that the cells reached by the vector can use the correct copy of the gene to produce otoferlin once more and so recover, at least in part, the ability to transmit the sound signal.

Hearing improves in all patients

At least six months after treatment, the average hearing threshold of the ten participants in the trial – children and young adults aged 1.5-23.9 years – fell from about 106 decibels to 52. That is a notable change: a hearing threshold above 100 decibels corresponds to an extremely severe loss of hearing, while a value of about 50 indicates significantly better hearing, albeit still some way from normal.

The improvement wasn't the same for all subjects: the best results were mostly observed in children aged 5-8. There was the especially significant case of a 7 year-old girl whose hearing, after treatment, returned to near normal levels and who, over the following months, was able to hold daily conversations with her mother.

The response was rapid in all cases: most subjects already showed a notable improvement just a month after the injection.

Older patients also respond well to gene therapy 

One of the more interesting aspects of this study was the age of the participants.

Previous trials on gene therapy for this type of genetic deafness had mostly involved very young children, but this research suggests that older people can also benefit.

This is especially important because the development of the auditory system and related language abilities mostly takes place in the first few years of life; it was therefore feared for a long time that the efficacy of late intervention would be limited.

Is this really a cure for congenital hearing loss? 

It is still too early to talk about a cure for congenital deafness. This study was an initial trial, conducted on a very limited number of subjects, with no control group and over a fairly short observation period.

There is also another fundamental limitation to bear in mind: the therapy was specifically developed for mutations in the OTOF gene, but the various types of hereditary deafness can also be caused by many other genes.

Despite this limitation, the results are also encouraging in terms of safety: during the 6-12-month observation period, no serious adverse events were noted attributable to the treatment.

This research thus shows something significant: it is now possible to use gene therapy to reach the cells of the inner ear and to recover auditory function. The next challenge will be to understand if a similar approach can also be developed for other forms of hereditary hearing loss.