[Un article de The Conversation écrit par Maoli Duan – Associate Professor, Senior Consultant, Karolinska Institutet]
It is estimated that nearly 3 in 1,000 newborns have a unilateral or bilateral hearing loss when they come to the world. If the installation of cochlear implants can improve the situation of these children, it is at the cost of an invasive surgery. In addition, these devices are not able to fully reproduce the finesse of natural hearing.
The results we have obtained recently, however, open another track: our research indicates that gene therapy can restore hearing, not only in some toddlers, but also in young adults with congenital deafness.
Our work focused on people with deafness due to changes in the OTOF gene, responsible for the production of the Otoferline protein. The latter ensures the transmission of hearing signals of the inner ear to the brain, which makes it essential.
Contrary to what is happening in the case of other forms of deafness of genetic origin, in individuals carrying mutations in the OTOF gene, the structures of the inner ear remain intact, which makes it perfect candidates for gene therapy. Indeed, this approach consists in replacing the defaulting gene with a functional version: in case of success, the existing structures work normally again, and the hearing is restored.
To transport a functional copy of the OTOF gene in the right place, that is to say in the hair cells of the inner ear, we used as vectors of modified viruses. These can be seen as “molecular postal workers”: they are able to “deliver” genetic repair precisely where it is required.
At first, modified viruses are fixed at the membrane of hair cells. They then induce their internalization, in other words their transport in said cells. Once entered, they continue their journey to the nucleus of the cells, where they release the genetic instructions which will allow the production of otoferline within auditory nerve cells.
We had previously tested this protocol in animals (primates), to confirm the safety of this viral therapy, before starting clinical studies in young children (aged five and eight years). We have thus been able to see its restoration potential: the hearing levels obtained after treatment sometimes turned out to be almost normal.
Nevertheless, two major questions remained unanswered: what would the effectiveness of this approach in older patients? And is there an optimal age group for the application of treatment?
To answer it, we have extended our clinical trial to five hospital centers, which allowed us to recruit ten participants aged 1 to 24, all suffering from OTOF deafness. Everyone received an injection into the inner ear.
Participants were then closely followed for 12 months, thanks to otological examinations and blood tests, in order to detect any problem.
Hearing improvements have been estimated in two ways: by objective tests for the brainstem, and by behavioral assessments. In the first case, patients hear rapid clicks (or beeps) corresponding to different frequencies, while sensors measure the automatic electrical response of their brain to these sound stimulation. In the second case, equipped with a helmet in which very low beeps are diffused, the patients report each stimulus perceived by pressing a button or raising the hand, whatever its intensity.
The progress observed has been both rapid and significant, especially among the youngest: from the first month, the average hearing improvement reached 62 % according to the evaluation by objective tests and 78 % according to behavioral assessments. Two participants found a perception of the almost normal voice; The mother of a seven -year -old child reported that her son perceived barely three days after the administration of treatment.
During the twelve months that the study lasted, low to moderate side effects were found in ten patients, the most common of them being a decrease in the number of white blood cells. No serious adverse event has been observed, which confirms that this therapy has a favorable security profile.
Genetic deafness treatment
It should be noted that this is the first time that such results have been obtained in adolescents and adults with OTOF deafness.
In addition, this work informed us about the ideal intervention window. Indeed, the most important gains have been observed in children aged five to eight. The hearing of toddlers and older patients has also improved, but progress has been less spectacular.
This observation, a priori counter-intuitive, suggests that the capacity of the brain to integrate sounds newly returned by the hearing system varies according to age. The reasons explaining this situation remain to be determined.
This essay constitutes a milestone: it made it possible to fill the gap that existed between experiments in animals and studies in humans, by covering moreover is a wide range of age. There are still questions unanswered about the persistence over time of the improvements noted. But gene therapy continues to progress, and the possibility of using it to cure deafness of genetic origin (and no longer only managing it) is becoming a reality.
These works focused on deafness linked to the mutations of the Otof gene, but this is only a start. Our team (and others) already develop therapies targeting different genes, also involved in deafness, but more widespread. These cases are much more complex to treat, however the preclinical results already obtained are promising. This allows us to consider with confidence the fact that in the future, gene therapy can be used to deal with many other forms of deafness of genetic origin.
With an unwavering passion for local news, Christopher leads our editorial team with integrity and dedication. With over 20 years’ experience, he is the backbone of Wouldsayso, ensuring that we stay true to our mission to inform.
