Up to three people in every 1,000 newborns have hearing loss in one or both ears. Cochlear implants provide significant hope for these children, but invasion surgery is required. These implants are also unable to fully replicate the nuances of natural hearing.
However, a recent study by my colleagues and I have shown that a form of gene therapy can successfully restore hearing in young children and young adults born with congenital hearing loss.
Our study focused specifically on young children and young adults born with OTOF-related hearing loss. This condition is caused by a mutation in the OTOF gene, which produces the otoferlin protein, an auditory important protein.
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Proteins transmit auditory signals from the inner ear to the brain. Mutations in this gene disrupt the transmission, leading to severe hearing loss from birth.
Unlike other types of genetic hearing loss, people with OTOF mutations have healthy hearing structures in their inner ear. The problem is simply that one important gene is not functioning properly. This makes it an ideal candidate for gene therapy. If the disordered genes can be modified, existing healthy structures should be able to restore hearing.
In our study, modified viruses were used as delivery systems to carry a working copy of the OTOF gene directly to auditory cells in the inner ear. Viruses act like molecular courier services, providing precise genetic modifications wherever necessary.
Related: Gene Therapy: What is it and how does it work?
The modified virus does this by first attaching itself to the surface of the hair cells, and then persuading the cells to swallow them as a whole. Once inside, they ride the cell’s natural transport system and all the way to its control center (nuclear). There, they eventually release the genetic instructions of otoferlin into auditory neurons.
Our team previously conducted studies of primates and young children (ages 5 and 8) who confirmed that viral therapy was safe. We were also able to explain the potential treatments that restore hearing.
However, important questions remained about whether treatment could work in older patients and the optimal age for patients to receive treatment.
To answer these questions, we enrolled 10 participants aged 1 to 24 years old and expanded the clinical trials in five hospitals. All were diagnosed with OTOF-related hearing loss. Viral therapy was injected into the inner ear of each participant.
We closely monitored the safety of the study over the 12 months through ear testing and blood tests. Audit improvement was measured using both objective brainstem response tests and behavioral hearing assessments.
From brainstem response tests, patients heard the sensor quickly click on sounds of various pitches or short beeps while measuring the brain’s automated electrical response. In another test, patients heard a constant, stable tone at different pitches, but the computer analyzed the brain waves to see if they automatically tracked the rhythm of these sounds.
For behavioral hearing assessment, patients wore headphones and heard faint beeps at different pitches. They pressed buttons and raised their hands every time they heard the beep.
Hearing improvement was rapid and important, especially in younger participants. Within the first month of treatment, mean hearing improvement reached 62% on objective brainstem response tests and 78% on behavioral hearing assessments. Two participants achieved almost normal speech recognition. Parents of one 7-year-old participant said their children could hear the sounds just three days after treatment.
During the 12-month study period, 10 patients experienced very mild to moderate side effects. The most common adverse effect was a decrease in leukocytes. Importantly, no serious adverse events were observed. This confirmed the preferred safety profile of this virus-based gene therapy.
Treatment of genetic hearing loss
This is the first time such results have been achieved in both adolescents and adult patients with OTOF-related hearing loss.
The findings also reveal important insights into the ideal treatment window, as children aged 5 to 8 show the most notable benefits.
Younger children and older participants also showed improvement, but their recovery was less dramatic. These counterintuitive outcomes in younger children are surprising. Although early conserved inner ear integrity and function should theoretically predict a better response to gene therapy, these findings suggest that the brain’s ability to process newly restored sounds may vary with age. The reason for this is not yet understood.
This exam is a milestone. By bridging the gap between animal and human studies and diverse patients of various ages, we are entering a new era in treating genetic hearing loss. As gene therapy continues to progress, there are still questions about how long the benefits of this therapy will last, but as genetic hearing loss is becoming a reality, it can not only be managed, but it can cure it.
OTOF-related hearing loss is just the beginning. We are working with other research teams to develop treatments targeting other more common genes associated with hearing loss. These are more complicated to treat, but animal studies have provided promising results. We are optimistic that in the future, gene therapy will become available for various types of genetic hearing loss.
This edited article will be republished from the conversation under a Creative Commons license. Please read the original article.
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