In this project, Professor Els Henckaerts at KU Leuven, Belgium, is developing a method to improve the efficacy of gene therapy for hearing loss caused by mutations in the OTOF gene.
Project start date: June 2024
Project end date: May 2026
Read about the project outcomes here.
About the project
Mutations in the OTOF gene cause hearing loss because they prevent the production or the correct functioning of the otoferlin protein, which is essential for the sound-sensing cells (called inner hair cells) of the ear to transmit sound signals to the brain. Currently, children with otoferlin-related hearing loss are offered cochlear implants, which do not fully restore natural hearing.
Researchers are developing gene therapies that aim to deliver a healthy copy of the OTOF gene directly to the affected inner hair cells, so they can function normally. These therapies use a harmless virus to transport the correct version of the OTOF gene into the ear. However, the OTOF gene is too large to fit into a single virus, so it is split in half, with each half of the gene delivered by a separate virus.
Once inside the cell, the two halves recombine to form the complete gene. The process of recombining the two gene halves inside the cell is inefficient, resulting in low levels of otoferlin protein production and only partial hearing restoration. This project aims to improve the efficiency of gene therapy for otoferlin-related hearing loss.
How it works
The researchers will use a new technology called “split inteins,” which mediates efficient recombination of two protein fragments rather than gene fragments. Early results generated in the lab suggest this technique significantly improves recombination, resulting in higher levels of otoferlin protein production. Once the team optimizes this technology in cells, they will test it in mouse models of
otoferlin-related hearing loss. Additionally, they will explore the safety and efficacy of combining gene therapy with cochlear implants.
How will this research benefit people with hearing loss?
If successful, this innovative approach could lead to long-lasting and effective treatments for children with otoferlin-related hearing loss, as well as other genetic forms of hearing loss.
It offers the potential for better hearing outcomes than current therapies, bringing us closer to restoring natural hearing in affected children.
What we’ve learned so far
PhD student Wout Verscheure has tested many conditions to find the most promising intein-based genetic constructs. Delivering gene therapies to the mouse cochlea is extremely delicate, so the researchers have established a robust platform for precise, reproducible cochlear injections. These constructs are now being evaluated in mouse models of otoferlin‑related hearing loss.
About the researchers
Professor Els Henckaerts leads the Trellis research group at KU Leuven. The team includes Wout Verscheure (PhD student), Thomas Matheussen, (research technician) and Simon Sinnaeve (PhD student).
As a researcher, my ultimate motivation has always been to bridge the gap between science and life-changing medicine. Seeing first-generation therapies offer hope to families affected by OTOF mutations is incredibly inspiring – but it also challenges us to make those treatments even better, safer, and more effective.”
Dr Filip de Vin leads the inner ear gene therapy programme within Trellis Research Group at KU Leuven.
My research goal is to fully restore hearing in children with DFNB9 by developing a next‑generation otoferlin gene therapy that is more efficient than current approaches. I have wanted to be a scientist for as long as I can remember, and turning difficult biological problems into concrete solutions for patients is what motivates me every day.”
