This is a Translational Research Grant awarded to Professor Els Henckaerts at the KU Leuven, Belgium. It started in June 2024.
Background
Approximately half of all childhood hearing loss has a genetic cause, with many different genes playing a role. One of these genes is the OTOF gene, which produces a protein called otoferlin. Otoferlin is essential for transmitting sound signals from inner hair cells in the ear to the brain.
When children have mutations in the OTOF gene, the otoferlin protein may not function properly, or may not be produced at all, leading to hearing loss.
Currently, children with otoferlin-related hearing loss are offered cochlear implants, which can improve hearing and speech comprehension. However, cochlear implants do not fully restore natural hearing.
Aim
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, because the OTOF gene is large, it cannot fit into a single virus. Instead, the gene is split in half, with each half delivered by a separate virus. Once inside the hair cells, the two halves must recombine to form a complete, functional gene.
While this method has been shown to restore hearing in clinical trials for children with OTOF-related hearing loss, it isn’t fully effective. The main issue is that 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 seeks to improve gene therapy for otoferlin-related hearing loss by using a new technology called “split inteins,” which mediates efficient recombination of two OTOF protein fragments rather than DNA fragments.
Early results generated in the lab suggest this technique significantly improves recombination, resulting in higher levels of otoferlin protein production.
Once the team optimises 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.
Benefit
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.