Discovery lays foundation for gene therapy in hereditary deafness

GAINESVILLE, Fla. — A new mechanistic discovery in a hereditary form of deafness could pave the way for using gene therapy to “tune” the ear’s sound-sensitive hair cells and change life for babies born with an inability to hear due to Usher syndrome.

The preclinical discovery in mice comes at a time of great excitement about the potential of inner-ear gene therapy to initiate or restore hearing: In April, the FDA approved the first-ever gene therapy for inherited deafness, for a similar but distinct condition caused by mutations in the otoferlin gene

Now, researchers hope they can follow a similar path for children born with the rare and devastating Usher syndrome, which causes combined deafness and blindness.

In a paper published in Nature Communications, a research team co-led by University of Florida neuroscientist Jonathan Bird, Ph.D., and collaborators at the University of Virginia and the University of Colorado describe how mutations in the MYO7A gene may affect a tuning mechanism required for auditory hair cells to detect sound.

MYO7A has been extensively studied in Usher syndrome type 1B and is thought to tune the hair cell’s response to sound, similar to changing the tension on a violin string. How this tension might be tuned, though, has remained a mystery until now.

To investigate the precise role of MYO7A, researchers ran genetic sequencing of hair cells in the cochlea, a snail-shell-like hollow tube in the inner ear that detects sounds of different frequencies. The sequencing revealed a new form of MYO7A that hadn’t been detected or studied before, and they named it MYO7A-N.

“Our paper is the first to show that an array of differing MYO7A proteins contributes to tuning this ‘violin string,’” said Bird, a researcher at UF’s McKnight Brain Institute. “When we then isolated and purified these MYO7A proteins, we found they had different motor activities. As you increase the amount of MYO7A-N, you can change the mechanical tuning of the system.”

The finding revealed an “unexpected layer of molecular diversity” within the ear’s machinery, the researchers reported.

The ear is full of microscopic hair-like “antennas” that are bridged by sensitive filaments which open a tiny channel when stimulated by sound. Like strings on a violin, these filaments have to be correctly tensioned or they won’t work properly. The MYO7A molecules are thought to act as “nanomotors” that work to maintain constant tension on these filaments.

Using mouse models, researchers demonstrated how different forms of MYO7A, including the newly discovered MYO7A-N, change their relative amounts as hair cells switch from detecting high- to low-pitch sounds, revealing the potential basis for a tuning mechanism.

Going forward, the study may offer a new framework for further research that could one day lead to a new treatment for Usher syndrome type 1B. One component, the study suggests, is that gene therapies would need to restore all the multiple forms of MYO7A protein to maximize the potential for therapeutic success.