We’re getting closer to a breakthrough on hearing loss

For years, researchers focused primarily on Atoh1.

The strategy made sense. Atoh1 functions as one of the earliest signals involved in hair cell formation. If scientists could reactivate it in damaged ears, perhaps new hair cells would emerge.

Some regenerated cells expressed genes characteristic of hair cells, but many remained developmentally immature. They lacked fully formed stereocilia bundles, many of the features that distinguish specialized inner and outer hair cells, or the neural connections required for hearing. Even so, the experiments put researchers on a promising new path.

“It opened the road for others to consider gene therapy,” says Alan Cheng, a surgeon and professor of otolaryngology at Stanford University.

The experience revealed an important lesson: Hair cells are not created by a single developmental instruction.

Researchers began adding other factors.

A 2020 study showed that multiple transcription factors could reprogram cells into hair-cell-like states. That work helped narrow the focus to the now widely studied combination of Atoh1, Gfi1 and Pou4f3.

Together, these three factors produced substantially more hair-cell-like cells than Atoh1 alone and increased the efficiency of cellular reprogramming. More recent studies have also shown that adding additional developmental regulators can push some regenerated cells toward more mature inner or outer hair-cell identities.

“Transcription factors often act in concert, just like a basketball team,” says Cheng. “They are more potent when they work together.”

The three factors appear to activate overlapping genetic programs involved in hair cell development. Rather than acting independently, they reinforce one another, turning on cascades of genes that help drive cells toward a hair cell identity.