Gene editing may be a path to restore partial hearing

When Wei Hsi “Ariel” Yeh was an undergraduate, one of her close friends went from normal hearing to complete deafness in one month.

He was 29 years old. Doctors didn’t know why then and still don’t. Frustrated and fearful for her friend, Yeh, who graduated last month with a Ph.D. from the Graduate School of Arts and Sciences, dedicated her research in chemistry to solving some of the vast genetic mysteries behind hearing loss.

One in eight people aged 12 years or older in the U.S. has hearing loss in both ears. Technologies like hearing aids and cochlear implants can amplify sound but can’t correct the problem. Perhaps gene editing could, scientists decided, since genetic anomalies contribute to half of all cases.

Two years ago, Yeh and David R. Liu, Thomas Dudley Cabot Professor of the Natural Sciences and a member of the Broad Institute and the Howard Hughes Medical Institute (HHMI), repaired a dominant mutation and prevented hearing loss in a mouse model for the first time. But, Liu said, “Most genetic diseases are not caused by dominant mutations. They’re caused by recessive ones, including most genetic hearing losses.”

Now, Liu, Yeh, and researchers at Harvard, the Broad, and HHMI have achieved another first: They restored partial hearing to mice with a recessive mutation in the gene TMC1 that causes complete deafness, the first successful example of genome editing to fix a recessive disease-causing mutation.

Dominant disease mutations, meaning those that affect just one of the body’s two copies of a gene, in some ways are easier to attack. Knock out the bad copy, and the good one can come to the rescue. “But for recessive diseases,” Liu said, “you can’t do that. By definition, the recessive allele means that you have two bad copies. So, you can’t just destroy the bad copy.” You have to fix one or both.

To hear, animals rely on hair cells in the inner ear, which ripple under the pressure of sound waves and send electrical impulses to the brain.

The recessive mutation to TMC1 that Liu and Yeh hoped to correct causes rapid deterioration of those hair cells, leading to profound deafness in mice at just 4 weeks of age.