Hearing in deaf mice was successfully restored using gene therapy.
Published in the journal, Science Translational Medicine, the study was a collaboration between Harvard Medical School, Boston Children's Hospital and the École Polytechnique Federale in Switzerland. The new findings may pave the way for gene therapy to be used on humans who suffer a genetic form of deafness.
According to the World Health Organization (WHO) an estimated 360 million people have a form of disabled hearing loss, and more than 70 different genes are known to cause deafness when affected. Prof. Jeffrey Holt of the Department of Otolaryngology, F.M. Neurobiology Centre at Boston and Harvard Medical School, worked with first-time author Charles Askew.
TMC1 was chosen as the specific gene to focus the study's efforts on because it is a common cause of genetic deafness, accounting for 4-8% of all cases. The gene encodes a protein that plays a central part in hearing by helping to convert sound into electrical signals.
Two types of mice were tested, one had the TMC1 gene deleted - a good model for humans with TMC1 mutations, as children who have two TMC1 mutations often undergo hearing loss at a very young age. The other mice carried a specific TMC1 gene mutation, known as Beethoven, which serves as a good model for TMC1 related deafness, where deafness occurs gradually between the ages of 10-15 years of age.
To deliver the healthy gene, scientists created an adeno-associated viral 1 (AAV1) together with a promoter, which serves as a genetic sequence that turns the gene on only in certain sensory cells of the inner ear known as hair cells.
Researchers screened several AAV1 serotypes and promoters to seek an efficient combination. They discovered one such combination was successful in restoring sensory transduction, auditory brainstem responses and acoustic startle reflexes in otherwise deaf mice.
The results proved to be outstanding. Scientists restored the ability of sensory hair cells to respond to sound enabling those mice carry the Beethoven gene to hear again. Hearing was tested by placing the mice in a "startle box" to measure their reactions. Prof. Holt explains: "Mice with TMC1 mutation will just sit there, but with gene therapy, they jump as high as normal mice."
Mice that carried the TMC1 gene deleted also showed promise, with some hearing partially restored.
A defining moment
The study was funded by the Bertarelli Foundation, and co-chair, Ernesto Bertarelli, described the result as a defining moment. He says:
"These findings mark a defining moment in the way we understand, and can ultimately challenge, the burden of deafness in humans. The results are a testament to the immense dedication of the research team and their commitment to bringing best-in-class science ever closer to the real world application."
The findings echo a study several years ago, in which researchers used a small genetic patch to successfully restore hearing in deaf mice with Usher syndrome.
AAV1 is already used in human gene therapy trials for blindness, heart disease, muscular dystrophy and other conditions. Holt believes these findings will pave the way for gene therapy to be used on humans in the "not too distant future." He says:
"I can envision patients with deafness having their genome sequenced and a tailored, precision medicine treatment injected into their ears to restore hearing. This is a great example of how the basic science can lead to clinical therapies."