Using a novel form of gene therapy, scientists at HMS and Massachusetts General Hospital have managed to restore partial hearing and balance in mice born with a genetic condition that affects both.
The model overcomes a long-standing barrier to accessing hair cells, the delicate sensors in the inner ear that capture sound and head movement and convert them to neural signals for hearing and balance. The findings appeared in the February issue of Molecular Therapy.
Although the approach is years away from use in humans, gene therapy could help restore hearing in several forms of genetic and acquired deafness. Some 30 million people in this country suffer from hearing loss, and every year, about one in 1,000 babies are born with a hearing impairment, according to the U.S. Centers for Disease Control and Prevention.
In their quest to restore hearing through gene therapy, scientists have long sought ways to improve gene delivery into hair cells. Previous approaches were only marginally effective as they reached one set of hair cells in the inner ear, while hair cells in the outer ear—equally critical for hearing—remained largely impenetrable.
“To treat most forms of hearing loss, we need to find a delivery mechanism that works for all types of hair cells,” says neurobiologist David Corey, the Bertarelli Professor of Translational Medical Science at HMS and co-senior investigator on the study.
To achieve that, the researchers used adeno-associated virus (AAV), which is already used as a gene-delivery vehicle for retinal disorders but had not been effective in hair cells.
To improve the chances of delivery into the hair cells, the team wrapped a form of AAV in cell-membrane bubbles called exosomes, an approach recently developed by study co-senior author Casey Maguire, an HMS assistant professor of neurology at Mass General, and research team member Xandra Breakefield, an HMS professor of neurology at Mass General. The membrane wrapping the virus is coated with proteins that bind to cell receptors. This protein coat may help the bubble-wrapped form of AAV, or exo-AAV, effectively bind to and penetrate the hair cells, says Maguire.
In lab dish experiments, exo-AAV penetrated 50 to 60 percent of hair cells, the researchers observed; AAV alone penetrated only 20 percent of the cells.
The researchers tested the approach in mice born without a gene critical for hair cell function. Such animals normally cannot hear even the loudest sounds and exhibit poor balance. Post-treatment tests revealed that the gene entered between 30 and 70 percent of hair cells and reached both inner and outer ear hair cells.
A month after treatment, nine of twelve mice had some level of hearing restored and could be startled by a loud clap, a standard behavioral test for hearing. Four could hear sounds of 70 to 80 decibel intensity, the rough equivalent of conversation in a loud restaurant. Treated mice also had notably improved balance, compared with their untreated counterparts, showing far less head tossing or running in circles, both markers of instability or disorientation.
Image: Harvard Medical School