New gene-delivery therapy restores partial hearing in mice

Using a novel form of gene therapy, scientists have successfully restored partial hearing and balance in mice born with a genetic condition that affects both.
The new 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.
These cells have been notoriously difficult to treat with previous gene-delivery techniques.
Researchers from Harvard Medical School and the Massachusetts General Hospital in the US, showed that the treatment leads to notable gains in hearing and allows mice that would normally be completely deaf to hear the equivalent of a loud conversation.

The approach also improved the animals' sense of balance.
The gene therapy carries the promise of restoring hearing in people with several forms of both genetic and acquired deafness, researchers said.

"To treat most forms of hearing loss, we need to find a delivery mechanism that works for all types of hair cells," said David Corey, professor at HMS.
To achieve that, researchers used the adeno-associated virus (AAV). It has been already used as a gene-delivery vehicle for retinal disorders.
To super-charge AAV as a gene carrier into the inner ear, the team used a form of the virus wrapped in protective bubbles called exosomes.

They grew regular AAV virus inside cells. Those cells naturally bud off exosomes - tiny bubbles made of cell membrane - that carry the virus inside them.
The membrane wrapping around the virus is coated with proteins that bind to cell receptors.
"Unlike current approaches in the field, we didn't change or directly modify the virus. Instead, we gave it a vehicle to travel in, making it better capable of navigating the terrain inside the inner ear and accessing previously resistant cells," said Casey Maguire, assistant professor at HMS.
In lab dish experiments, exo-AAV successfully penetrated 50-60 per cent of hair cells, researchers observed. By contrast, AAV alone reached a mere 20 per cent of hair cells.

To test the approach in living animals, researchers worked with mice born without a gene critical for hair cell function. Such animals normally cannot hear even the loudest sounds and exhibit poor balance.
Researchers injected exo-AAV preloaded with the missing gene into the inner ears of mouse pups, shortly after birth.
Post-treatment tests showed that the gene entered between 30 and 70 per cent of hair cells, reaching both inner and outer hair cells.
A month after treatment, nine of 12 mice had some level of hearing restored and could be startled by a loud clap.
Four could hear sounds of 70 to 80 decibel intensity, the rough equivalent of conversation in a loud restaurant.

Treated mice had notably improved balance, showing far less head tossing or running in circles, both markers of instability or disorientation.