Using gene therapy, researchers have restored hearing in mice with a genetic form of deafness. Their work, published online in the journal Science Translational Medicine, could pave the way for gene therapy in people with hearing loss caused by genetic mutations.
More than 70 different genes are known to cause deafness when mutated. The researchers focused on a gene called TMC1. They chose TMC1 because it is a common cause of genetic deafness, accounting for 4 to 8 percent of cases, and encodes a protein that plays a central role in hearing, helping convert sound into electrical signals that travel to the brain.
The researchers tested gene therapy in two types of mutant mice. One type had the TMC1 gene completely deleted, and is a good model for recessive TMC1 mutations in humans: Children with two mutant copies of TMC1 have profound hearing loss from a very young age, usually by around 2 years.
The other type of mouse, called Beethoven, has a specific TMC1 mutation - a change in a single amino acid - and is a good model for the dominant form of TMC1-related deafness. In this form, less common than the recessive form, a single copy of the mutation causes children to gradually go deaf beginning around the age of 10 to 15 years.
To deliver the healthy gene, the team inserted it into an engineered virus called adeno-associated virus 1, or AAV1, together with a promoter - a genetic sequence that turns the gene on only in certain sensory cells of the inner ear known as hair cells. They then injected the gene-bearing AAV1 into the inner ear.
In the recessive deafness model, gene therapy with TMC1 restored the ability of sensory hair cells to respond to sound - producing a measurable electrical current - and also restored activity in the auditory portion of the brainstem.
Most importantly, the deaf mice regained their ability to hear. To test hearing, the researchers placed the mice in a "startle box" and sounded abrupt, loud tones. Mice with TMC1 mutations will just sit there, but with gene therapy, they jump as high as a normal mouse. The force of their jump was measured by a plate on the floor underneath them; it was detectable at sounds beginning around 80 decibels.
In the dominant deafness model, gene therapy with a related gene, TMC2, was successful at the cellular and brain level, and partially successful at restoring actual hearing in the startle test.
AAV1 is considered safe as a viral vector and is already in use in human gene therapy trials for blindness, heart disease, muscular dystrophy and other conditions. The researchers screened various types of AAV and various types of promoters to choose the best-performing combination. They plan to further optimize their protocol and follow their treated mice to see if they retain hearing longer than the two months already observed. They hope to start clinical trials of TMC1 gene therapy within 5 to 10 years.
Based on material originally posted by Boston Children's Hospital.