Some grow up in a world of silence — others retreat there quietly. According to the American Academy of Otolaryngology, congenital deafness — hearing loss caused by a mutation of genes — is one of the most commonly observed birth defects. It has been estimated that it can affect as many as three in every thousand babies. Now new hope might be on the way thanks to a team of scientists and a mouse called Beethoven.
The teams at Boston Children's Hospital, Harvard Medical School and École Polytechnique Fédérale de Lausanne in Switzerland have used gene therapy to restore the hearing of mice suffering from a genetic form of deafness. This breakthrough, it is thought, could offer hope for humans, too. Dr. Jeffrey Holt and his colleagues looked at a gene called TMC1. Though more than 70 different genes are known to cause deafness when they mutate, TMC1 was chosen because it is one of the most common causes, accounting for 4% to 8% of cases.
The researchers looked at two types of mice. The first had their TMC1 gene completely deleted, which meant it was a good representation of TMC1 problems in humans. Children born with two mutant copies of TMC1 have profound hearing loss from a very young age, usually from around 2 years old. In the other type of mouse — which the scientists named Beethoven — the TMC1 gene was mutated. The researchers tinkered with a single amino acid giving them a good model for the less common form of TMC1 deafness that causes children to gradually go deaf between the ages of 10 and 15 years.
The TMC1 gene is in charge of making the TMC1 protein. In 2013, Holt's team showed how TMC1 — and the related protein TMC2 — are vital for hearing. Hair cells in the inner ear have tiny projections called microvilli that use TMC1 and TMC2 proteins to form connections to the brain. When sound waves pass through the microvilli, the movement causes mechanical stimulation, which generates an electrical signal that, in turn, transmits aural messages to the brain.
Because this chain of communication relies on the TMC1 and TMC2 proteins to work properly, any mutation in the gene can lead to deafness. Holt's study also showed that gene therapy with TMC2 could compensate for loss of a TMC1 gene. The work proved that it was possible to restore hearing in the first mouse group — the deafness affecting younger children — and partially restore it in the "older" Beethoven group.
To deliver the gene to where it needed to be, the scientists used a specially engineered virus called AAV1, a technique that is considered safe and which is already in use to treat blindness, heart disease, muscular dystrophy and other conditions. The scientists say their work — published online July 8 by the journal Science Translational Medicine — shows great promise for the treatment of humans.
Most importantly, they say, 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," says Holt. In the Beethoven group, gene therapy with TMC2 was successful at the cellular and brain level, and partially successful at restoring actual hearing in the startle test.
Holt's team plan to refine their tests while following the treated mice to see if they retain hearing longer than the two months already observed. The long-term goal is to aim for clinical trials of TMC1 gene therapy within five to 10 years."Our gene therapy protocol is not yet ready for clinical trials," says Holt. "We need to tweak it a bit more — but in the not-too-distant future we think it could be developed for therapeutic use in humans."
Margaret Kenna MD, a specialist in genetic hearing loss at Boston Children's Hospital who is familiar with the research, is optimistic about the team's findings. "Current therapies for profound hearing loss like that caused by the recessive form of TMC1 are hearing aids, which often don't work very well, and cochlear implants," she says. "Cochlear implants are great, but your own hearing is better in terms of range of frequencies, nuance for hearing voices, music and background noise, and figuring out which direction a sound is coming from. Anything that could stabilize or improve native hearing at an early age is really exciting and would give a huge boost to a child's ability to learn and use spoken language."