Gene therapy tests restore hearing in deaf mice

Written By: Eric Hopton

Published Date: July 9, 2015 Last Edited: July 9, 2015

Emily Bills

Eric Hopton for redOrbit.com – Your Universe Online

Researchers at Boston’s Children’s Hospital and Harvard Medical School have made a significant breakthrough by using gene therapy to restore hearing in deaf mice. The proof of concept project could be a defining moment in the fight against genetic forms of deafness in humans.

Severe to profound hearing loss in both ears affects between 1 and 3 babies for every 1,000 live births, and scientists have identified more than 70 different genes that can cause deafness when mutated. But the Boston and Harvard team focused on a gene called TMC1 that’s involved in 4 to 8 percent of cases. TMC1 encodes a protein playing a central role in hearing and helps convert sound into electrical signals which are then sent to the brain.

The “Beethoven” mouse

Two types of mutant mice were tested. One type had the TMC1 gene completely deleted. This is a good model for recessive TMC1 mutations in humans as children with two mutant copies of TMC1 have profound hearing loss from a very young age, usually by around 2 years old.

The other type of mouse, called the Beethoven mouse, 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 less common form, a single copy of the mutation causes children to gradually go deaf beginning around the age of 10 to 15.

The team first inserted the healthy gene into an engineered virus called adeno-associated virus 1, (AAV1) together with a promoter – a genetic sequence which 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.

Exciting results

In the recessive deafness model, TMC1 gene therapy 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,” said Jeffrey Holt, PhD, a scientist in Boston’s Department of Otolaryngology.

In the dominant deafness model, gene therapy with TMC2, was successful at the cellular and brain level, and partially successful at restoring actual hearing as shown in the startle test.

“Our gene therapy protocol is not yet ready for clinical trials. 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,” said Holt.

Tailor-made precision treatment on the way

The team plans to further optimize their protocol and follow the 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.

Holt believes the same gene therapy strategy could also work for other forms of genetic deafness. “I can envision patients with deafness having their genome sequenced and a tailored, precision medicine treatment injected into their ears to restore hearing,” he said.

“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. 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,” said Margaret Kenna, MD, MPH, and a specialist in genetic hearing loss at Boston Children’s Hospital.

“These findings mark a defining moment in the way we understand, and can ultimately challenge the burden of deafness in humans,” said Ernesto Bertarelli, co-chair of the Bertarelli Foundation, the primary funder of the research.

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