Scientists at Boston Children’s Hospital have successfully used gene therapy to reverse a form of genetic hearing loss in mice. The team corrected a gene mutation that affects sensory hair cells in the inner ear, and the new jigsaw-like method could help improve gene therapy for other disorders.

The target of the new treatment was a gene called STRC, which is implicated in up to 16 percent of all genetic hearing loss cases. This gene encodes for a protein called stereocilin, which builds a scaffold for hair cells in the ear that keeps them in contact with the tectorial membrane. This membrane vibrates in response to sound, and the hair cells pick up these vibrations and convert them into electrical signals that are then sent to the brain. But a mutation to the STRC gene can interrupt this process.

“If stereocilin is mutated, you don’t have that contact, so the hair cells are not stimulated properly,” says Jeffrey Holt, senior investigator of the study. “But importantly, the hair cells still remain functional, so they are receptive to the gene therapy. We think this will provide a broad window of opportunity for treatment – from babies to adults with hearing loss.”

To target the mutation, the team packaged a healthy version of the STRC gene into a synthetic vehicle called an adeno-associated virus (AAV), designed to seek out hair cells. This gene therapy was then administered to mice with STRC hearing loss. A few weeks after the treatment, the team examined the mouse cochleas under a microscope and found that up to 64 percent of their hair cell bundles were more organized.

Next, the team tested how this affected their hearing, using a hearing test similar to those used for babies, as well as measuring their brain responses to different sounds. And sure enough, the treated mice scored much higher, displaying sensitivity to subtle sounds and the ability to differentiate between frequencies. In some cases, the mice were hearing at normal levels again.

With these promising results in mice, the team next plans to test the technique in human cells in the lab, taken from patients with STRC hearing loss. If that works, human testing may follow. But the study may also have wider implications for other gene therapies as well, after the team had to develop a creative workaround for a problem they encountered.

“The challenge we faced was that the gene for stereocilin is too big to fit into the gene therapy vector,” says Holt. “The gene is about 6,200 DNA base pairs long, but the AAV only has a capacity of 4,700 base pairs.”

So the researchers split the gene in half, and placed each part into two separate AAVs. They added sequences to both halves to ensure they all reached the same location, and once there find each other and form one complete whole again, like a jigsaw puzzle. The success of the technique in this study shows that it could be applied to other gene therapies involving genes that are too large for their vectors, the team says.

The research was published in the journal Science Advances.