Researchers at Boston Children’s Hospital found that replacing a mutated protein in the inner ear reversed severe hearing loss in mice, according to a study published in the journal Science Advances. The first-of-its-kind gene therapy technique involved replacing a mutated protein called stereocilin, (STRC), in the inner ear. The investigators said it reversed severe hearing loss in mice and in some cases, restored it to normal levels of hearing, according to a news release.
The researchers explained in the release, that hearing loss has been associated with mutations of at least 100 different genes. The researchers stated that up to 16 percent of genetic hearing loss could be linked to the gene STRC, which they noted is also the second most common genetic cause.
“Patients who carry STRC mutations lack cochlear amplification entirely and, as a result, suffer from reduced auditory sensitivity and have difficulty with frequency discrimination and speech perception”, the authors stated in the published report in the peer-reviewed journal.
In order to hear sound, sensory hair cells in the inner ear need to make contact with the tectorial membrane the researchers reported. The membrane responds to sound by vibrating and converting the vibrations into signals that travel to the brain.
The investigators say the stereocilin protein acts like a scaffold and helps the hair cells stand up in an organized bundle, which allows the hair cell tips to touch the tectorial membrane.
“If stereocilin is mutated, you don’t have that contact, so the hair cells are not stimulated properly,” Jeffrey Holt, Ph.D., a scientist in the Department of Otolaryngology and Neurology at Boston Children’s, said.
“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,” Holt, who is also the study’s senior investigator, said in the release.
Using a generated mouse model, the researchers designed a dual-vector protein-recombination strategy to replace full-length wild-type Strc in the outer hair cells of mice that carry STRC mutations, according to the study. The investigators discovered what they described as “robust restoration of full–length stereocilin protein” in the mice and noted hair bundles that had a normal appearance and were able to contact the tectorial membrane, according to the report.
The researchers then performed two types of hearing tests. One is often used in babies and another one that used electrodes on the scalp to measure auditory brainstem responses to a range of sound frequencies and intensities.
The study findings revealed the mice were more sensitive to subtle sounds. The Boston team also discovered the mice had improved cochlear amplification, which they described as increased ability to amplify soft sounds, tamp down the response to loud sounds, and more accurately discriminate between sounds of different frequencies. Hearing was restored to normal levels in some mice, according to the release.
“The results were remarkable and are the first example of hearing restoration using dual-vector gene therapy to target sensory outer hair cells,” said Olga Shubina-Oleinik, PhD who is the study’s first author. Eliot Shearer, MD, PhD, who is a co-author of the study and worked with the Children’s Rare Disease Cohort Initiative to screen a large genomic data set for STRC mutations, said in a release, that 2.3 million people worldwide carry STRC mutations and could potentially benefit from this therapy.
“It turns out that STRC gene variations are more common than we thought which makes gene therapy for this disorder so important.”
The Boston team plans to investigate if the gene therapy technique works with the human stereocilin gene using human inner ear cells in a dish, derived from patients with STRC hearing loss. If it restores auditory function at the tissue level, the researchers hope to apply to the FDA for permission to test it in humans, according to the news release.