A new synthetic gene therapy vector effectively penetrates both inner and outer hair cells of the cochlea in mice. Credit Charlie Askew and Jeffrey Holt
Building on a previous breakthrough, researchers were able to use an improved gene therapy vector to improve the hearing of genetically deaf mice.
In 2015 a team from Harvard Medical School and Boston Children’s Hospital reported restoring rudimentary hearing in genetically deaf mice using gene therapy. A recent report by the Boston Children’s Hospital research team, shows a much higher level of hearing being restored, down to 25 decibels, the equivalent of a whisper.
Previous vectors have only been able to penetrate the cochlea’s inner hair cells, however an improved synthetic vector known as Anc80— developed at Massachusetts Eye and Ear—safely transferred genes to the hard-to-reach outer hair cells when introduced into the cochlea.
Dr. Konstantina Stankovic, Ph.D., of Massachusetts Eye and Ear, explained the success of the vector.
“We have shown that Anc80 works remarkably well in terms of infecting cells of interest in the inner ear,” Stankovic said in a statement. “With more than 100 genes already known to cause deafness in humans, there are many patients who may eventually benefit from this technology.”
The most recent study, which was led by Gwenaëlle Géléoc, HMS assistant professor of otolaryngology and a member of the F.M. Kirby Neurobiology Center at Boston Children’s, used Anc80 to deliver a specific corrected gene in a mouse model of Usher syndrome, the most common genetic form of deaf-blindness that also impairs balance function.
“This strategy is the most effective one we’ve tested,” Géléoc said in a statement. “Outer hair cells amplify sound, allowing inner hair cells to send a stronger signal to the brain.
“We now have a system that works well and rescues auditory and vestibular function to a level that’s never been achieved before.”
Géléoc and colleagues studied mice with a mutation in Ush1c, the same mutation that causes Usher type 1C in humans and causes a protein called harmonin to be nonfunctional. This resulted in the sensory hair cell bundles that receive sound and signal the brain deteriorate and become disorganized, leading to profound hearing loss.
However, a corrected Ush1c gene was introduced into the inner ears of the mice, which caused the inner and outer hair cells in the cochlea to begin to produce normal full-length harmonin. The hair cells that formed normal bundles responded to sound waves and signaled the brain.
The researchers began testing the mice in a startle box, which detects whether a mouse jumps in response to sudden loud sounds. They then measured responses in the auditory regions of the brain, which showed the mice responding to much quieter sounds.
In total 19 of the 25 mice heard sounds quieter than 80 decibels and a few heard sounds as soft as 25-to-30 decibels like normal mice.
Margaret Kenna, HMS professor of otolaryngology and a specialist in genetic hearing loss at Boston Children’s who does research on Usher syndrome, said the research could lead to help human’s suffering from the disease.
“Anything that could stabilize or improve native hearing at an early age would give a huge boost to a child’s ability to learn and use spoken language,” she said in a statement. “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.
“In addition, the improvement in balance could translate to better and safer mobility for Usher syndrome patients,” she added.
Gene therapy also showed promise in restoring balance in some patients by eliminating the erratic movements of mice with vestibular dysfunction.
The researchers will now test gene therapy in larger animals and plan to develop novel therapies for other forms of genetic hearing loss.
