The idea of gene therapy is to deliver a corrected version of therapeutic DNA into the genomes of cells, which corrects genetic diseases.
Viruses can be altered in a laboratory to provide a "vector" that can carry the corrected therapeutic DNA into the cells. The abnormal gene expression is then altered, and the genetic disease corrected.
Previous studies have used vectors to attempt the restoration of hearing among deaf mice. However, the vectors have only managed to penetrate the inner hair cells of the cochlea.
The cochlea is a spiral-shaped tube that changes sounds to nerve messages and sends the information to the brain. Tiny hairs in the cochlea vibrate to carry information about sound to the brain.
Two new studies, published in Nature Biotechnology, have further explored vectors in mice to determine whether other hair cells of the cochlea, which are harder to reach, could be penetrated and corrected.
The first study was led by Harvard Medical School senior investigators Jeffrey R. Holt, Ph.D., of Boston's Children's Hospital in Massachusetts, Konstantina Stankovic, Ph.D., of Massachusetts Eye and Ear, and Luk H. Vandenberghe, Ph.D. The trio developed a new synthetic vector called Anc80 in 2015 at Massachusetts Eye and Ear's Grousbeck Gene Therapy Center.
The new study found that Anc80 could successfully transfer genes to the harder-to-reach areas of the outer hair cells when introduced into the cochlea. "We have shown that Anc80 works remarkably well in terms of infecting cells of interest in the inner ear," says Stankovic. "With more than 100 genes already known to cause deafness in humans, there are many patients who may eventually benefit from this technology."
Gwenaëlle Géléoc, Ph.D., of the department of otolaryngology and F.M. Kirby Neurobiology Center at Boston's Children's Hospital, led the second study. The study tested Anc80 in a mouse model of Usher syndrome. Usher syndrome is a genetic condition caused by abnormalities of the inner ear. The condition causes partial or total hearing and vision loss that becomes worse over time, eventually impairing balance.
Géléoc and colleagues aimed to find out whether delivering a corrected gene using a vector in a mouse model of Usher syndrome would enhance hearing and balance.
"This strategy is the most effective one we've tested," says Géléoc. "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," she adds.
Treated mice could detect sounds at decibels matching a whisper
Géléoc and the Boston's Children's Hospital team studied mice with an Ush1c gene mutation - the mutation that causes Usher type 1c among humans. The gene mutation stops a protein called harmonin from functioning, which causes the hair cells that receive sound and communicate with the brain to deteriorate, leading to hearing loss.
Introducing a corrected version of Ush1c to the inner ear of the mice shortly after birth resulted in the inner and outer hair cells in the cochlea producing normal harmonin. Furthermore, the hair cells responded to sound waves and communicated with the brain, thus enabling hearing.
The team found that 19 out of 25 mice heard sounds below 80 decibels and that some of the mice could hear sounds as quiet as 25-30 decibels. "Now, you can whisper, and they can hear you," says Géléoc. The researchers also discovered that the gene therapy restored balance in the mice and eliminated erratic movements.
Hearing and balanced improved in the mice that were treated soon after birth. However, hearing and balance were not restored in the mice that were treated 10-12 days after birth.
"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," notes Margaret Kenna, a specialist in genetic hearing loss at Boston's Children's Hospital who conducts research into Usher syndrome.
"This is a landmark study. Here we show, for the first time, that by delivering the correct gene sequence to a large number of sensory cells in the ear, we can restore both hearing and balance to near-normal levels."
Jeffrey R. Holt
Future work for the researchers will involve examining why mice treated 10-12 days after birth did not improve. They also aim to test gene therapy in larger animals and plan to develop treatments for other types of genetic hearing loss. With further work, this research may one day lead to treatments that can benefit patients.