Usher syndrome is the most common genetic form of deaf-blindness that also
impairs balance function. In the summer of 2015, a team at Boston Children's Hospital and
Harvard Medical School reported restoring rudimentary hearing in
genetically deaf mice using gene therapy.
Now the Boston Children's
research team reports restoring a much higher level of hearing - down
to 25 decibels, the equivalent of a whisper - using an improved gene
therapy vector developed at Massachusetts Eye and Ear.
‘A higher level of hearing - equivalent of a whisper - has been restored by using an improved gene therapy vector in genetically deaf mice.’
The new vector and the mouse studies are described in two back-to-back papers in Nature Biotechnology
While previous vectors have only been able to penetrate the cochlea's inner hair cells, the first Nature Biotechnology
study showed that a new synthetic vector, Anc80, safely transferred
genes to the hard-to-reach outer hair cells when introduced into the
cochlea (see images).
This study's three Harvard Medical School senior
investigators were Jeffrey R. Holt of Boston Children's Hospital;
Konstantina Stankovic of Mass. Eye and Ear and Luk H.
Vandenberghe, who led Anc80's development in 2015 at Mass. Eye and
Ear's Grousbeck Gene Therapy Center.
"We have shown that Anc80 works remarkably well in terms of
infecting cells of interest in the inner ear," says Stankovic, an
otologic surgeon at Mass. Eye and Ear and associate professor of
otolaryngology at Harvard Medical School. "With more than 100 genes
already known to cause deafness in humans, there are many patients who
may eventually benefit from this technology."
The second study, led by Gwenaëlle Géléoc of the Department of
Otolaryngology and F.M. Kirby Neurobiology Center at Boston Children's,
used Anc80 to deliver a specific corrected gene in a mouse model of
"This strategy is the most effective one we've tested," Géléoc says.
"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
Ushering in gene therapy for deafness
Géléoc and colleagues at Boston Children's Hospital studied mice
with a mutation in Ush1c, the same mutation that causes Usher type 1c in
humans. The mutation causes a protein called harmonin to be
nonfunctional. As a result, the sensory hair cell bundles that receive
sound and signal the brain deteriorate and become disorganized, leading
to profound hearing loss.
When a corrected Ush1c gene was introduced into the inner ears of
the mice, the inner and outer hair cells in the cochlea began to produce
normal full-length harmonin. The hair cells formed normal bundles (see
images) that responded to sound waves and signaled the brain, as
measured by electrical recordings.
Most importantly, deaf mice treated soon after birth began to hear.
Géléoc and colleagues showed this first in a "startle box," which
detects whether a mouse jumps in response to sudden loud sounds. When
they next measured responses in the auditory regions of the brain, a
more sensitive test, the mice responded to much quieter sounds: 19 of 25
mice heard sounds quieter than 80 decibels, and a few could heard
sounds as soft as 25-30 decibels, like normal mice.
"Now, you can whisper, and they can hear you," says Géléoc, also an
assistant professor of otolaryngology at Harvard Medical School.
Margaret Kenna, a specialist in genetic hearing loss at
Boston Children's who does research on Usher syndrome, is excited about
the work. "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 says. "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."
Restoring balance and potentially vision
Since patients (and mice) with Usher 1c also have balance problems
caused by hair-cell damage in the vestibular organs, the researchers
also tested whether gene therapy restored balance. It did, eliminating
the erratic movements of mice with vestibular dysfunction (see images)
and, in another test, enabled the mice to stay on a rotating rod for
longer periods without falling off.
Further work is needed before the technology can be brought to
patients. One caveat is that the mice were treated right after birth;
hearing and balance were not restored when gene therapy was delayed
10-12 days. The researchers will do further studies to determine the
reasons for this. However, when treated early, the effects persisted for
at least six months, with only a slight decline between six weeks and three
months. The researchers also hope to test gene therapy in larger
animals, and plan to develop novel therapies for other forms of genetic
Usher syndrome also causes blindness by causing the light-sensing
cells in the retina to gradually deteriorate. Although these studies did
not test for vision restoration, gene therapy in the eye is already
starting to be done for other disorders.
"We already know the vector works in the retina," says Géléoc, "and
because deterioration is slower in the retina, there is a longer window
"Progress in gene therapy for blindness is much further along than
for hearing, and I believe our studies take an important step toward
unlocking a future of hearing gene therapy," says Vandenberghe, also an
assistant professor of ophthalmology at Harvard Medical School. "In the
case of Usher syndrome, combining both approaches to ultimately treat
both the blinding and hearing aspects of disease is very compelling, and
something we hope to work toward."
"This is a landmark study," says Holt, director of otolaryngology
research at Boston Children's Hospital, who was also a co-author on the
second paper. "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."