A promise to restore hearing

Date:
June 3, 2020
Source:
Harvard University
Summary:
For the first time, researchers have used base editing to restore
partial hearing to mice with a recessive mutation in the gene
TMC1 that causes complete deafness, the first successful example
of genome editing to fix a recessive disease-causing mutation.



FULL STORY ==========================================================================
When Wei Hsi (Ariel) Yeh was a young undergraduate student, one of her
close friends went from normal hearing to complete deafness in the span
of one month.

He was 29 years old. No one knew why he lost his hearing; doctors still
don't know. Frustrated and fearful for her friend, Yeh, who graduated
last month with her Ph.D. in chemistry from Harvard University, dedicated
her graduate studies to solving some of the vast genetic mysteries behind hearing loss.


==========================================================================
In the United States, one in eight people aged 12 years or older
has hearing loss in both ears. While technologies like hearing
aids and cochlear implants can amplify sound, they can't correct the
problem. But gene editing could - - genetic anomalies contribute to half
of all cases. Two years ago, Yeh and David R. Liu, Thomas Dudley Cabot Professor of the Natural Sciences and a member of the Broad Institute
and the Howard Hughes Medical Institute, repaired a dominant mutation
and prevented hearing loss in a mouse model for the first time. But,
Liu said, "Most genetic diseases are not caused by dominant mutations,
they're caused by recessive ones, including most genetic hearing losses."
Now, Liu, Yeh and researchers at Harvard University, the Broad Institute,
and the Howard Hughes Medical Institute achieved another first: They
restored partial hearing to mice with a recessive mutation in the gene
TMC1 that causes complete deafness, the first successful example of
genome editing to fix a recessive disease-causing mutation.

Dominant disease mutations, meaning those that sully just one of the
body's two copies of a gene, in some ways are easier to attack. Knock
out the bad copy, and the good one can come to the rescue. "But for
recessive diseases," Liu said, "you can't do that. By definition, the
recessive allele means that you have two bad copies. So, you can't just
destroy the bad copy." You have to fix one or both.

To hear, animals rely on hair cells in the inner ear, which bend under the pressure of sound waves and send electrical impulses to the brain. The recessive mutation to TMC1 that Liu and Yeh hoped to correct caused
rapid deterioration of those hair cells, leading to profound deafness
at just 4 weeks of age.

Jeffrey Holt, Professor of Otolaryngology and Neurology at the Harvard
Medical School and an author on the paper, successfully treated
TMC1-related deafness with gene therapy -- they sent cells with
healthy versions of the gene in among the unhealthy to counteract
the disease-causing mutation. But Volha (Olga) Shubina-Aleinik,
a postdoctoral fellow in the Holt lab, said gene therapy may have a
limited duration. "That is why we need more advanced techniques such as
gene editing, which may last a lifetime." Yeh spent years designing a
base editor that could find and erase the disease- causing mutation and
replace it with the correct DNA code. But even after she demonstrated
good results in vitro, there was a problem: Base editors are too large
to fit in the traditional delivery vehicle, adeno-associated virus or
AAV. To solve this problem, the team split the base editor in half,
sending each piece in with its own viral vehicle. Once inside, the two
viruses needed to co-infect the same cells where the two base editor
halves would rejoin and head off to find their target. Despite the
labyrinthine entry, the editor proved to be efficient, causing only a
minimum of undesired deletions or insertions.

"We saw very little evidence of off-target editing," Liu said. "And we
noticed that the edited animals had much-preserved hair cell morphology
and signal transduction, meaning the hair cells, the critical cells that convert sound waves to neuronal signals appeared more normal and behaved
more normally." After the treatment, Yeh performed an informal test:
She clapped her hands.

Mice that had previously lost all hearing ability, jumped and turned
to look.

Formal tests revealed the base editor worked, at least in part: Treated
mice had partially restored hearing and could respond to loud and even
some medium sounds, Yeh said.

Of course, more work needs to be done before the treatment can be used
in humans. Unedited cells continued to die, causing deafness to return
even after the base editor restored function to others.

But the study also proved that the clandestine AAV delivery method works.

Already, Liu is using AAV to tackle other genetic diseases, including
progeria, sickle cell anemia, and degenerative motor diseases. "We're
actually going after quite a few genetic diseases now, including some
prominent ones that have caused a lot of suffering and energized pretty passionate communities of patients and patient families to do anything
to find a treatment," Liu said.

"For progeria, there's no cure. The best treatments extend a child's
average lifespan from about 14 to 14.5 years." For Yeh, whose friend
still has no answer, much less a cure for his hearing loss, genetic
deafness is still her primary target. "There's still a lot to explore,"
she said. "There's so much unknown."

========================================================================== Story Source: Materials provided by Harvard_University. Original written
by Caitlin McDermott-Murphy. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Wei-Hsi Yeh, et al. In vivo base editing restores sensory
transduction
and transiently improves auditory function in a mouse model of
recessive deafness. Science Translational Medicine, Jun 3rd,
2020 DOI: 10.1126/ scitranslmed.aay9101 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200603144338.htm https://www.sciencedaily.com/releases/2020/06/200603144338.htm

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