Could a drug prevent hearing loss from loud music and aging?
University of California - San Francisco
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A person's hearing can be damaged by loud
noise, aging and even certain medications, with little recourse beyond a
hearing aid or cochlear implant.
But now, UCSF scientists have achieved a
breakthrough in understanding what is happening in the inner ear during hearing
loss, laying the groundwork for preventing deafness.
The research, published on Dec. 22, 2023,
in the Journal of Clinical Investigation Insight, links animal
studies on hearing loss with a rare type of inherited deafness in humans. In
both cases, mutations to the TMTC4 gene trigger a molecular domino effect known
as the unfolded protein response (UPR), leading to the death of hair cells in
the inner ear.
Intriguingly, hearing loss from loud noise
exposure or drugs such as cisplatin, a common form of chemotherapy, also stems
from activation of the UPR in hair cells, suggesting that the UPR may underly
several different forms of deafness.
There are several drugs that block the UPR
-- and stop hearing loss -- in laboratory animals. The new findings make a
stronger case for testing these drugs in people who are at risk of losing their
hearing, according to the researchers.
"Millions of American adults lose their hearing due to noise exposure or aging each year, but it's been a mystery what was going wrong," said Dylan Chan, MD, PhD, co-senior author on the paper and director of the Children's Communication Center (CCC) in the UCSF Department of Otolaryngology.
"We now have solid evidence that TMTC4 is a
human deafness gene and that the UPR is a genuine target for preventing
deafness."
How hair cells in the ear self-destruct
In 2014, Elliott Sherr, MD, PhD, director
of the UCSF Brain Development Research Program and co-senior author of the
paper, noticed that several of his young patients with brain malformations all
had mutations to TMTC4. But laboratory studies of this gene soon presented a
conundrum.
"We expected mice with TMTC4 mutations
to have severe brain defects early on, like those pediatric patients, yet to
our surprise, they seemed normal at first," Sherr said. "But as those
animals grew, we saw that they didn't startle in response to loud noise. They
had gone deaf after they had matured."
Sherr partnered with Chan, an expert on the inner ear, to look into what was happening to the mice, which looked like an accelerated version of age-related hearing loss in humans.
They showed that
mutations to TMTC4 primed hair cells in the ear to self-destruct, and loud
noise did the same thing. In both cases, hair cells were flooded with excess
calcium, throwing off the balance of other cellular signals, including the UPR.
But they found there was a way to stop
this. ISRIB, a drug developed at UCSF to block the UPR's self-destruct
mechanism in traumatic brain injury, prevented animals who were exposed to
noise from going deaf.
The first adult human deafness gene
In 2020, scientists from South Korea, led
by Bong Jik Kim, MD, PhD, connected Chan and Sherr's 2018 findings with genetic
mutations they found in two siblings who were losing their hearing in their
mid-20s. The mutations were in TMTC4 and matched what Chan and Sherr had seen
in animals, although they were distinct from those in Sherr's pediatric
neurology patients.
"It's rare to so quickly connect mouse
studies with humans," Sherr said. "Thanks to our Korean
collaborators, we could more easily prove the relevance of our work for the
many people who go deaf over time."
Kim, an otolaryngologist at the Chungnam
National University College of Medicine (Korea), facilitated the shipping of
cells from those patients to UCSF. Sherr and Chan tested those cells for UPR
activity and found that, indeed, this flavor of TMTC4 mutation turned on the
destructive UPR pathway in a human context.
When Chan and Sherr mutated TMTC4 only in
hair cells in mice, the mice went deaf. When they mutated TMTC4 in cells from
individuals in the Korean family who hadn't gone deaf, and in laboratory human
cell lines, the UPR drove the cells to self-destruct. TMTC4 was more than a
deafness gene in mice -- it was a deafness gene in humans, too.
Translating a discovery to prevent deafness
Understanding TMTC4 mutations gives
researchers a new way of studying progressive deafness, since it is critical
for maintaining the health of the adult inner ear. The mutations mimic damage
from noise, aging or drugs like cisplatin.
The researchers envision a future where
people who must take cisplatin, or who have to be exposed to loud noises for
their jobs, take a drug that dampens the UPR and keeps hair cells from
withering away, preserving their hearing.
The science also suggests that the UPR
could be targeted in other contexts where nerve cells become overwhelmed and
die, including diseases long thought to be incurable, like Alzheimer's or Lou
Gehrig's disease.
"If there's any way that we can get in the way of the hair cells dying, that's how we're going to be able to prevent hearing loss," Chan said.
