Can a drug prevent hearing loss from loud music and aging?

A person’s hearing can be damaged by loud noise, aging, and even certain medications, with little help other than a hearing aid or cochlear implant.

But now UCSF scientists have made a breakthrough in understanding what happens in the inner ear during hearing loss, laying the groundwork for preventing deafness.

The study, published on December 22, 2023 in Journal of Clinical Investigation Insight, links animal studies of hearing loss to a rare type of inherited deafness in humans. In both cases, mutations in 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.

Interestingly, hearing loss from exposure to loud noise or drugs such as cisplatin, a common form of chemotherapy, also results from activation of the UPR in hair cells, suggesting that the UPR may underlie several different forms of deafness .

There are several drugs that block the UPR—and stop hearing loss—in laboratory animals. According to the researchers, the new findings make a stronger case for testing these drugs in people who are at risk of hearing loss.

“Millions of American adults lose their hearing due to noise exposure or aging each year, but it’s a mystery what went wrong,” said Dylan Chan, MD, PhD, co-senior author of the paper and director of the Center for Children’s Communication (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 real target for preventing deafness.”

How hair cells in the ear self-destruct

In 2014, Dr. Elliot Sher, director of UCSF’s Developmental Brain Research Program and co-author of the paper, noticed that several of his young patients with brain malformations had TMTC4 mutations. But laboratory studies of this gene soon posed a conundrum.

“We expected mice with TMTC4 mutations to have severe brain defects at baseline, like these pediatric patients, but to our surprise, they appeared normal at baseline,” Sher said. “But as these animals grew up, we saw that they did not startle in response to a loud noise. They are deafened after ripening.

Sher teamed up with Chan, an expert on the inner ear, to study what happens to mice in what appears to be an accelerated version of age-related hearing loss in humans. They showed that TMTC4 mutations prime the hair cells in the ear to self-destruct, and loud noise does the same. In both cases, the hair cells were flooded with excess calcium, throwing off the balance of other cellular signals, including the UPR.

But they discovered there was a way to stop this. ISRIB, a drug developed at UCSF to block the self-destruct mechanism of the UPR in traumatic brain injury, prevents deafening in animals that have been exposed to noise.

The first gene for deafness in an adult

In 2020, South Korean scientists led by Bong Jik Kim, MD, PhD, linked Chan and Sher’s 2018 findings to genetic mutations they found in two siblings who were losing their hearing in their mid-20s. they are years. The mutations were in TMTC4 and matched what Chan and Sher had seen in animals, although they were different from those in Sher’s pediatric neurological patients.

If there is any way we can prevent hair cells from dying, this is how we will be able to prevent hearing loss.

Dylan Chan, MD, PhD

“It’s rare to connect mouse research to humans so quickly,” Sher said. “Thanks to our Korean collaborators, we could more easily prove the relevance of our work to the many people who become deaf over time.”

Kim, an otolaryngologist at Chungnam National University College of Medicine (Korea), facilitated the shipment of cells from these patients to UCSF. Sher and Chan tested these cells for UPR activity and found that indeed this flavor of TMTC4 mutation involved the disruptive UPR pathway in the human context.

When Chan and Sher mutated TMTC4 only in hair cells in mice, the mice became deaf. When they mutated TMTC4 in cells from individuals in the Korean family who were not deafened and in laboratory human cell lines, the UPR caused the cells to self-destruct. TMTC4 was more than just a gene for deafness in mice—it was a gene for deafness in humans, too.

Translating discovery to prevent deafness

Understanding TMTC4 mutations gives researchers a new way to study progressive deafness, as it is critical to maintaining the health of the adult inner ear. The mutations mimic damage from noise, aging, or drugs like cisplatin.

The researchers envision a future in which people who must take cisplatin or who must be exposed to loud noises for work take a drug that suppresses the UPR and prevents hair cells from drying out, preserving their hearing.

Science also suggests that the UPR can be targeted in other contexts where nerve cells become overloaded and die, including diseases long considered incurable, such as Alzheimer’s disease or Lou Gehrig’s disease.

“If there’s any way we can prevent hair cells from dying, that’s the way we’ll be able to prevent hearing loss,” Chan said.

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