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A major breakthrough has been announced in genetic investigation aimed at a future when persons vulnerable to hearing loss might take a drug to protect their auditory health from threats such as loud noise or the ototoxic medicine cisplatin.

Reported in the December 2023 issue of the Journal of Clinical Investigation Insight, a study by scientists from the University of California San Francisco has linked its authors’ new experiments on genetically modified mice to the findings of other recent research; the outcome is a deeper understanding of how progressive hearing loss occurs in the inner ear. This breakthrough focuses on the role of the gene TMTC4, mutation of which was known to cause deafness in mice but is now appreciated with greater clarity as also impacting humans.

And the key to this firmer understanding lies in a mechanism known as unfolded protein response (UPR). Mutations to the TMTC4 gene trigger this molecular domino effect, UPR, which causes hair cells in the inner ear to self-destruct. It was known to the UCSF researchers that loud noise and the chemotherapy drug cause deafness through this same underlying UPR mechanism.

Blocking UPR, therefore, became an objective in research, and previous experiments achieved this in animals with a drug developed by UCSF biochemists in 2013 and tested successfully in 2018, by Dr. Dylan Chan, co-senior author on this new paper and director of the Children’s Communication Center (CCC) in the UCSF Department of Otolaryngology: the compound, ISRIB (Integrated Stress Response Inhibitor) inhibits part of the UPR and has been shown to reverse memory failure caused by traumatic brain injury in mice and to kill aggressive prostate cancer cells. Several other drugs have also been found to inhibit UPR.

The strength of this newly published study is not only that it develops and characterises a Tmtc4–conditional modified mouse to reveal the cell type etiology of Tmtc4-associated progressive hearing loss. The paper also provides what is, to the authors’ knowledge, the first genetic and functional evidence that TMTC4 is involved in human hearing. They studied 2 missense variants of TMTC4, implicating UPR in the hearing loss of siblings with progressive hearing loss in one single family, a younger brother who showed worse hearing than his older sister, and whose work exposed to noise in an amusement park may have contributed to a syngergistic effect of combined noise exposure and UPR hypersensitivity conferred by TMTC4 mutations. This describes the first human family with evidence for a combined TMTC4 and UPR-associated hearing loss.

"We now have solid evidence that TMTC4 is a human deafness gene and that the UPR is a genuine target for preventing deafness," said Dr. Chan.

Targeting UPR could also bring therapeutic positives 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," Dr. Chan said.

Source: University of California/JCI Insight