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Hearing Loss Restored in Mice Using Gene “Switch”

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Researchers reversed hearing loss in mice by restoring the function of a defective gene. The proof-of-concept study, which suggests that some types of hearing loss caused by reduced gene activity could be reversible, is published in the Proceedings of the National Academy of Sciences of the United States of America.

New approaches needed to treat hearing loss

Many neurological diseases – including hearing loss – are considered irreversible. Approximately 50% of people over 75 years of age are classified as having disabling hearing loss. For these groups of older adults, impaired hearing is linked to increased risks of developing depression, cognitive decline and dementia.

Devices such as hearing aids and cochlear implants can go some way to restoring hearing, but they do not affect the underlying cause or progression of hearing loss. This means that there is a significant unmet need for new approaches to slow or reverse hearing loss.

Hearing loss has many different causes – a common form of age-related hearing loss involves the maintenance of the fluid in the inner ear. This fluid coats tiny hairs that sense sound waves in the form of vibrations and is maintained at a positive electrical voltage, called the endocochlear potential (EP), which is essential for the sensitivity of these hair cells.

Researchers from King’s College London investigated this very area, developing a mouse model with hearing loss caused by impaired EP from a mutated gene called Spinster homolog 2 (Spns2).

“Degenerative diseases such as progressive hearing loss are often believed to be irreversible, but we have shown that at least one type of inner ear dysfunction can be reversed,” said Karen Steel, a professor of sensory function at King’s College London and senior author of the study. “We used a genetic method to show this reversal as a proof-of-concept in mice, but the positive results should encourage research into methods like gene therapy or drugs to reactivate hearing in people with a similar type of hearing loss.”

Decreased efficacy with age

The researchers genetically engineered mice with inactivated Spns2 genes and administered an enzyme at different ages that reactivated the gene. The mice’s hearing improved after the gene was activated, improving their ability to hear low- to mid-range frequencies. However, the researchers found that reactivation was most effective when the mice were at a younger age.

The longer they waited to activate the gene and the older the mice got, the weaker the positive effects, suggesting there could be a “critical period” in which to reverse hearing loss.

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“Seeing the once-deaf mice respond to sounds after treatment was truly thrilling,” said Dr. Elisa Martelletti, first author of the study and research associate at King’s College London. “It was a pivotal moment, demonstrating the tangible potential to reverse hearing loss caused by defective genes. This groundbreaking proof-of-concept study unlocks new possibilities for future research, sparking hope for the development of treatments for hearing loss.”

Could this be translatable to humans?

It is important to note that very few cases of SPNS2 mutations have been reported in people. The authors, however, acknowledged that, “The genetic approach we adopted would not be directly transferable to humans, but our findings do suggest that increasing the level of transcription of the normal version of an affected gene, for example, using gene therapy, could be clinically beneficial.”

“Our finding of reversal of hearing loss in individual mice after activation of the Spns2 gene is an important proof-of-concept that deafness associated with EP deficiency not only can be halted in its progression but also can be reversed. This demonstration raises the prospect that this type of hearing loss may be reversible in humans,” they summarized in the paper.

Reference: Martelletti E, Ingham NJ, Steel KP. Reversal of an existing hearing loss by gene activation in Spns2 mutant mice. PNAS. 2023;120(34):e2307355120. doi: 10.1073/pnas.2307355120

This article is a rework of a press release issued by King's College London. Material has been edited for length and content.