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Researchers Report Reversing Hearing Loss in Mice: A Breakthrough in Gene Activation

Critical timing: Gene activation window may hold key to successful reversal of hearing loss
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A new study published in the August 8th online edition of PNAS demonstrates the reversal of hearing loss in mice through gene activation, challenging the perception of neurological disorders as irreversible.

In a groundbreaking study, researchers from King’s College London report they have achieved a remarkable feat: reversing hearing loss through gene activation in mutant mice. The study published in the August 8 online edition of the Proceedings of the National Academy of Sciences (PNAS) focuses on a specific form of hearing loss and sheds light on the potential for gene-based interventions to not only prevent but also reverse debilitating conditions when caught early enough. Specifically, they found that one type of hearing loss associated with the stria vascularis in the cochlea may be reversed if the treatment is delivered within a critical period early in disease progression.

Hearing loss can be caused by many different things, affecting individuals in all age groups; however, genetic hearing loss is thought to account for about half of all cases of hearing loss. Approximately 1 in 10 people have at least some hearing loss, and a recent study revealed nearly two-thirds of people aged 71+ and almost all people over 90 have some hearing loss. Untreated hearing loss is linked to many chronic diseases, social isolation, depression, and even cognitive decline and dementia. While hearing aids and cochlear implants are exceptional for improving communication and are even showing promise in reducing the risk for adverse medical conditions, they all fall short of restoring normal auditory function and do not stop the disease process.

Several different genetic approaches are currently being investigated to suppress or stop genetic hearing loss, including gene suppression and replacement, as well as editing genes to repair mutations. For example, otoferlin injected into the ears of young mice has been shown to thwart abnormal inner hair cell (IHC) function and deafness. The researchers in the present study wanted to see if an existing hearing impairment can be reversed because the highest demand for treatments is from people with progressive age-related hearing loss.

Gene activation in Spns2 mutant mice

To investigate this question, the team at King’s College London used a genetic approach in mice that had a mutation in the Spns2 gene, which plays a crucial role in maintaining the ion balance necessary for sensory hair cell function in the cochlea. Hair cells are responsible for converting sound waves into electrical signals, which are then sent to the brain for processing, and these hair cells are highly dependent on a fluid called endolymph. Endolymphatic fluid bathes the top of sensory hair cells in the inner ear and serves crucial functions for hearing and balance. Mice with the Spns2 gene mutation have rapidly progressive hearing loss associated with a dramatic decline in endocochlear potential (EP)—a critical parameter of ion balance that maintains the sensory hair cell environment—between 2 to 3 weeks after birth.

Cochlear Hair Cells

Hair cells are tiny structures that are tuned to sound vibrations within the cochlea, the spiral-shaped part of our inner ear responsible for hearing. The hair cells are arranged in bundles like those shown here and bathed by endolymphatic fluid which, under normal circumstances, keeps them functioning properly and acts as a medium for the transmission of sound waves from the eardrum and middle ear.

The team’s method involved controlling the gene activation of Spns2 at different stages of disease progression—mimicking different treatment timings in humans. They hypothesized that, by restoring the function of the Spns2 gene, they could reverse the hearing loss associated with this genetic mutation.

The results were surprising. Mice that received gene activation early in their development showed significant improvements in auditory function. Auditory brainstem response (ABR) measurements—a key indicator of hearing function—demonstrated that these mice achieved near-normal thresholds for hearing. Delaying gene activation led to less effective recovery, suggesting there is a critical window of time for intervention.

Notably, the benefits extended beyond improved hearing thresholds. Early gene activation not only restored auditory function but also protected sensory hair cells from secondary degeneration. This finding suggests that the approach may have broader implications for preserving neural structures and functions beyond just the auditory system.

“Our finding that this type of deafness associated with reduced EP can, in principle, be reversed gives added impetus to efforts to develop medical treatments for the disease processes underlying progressive hearing loss,” says co-author Karen Steel, FMedSci, FRS, of the Wolfson Centre for Age-Related Diseases at King's College London.

Karen Steel King S College London

Professor Karen Steel, FMedSci, FRS.

The study also highlighted the importance of the EP, which acts like a battery for the sensory hair cells, boosting their sensitivity. Mice with restored Spns2 function exhibited higher EP levels, indicative of a healthier environment surrounding the hair cells. The researchers also observed a correlation between lower ABR thresholds (i.e., better hearing) and higher EP levels, which points to the significance of EP in hearing function.

However, the investigation did uncover a limitation. While reversing hearing loss was achieved, the effectiveness of the intervention diminished as the degeneration of sensory hair cells progressed. This observation underscores the importance of early intervention and suggests a limited timeframe exists for effectively reversing hearing loss using this type of treatment.

The study’s implications reach beyond hearing care, serving as a proof of concept for the reversibility of some specific neurological conditions and challenging the notion that these disorders are inherently irreversible. Previous research had hinted at potential reversals in various mouse models of neurological disorders, including Rett syndrome, Kabuki syndrome, Rubinstein-Taybi syndrome, SYNGAP1 deficiency, and certain autism spectrum disorders, say the authors.

Although the current method may not be directly translatable to humans, the findings underscore the potential of gene-based therapies in addressing debilitating conditions. By increasing transcription of the normal version of affected genes, researchers could potentially develop therapeutic strategies to halt or even reverse disease progression. This approach holds promise for a wide array of neurological disorders, sparking hope for innovative interventions in the future.

“Our next steps are to discover if other types of pathology leading to deafness can also be reversed after the onset of hearing loss, such as hair cell defects or abnormal neural connections,” Steel told HearingTracker. “Then better diagnostic tools will be needed to distinguish these fundamentally different pathologies in humans so that clinical trials can focus on the people with the appropriate disease and ultimately the best treatment selected for each person depending on their need.”

The study's insights into the critical period for intervention also carry significant implications. Just as the timing of gene activation played a pivotal role in reversing hearing loss in mice, early intervention in humans may be the key to successful outcomes. Identifying and targeting this critical window could help revolutionize treatment strategies for various neurological disorders, potentially altering the trajectory of irreversible conditions.

This new study offers a glimmer of hope for those with hearing loss and other neurological disorders beyond present amplification and implant devices. The power of gene activation to reverse hearing impairment in mice challenges conventional wisdom and opens doors to innovative therapeutic approaches.


Editor in Chief

Karl Strom is the editor-in-chief of HearingTracker. He was a founding editor of The Hearing Review and has covered the hearing aid industry for over 30 years.