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Shattering the Silence with Potential Drug-based Therapy for Hearing Loss

Researchers from Kobe University and the Kyoto Prefectural University of Medicine have discovered superoxide-producing cells in the inner ear that are responsible for acquired hearing loss, paving way for new drug-based therapeutics for hearing impairment.

If the eyes are the window to the soul, then the ears are the portal to the mind. But for many, this gateway has been shut. Sensorineural hearing loss is the most common type of sensorineural impairment, affecting around 55 per cent of the global population. In 2019, the World Health Organisation (WHO) estimated 50 per cent of young people between the ages of 12-35 are in danger of noise-induced hearing loss. Apart from noise, ageing and drugs can also cause hearing impairment. Despite this, there has yet to be any established pharmacological treatments available.

One of the primary contributors to sensorineural hearing loss is a reactive oxygen species known as superoxide produced by NADPH oxidases (NOXs). It had been previously established that NADPH oxidase 3 (NOX3) is only expressed in the inner ear, thus acting as the major producer of superoxide and catalysing hearing loss. However, the search for the exact cellular origins of superoxide has been challenging, and the mechanism by which it contributes to hearing loss has remained unresolved.

In a recent discovery by Professor Ueyama Takehiko (Biosignal Research Center, Kobe University) and the inner ear research group (Kyoto Prefectural University of Medicine), they have successfully pinpointed the cells responsible for producing superoxide, NOX3, in the inner ear cochlea. Their study highlighted the significant role of superoxide in promoting hair cell apoptosis (or, cell death). NOX3-producing cells were also observed to increase in number when subjected to stimuli such as ageing, noise and ototoxic drugs. In effect, these cells are destroyed by the superoxide they produce themselves, prompting the onset of acquired hearing loss.

Using specially engineered genetically modified mice models tagged with fluorescent light-emitting proteins, they tracked the expression of fluorescence in NOX3-expressing cells in the cochlea. They compared mice with functional and non-functional NOX3-expressing cells to identify specific cells that play a crucial role in producing superoxide. They identified fluorescence primarily in hair cells, hair-supporting cells, and spiral ganglion neurons, indicating that they are key superoxide-producing cells. When inner hair cells were compared with outer ones, it was found that the latter is more vulnerable to damage. Additionally, NOX3-expressing outer hair cells can be also poisoned by superoxide produced by neighbouring supporting cells, thus inducing apoptosis or cell death, resulting in hearing loss.

This ground-breaking work is expected to pave the way for the development of the world’s first drug-based treatment for hearing loss. By obtaining a better understanding of the underlying mechanisms of superoxide-producing cells, researchers foresee the potential to develop novel therapeutics and pharmacological interventions that target NOX3 production to prevent hearing impairment.

Future treatment options also include removing, inhibiting or suppressing the production of superoxide. NOX3 inhibitors, in particular, show promise as a drug with mild side effects as NOX3 is specifically expressed in the inner ear. Such drug-based treatments addressing noise-, age- and drug-related hearing loss would be the first of its kind that may also open doors for therapeutics for genetic hearing loss. [APBN]

Source: Mohri et al. (2021). Nox3-Derived Superoxide in Cochleae Induces Sensorineural Hearing Loss. Journal of Neuroscience, 41(21), 4716-4731.