A New Purpose for an Old Drug

Millions of people worldwide suffer from hearing loss, whether caused by noise exposure, certain chemotherapy drugs, or the natural effects of aging. Currently, there is only one FDA-approved medication for preventing a specific type of hearing loss in children undergoing cancer treatment. Researchers at Creighton University may have discovered a new use for an existing drug that could help many more people at risk of hearing impairment.

Oseltamivir, more commonly known by its brand name Tamiflu, was approved in 1999 as an antiviral medication for the treatment and prevention of influenza. As a protease inhibitor, Tamiflu blocks the neuraminidase enzyme that influenza viruses need to spread infection. Over two decades of widespread use has established Tamiflu as generally safe and well-tolerated. Its oral formulation also means it is easily administered.

These properties make Tamiflu an appealing candidate for “drug repurposing” – investigating whether an existing drug approved for one indication may also help treat an unrelated condition. Compared to developing a new drug from scratch, repurposing has several advantages in terms of risk, cost, and speed to patient access. Creighton researchers decided to screen FDA-approved drugs for potential otoprotective properties to prevent hearing loss caused by chemotherapy or noise exposure.

In lab-dish and mouse studies, Tamiflu stood out as dramatically reducing cell death and hearing impairment from the chemotherapy drug cisplatin. Further testing revealed Tamiflu could protect hair cells in the cochlea, the sensory receptors crucial for hearing, from both cisplatin and excessive noise. Oral doses as low as 10mg/kg twice daily significantly reduced hearing threshold shifts and cell loss in mice. Perhaps most surprisingly, Tamiflu appeared to work even when given up to one day after auditory injuries occurred.

How might an anti-influenza drug protect hearing? The researchers considered whether Tamiflu interfered with mammalian counterparts to the neuraminidase enzymes it targets in flu viruses. However, other neuraminidase inhibitors did not replicate Tamiflu’s benefits, indicating a novel mechanism must be involved. Computational modeling predicted Tamiflu could interact with proteins in the ERK/MAPK cell signaling pathway, which is activated in the inner ear during both cisplatin toxicity and noise exposure. Experiments confirmed Tamiflu reduced ERK phosphorylation triggered by cisplatin.

Tamiflu may also curb inflammation tied to hearing damage. In noise-exposed mice, the drug lessened immune cell infiltration into vulnerable inner ear structures. Ongoing work seeks to further elucidate Tamiflu’s molecular mode of action, while safety testing assesses any interference with cisplatin’s cancer-fighting effects. Assuming positive results, clinical trials could ultimately evaluate Tamiflu’s potential for preventing chemotherapy- or noise-induced hearing loss in people.

The fact that an existing drug approved for influenza might help hearing problems comes as a surprise. But uncovering unintended therapeutic benefits is a recurring theme in medicinal innovation. Perhaps the most famous example is sildenafil, originally developed as an angina treatment in the 1990s. During clinical testing, doctors observed some male trial participants experiencing—how shall we say—unexpected side effects. This led to sildenafil’s blockbuster approval and marketing as Viagra for erectile dysfunction.

More generally, the drug development process has historically focused on targeting single proteins or pathways believed causative for a given disease. This narrow approach risks overlooking multifaceted conditions with many contributing molecular factors. Drug repurposing helps address this limitation by agnostically screening compounds’ effects across an organism or tissue, without bias toward any one biological pathway. Off-target interactions are no longer liabilities but opportunities, as Tamiflu’s hearing protection may demonstrate.

If Tamiflu passes muster in clinical trials, it could significantly expand treatment options for noise- and chemotherapy-induced hearing loss. As a readily available generic, Tamiflu also holds promise as an affordable therapeutic worldwide. More patients might benefit from this drug’s second wind thanks to research open-minded enough to consider impacts outside Tamiflu’s original anti-influenza focus. By thinking beyond initial assumptions, scientists may frequently uncover fresh applications hiding in plain sight for existing medicines. For those at risk of hearing impairments, that open-minded approach could resound with new hope.

Reference(s)

1. bioRxiv DOI: 10.1101/2024.05.06.592815

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