The root cause of most hearing loss is the death of cochlear hair cells, the tiny cilia in the inner ear that capture incoming sound waves and translate them into the electrical signals interpreted by the brain as sound. Once hair cells die, they can’t be regenerated, so hearing loss is both progressive and irreversible.
Jian Zuo is a professor of developmental neurobiology at St. Jude’s Children’s Research Hospital and a hearing loss specialist. Most of his work has been with adolescent cancer patients who suffer hearing loss after chemotherapy. In fact, 50 to 70 percent of all cancer patients with solid tumors or brain cancer experience varying degrees of permanent hearing loss after chemotherapy.
The culprit, Zuo told Seeker, is a drug called cisplatin, which is the only viable treatment for certain aggressive forms cancer. It is a powerful chemotherapy drug that’s known to inflict collateral damage on cochlear hair cells and kidney cells.
The side effects of cisplatin are unfortunate, but they also create a unique clinical opportunity. If scientists can figure out exactly how cisplatin kills hair cells, and develop a drug that blocks that damage in chemo patients, it could lead to a preventative cure for all forms of hearing loss.
And that’s exactly what Zuo and his colleagues think they may have found.
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In a paper published in the Journal of Experimental Medicine, Zuo made the case for a compound called kenpaullone, which appears to effectively protect mice and rats against hearing damage caused by both cisplatin and exposure to loud noise.
To find the winning drug, Zuo and his lab created a high-throughput screening process where 4,385 unique compounds could be tested simultaneously on mouse cochlear cells treated with cisplatin. From that huge assay, Zuo narrowed the top contenders down to ten, which were then tested in vivo in mice and rats also treated with cisplatin.
Animals injected with small doses of kenpaullone directly into the middle ear experienced up to 41 decibels of protection from cisplatin-induced hearing loss compared to animals which didn’t get the treatment. Since every increase of 10 decibels equals 10 times the sound intensity, a protection of 41 decibels is 10,000 times better than no protection at all.
Even better, the effectiveness of kenpaullone offers important clues to the underlying mechanism of cisplatin-induced hearing loss and perhaps hearing loss in general.
Kenpaullone is a kinase inhibitor. Kinases are enzymes that add a phosphate group during many critical cellular processes. Kenpaullone is particularly effective against a kinase called CDK2, an enzyme that acts as a catalyst in mitochondrial reactions.
When hair cells are under stress — from exposure to cisplatin, for example — the CDK2 enzyme prompts the mitochondria within the cell to produce a substance called reactive oxygen species, a toxic form of oxidative stress. Oxidative stress has been implicated in damage to lipids, proteins, and DNA, and may even be one of the chief drivers of age-related disease. (That’s why so many healthy foods are prized for their “antioxidant” properties.)
Zuo theorizes that the release of reactive oxygen species signals the activation of the hair cells’ death program. They essentially “commit suicide,” he said.
But when cells are injected with kenpaullone, they inhibit the activity of CDK2, prevent the release of reactive oxygen species, and sidestep hair cell death, preserving hearing in the process.
Zuo thinks that the same oxidative stress process is at work in noise-induced hearing loss, although to a lesser degree. In the lab, he exposed mice to 100 decibels of noise for two hours and then immediately injected half of them with a shot of kenpaullone. By measuring the mice’s brain activity afterward — mice are terrible at the “hear a beep, raise your paw” test — it was clear that the treated cohort suffered far less noise-induced hearing loss than the rest.
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The next step is to win approval for human trials to test kenpaullone in actual chemotherapy patients. The advantage is that these patients are already getting a controlled dose of cisplatin, so it’s easy to administer the counter doses of kenpaullone and track their progress. Kenpaullone also has natural tumor-fighting properties, so it could even speed their recovery.
Prior to the kenpaullone discovery, Zuo’s lab identified a specific gene mutation responsible for making certain chemotherapy patients far more sensitive to hearing loss than others. His lab is actively seeking funding from both government agencies and private investors to combine the two discoveries into a game-changing therapy.
“Our goal is not only to predict who will develop hearing loss with chemotherapy,” said Zuo, “but treat those people with drugs so we can prevent cisplatin-induced hearing loss.”
The long-term goal, if kenpaullone proves as effective as Zuo hopes, is to see how the drug works with all types of hearing loss. For example, age-related hearing loss, which affects more than half the population in their 60s and 70s, is believed to be caused by the accumulated damage from both noise and oxidative stress over time.
It’s not hard to imagine a day when adults get preventative boosters of kenpaullone or another CDK2 inhibitor to keep their hearing sharp.