St. Jude Children’s Research Hospital scientists have discovered a compound that prevents hearing loss in adult rodents caused by noise or the chemotherapy drug cisplatin. The findings appear today in the Journal of Experimental Medicine.
The candidate drug, kenpaullone, works by binding to and inhibiting the enzyme CDK2. Researchers showed that reducing the activity of CDK2 preserved hearing, in part by protecting hair cells in the inner ear. The hair cells are irreplaceable and essential for hearing.
Treatment with kenpaullone protected adult mice from hearing loss induced by cisplatin or noise when the compound was delivered to the inner ear.
“This discovery has the potential to transform prevention and treatment of hearing loss resulting from a wide range of acoustic insults, including noise, drug toxicity and possibly aging,” said corresponding author Jian Zuo, Ph.D., a member of the St. Jude Department of Developmental Neurobiology. In laboratory tests, researchers reported that kenpaullone proved more effective at protecting hair cells than four compounds currently in clinical trials for prevention of hearing loss.
Additional studies are needed before kenpaullone or related compounds are ready for clinical trials in humans.
There are no approved drugs in the U.S. to prevent or treat hearing loss, which the World Health Organization estimates affects 360 million people worldwide, including 32 million children. “The current situation is unacceptable, given the toll of hearing loss worldwide,” Zuo said. Those at risk include cancer patients whose treatment includes cisplatin. Cisplatin toxicity leads to hearing loss in 50 to 70 percent of patients of all ages.
In an effort to address the treatment gap, researchers screened a St. Jude library of 4,385 approved drugs and small molecules for evidence they protected mouse cochlear cells growing in the laboratory from cisplatin toxicity. The cochlea is part of the inner ear involved in hearing.
The 10 most promising compounds included kenpaullone and two other CDK2 inhibitors. Also on the list were three drugs approved for treatment of other diseases that have not been tested for inner ear problems.
Additional testing of the top compounds in zebrafish and mouse cochleae cultured in the laboratory prompted researchers to focus on kenpaullone. This compound has been previously identified as a candidate for treatment of the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, and a heart problem known as cardiac parasympathetic dysfunction.
The presence of CDK2 inhibitors on the Top 10 list of promising compounds was unexpected, the researchers noted. The protein is associated with cell growth. In humans and other mammals, auditory hair cells stop dividing after birth, and this research included adult mice and rats. But Zuo and his colleagues used several methods to show kenpaullone directly inhibits CDK2. In addition, CDK2-deficient mice displayed enhanced resistance to cisplatin- and noise-induced hearing loss.
The research also revealed that, in response to stress, CDK2 promotes programmed death (apoptosis) of hair cells. Hearing loss has a variety of causes, but evidence from various researchers has suggested that almost all involve the loss of functional hair cells in the inner ear. Hair cells help transform sound waves into the electrical impulses that stimulate the auditory nerves.
Kenpaullone protection against cisplatin and noise may involve different mechanisms, scientists reported.
For example, cisplatin is associated with increased production by mitochondria of molecules called reactive oxygen species. Mitochondria are structures that produce energy to power cells. The reactive oxygen species damage hair cells and trigger apoptosis. Evidence in this study suggests kenpaullone protects hearing during cisplatin treatment by inhibiting production of reactive oxygen species.
In contrast, prolonged exposure to 100-decibel noise, which is comparable to sound produced by motorcycles or power lawn mowers, damaged hearing in mice without the loss of hair cells. There were changes, however, in the connections between the hair cells and the nerve cells that carry the message to the brain. Hearing was protected in adult mice treated with kenpaullone.
“Interestingly, kenpaullone did not protect mice exposed to louder sounds. That suggests another mechanism may be involved in hearing loss at higher levels,” Zuo said. “But 100 decibels presents a significant threat, since that is the noise level that often makes up the soundscape of our lives. That suggests kenpaullone could have significant clinical application in treating noise-induced hearing loss.”
There was no evidence that, when directly delivered to the inner ear, kenpaullone was toxic or inhibited the anti-tumor activity of cisplatin.
“This research would not have been possible without the collaboration of scientists in six departments across St. Jude,” Zuo said. “Our shared expertise has laid the groundwork to transform clinical prevention and treatment of hearing loss.”
Tal Teitz, Ph.D., a staff scientist in Zuo’s laboratory, is the first author. The other authors are Jie Fang, Justine Bonga, Shiyong Diao, Robert Hazlitt, Luigi Iconaru, Duane Currier, Yinmei Zhou, Cheng Cheng, Jaeki Min, Burgess Freeman, Junmin Peng, Martine Roussel, Richard Kriwacki and Taosheng Chen, all of St. Jude; and Asli Goktug, Marie Morfouace, Robyn Umans, Michael Taylor and R. Kiplin Guy, all formerly of St. Jude.
The research was funded in part by grants (DC006471, DC01501001A1, DC01544401, DC01387901, CA09632, GM118041, CA21765) from the National Institutes of Health; grants (N000140911014, N000141210191, N000141210775, N000141612315) from the Office of Naval Research; and ALSAC, the fundraising and awareness organization of St. Jude.
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