Regenerative drugs can treat hearing loss in humans

According to the World Health Organization, an estimated 466 million people worldwide have lost hearing ability, a number that will double the organization ‘s projects by 2050 to affect 1 in 10 people. However, a groundbreaking study at Creighton University School of Medicine has identified a drug that has the potential to protect against or treat hearing loss in humans.

The findings are important because such a drug is not currently FDA-approved, and the drug that has shown efficacy to protect hearing in animal models in the study, dabrafenib, is an FDA-approved drug that is currently used in the treatment of cancers.

FDA-approved drug replacement is an attractive and effective option as it can significantly reduce the development timeline (up to 5 to 8 years) and cost (up to 40%) for public delivery compared to new chemical fertilizers.

Permanent hearing loss is a major side effect that cancer patients experience after receiving cisplatin chemotherapy, affecting 40% to 60% of people who receive the treatment. Dabrafenib is a medication that can be taken orally to fight cancers with an activated gene called BRAF, such as melanoma, small cell lung carcinoma, and thyroid and biliary tract cancers.

In a paper published by Advances in science, Creighton scientists and students involved in the research found that dabrafenib can be reabsorbed to prevent cisplatin- and hearing loss in mice. Six other drugs in the BRAF signaling pathway also showed significant protection from cisplatin-induced cell loss.

Because dabrafenib has gone through clinical trials in cancer in humans and its side effects are known and relatively small, it is a good candidate to go through clinical trials, Tal Teitz said, PhD, assistant professor in the Department of Pharmacology and Neuroscience at Creighton University. , School of Medicine, group leader and corresponding author of the study.

There are many types of hearing loss caused by cisplatin treatment, sound exposure, antibiotics and aging. Our view was that there may be some cellular pathways between the different types of hearing loss, “

Interestingly, we were able to identify a drug that was effective in protecting against hearing loss with sound and cisplatin. The BRAF / MEK / ERK cellular pathway we are targeting in this study is known to contribute to cell growth in growing tumor cells, but only interestingly when it is blocked, it can protect against death in the undifferentiated cells in the ear. “

Tal Teitz, PhD, Associate Professor, Department of Pharmacology and Neuroscience, School of Medicine, Creighton University

According to Matthew Ingersoll, the paper’s first author and postdoctoralist who handled the day-to-day experimental work in the laboratory, the study showed that when cisplatin-receiving mice are given oral dabrafenib, that it inhibits the BRAF kinase pathway to provide immune defense by preventing cell death in the inner ear.

Hearing protection also occurred in mouse cochlear explants pretreated with dabrafenib one hour before cisplatin treatment.

“Dabrafenib has not shown any adverse effects on cisplatin tumor killing ability in tumor cell lines, and from having gone through a previous FDA approval process, we already know that some of the possible side effects the drug such as headaches and skin broth are easy to manage, especially when the drug is administered for short periods of time, “Ingersoll said.

The study also tested whether dabrafenib protects against sound hearing loss. Before mice were exposed to 100 decibels (the normal sound level for a lawn mower) for two hours – enough for permanent hearing loss – they were treated with dabrafenib. Significant hearing protection was achieved.

Because sound exposure is often invisible, the study also investigated whether dabrafenib could provide hearing protection after damaging noise. Mice received dabrafenib treatment starting 24 h after sound exposure, administered alone and in combination with the AZD5438, another oral drug identified by the group for hearing protection.

The drugs showed hearing protection in mice after sound exposure, and full protection was achieved with the drug combination.

“What makes dabrafenib particularly promising is that it can be taken orally – the least aggressive and cost-effective method of treatment,” Ingersoll said. “The surgical treatments already exist for hearing loss as cochlear implants are very aggressive and expensive. “Teitz said the promising results will lead to more preclinical studies testing the efficacy of dabrafenib when mice receive lower doses of cisplatin treatment for a longer period of time, and also receive dabrafenib in lower doses for a similar length of time.

“This will better report what we do in clinics because patients usually receive cisplatin in a few cycles, which involves treatment each day for one week, and then three weeks without chemotherapy, “said Teitz. “In this study, we administered one large dose of cisplatin, so we also want to test efficacy in mice receiving smaller doses of cisplatin over very few cycles in a 60-day period. We will also test lower doses of dabrafenib – the lower we can get the dose, the better it will be taken by patients treated with cisplatin Dabrafenib can also be helpful for overcoming the side effects of cisplatin chemotherapy in other organs of the body, such as the kidneys and brain, and our research group is currently investigating this further. “

Ingersoll confirmed that while the findings of the research are based on animal preliminary studies, he said the field of hearing is an interesting development. “More studies are needed, but we are excited to continue to study this drug and understand more about its effectiveness and how it works to treat hearing loss, “Ingersoll said.” It is promising research, and I hope that it can be used in the future to improve the quality of life of people affected by hearing loss. “