Novel Approaches for Protecting the Inner Ear from Hearing Loss

In 2015, Andre Hoelz, the Mary and Charles Ferkel Professor of Chemistry and Biochemistry and a Howard Hughes Medical Institute investigator, learned he had a rare brain tumor that was pressing on his acoustic nerve. The chemist, who normally focuses on solving the structure of protein assemblies in the lab, set out to learn everything he could about the workings of the auditory system.

Eventually he teamed up with his surgeon, Rick Friedman, who is also a research scientist and vice chair at UC San Diego specializing in disorders of the ear. The two have taken on the search for methods of protecting the inner ear against hearing loss. Now Hoelz and Friedman have received a grant to extend their experimental agenda.

The inner ear is a remarkable but somewhat fragile vehicle for carrying sound from the outer ear to the brain. It does this by means of tiny bundles of hair-like cells that respond to incoming sound waves by releasing neurotransmitters that send sonic information to the brain along the acoustic nerve. These inner ear hair cells are crucial to our hearing. Sadly, however, they cannot be regenerated. Once lost, they are gone forever, and the hearing they enabled is gone with them.

"There are some cells in our body that are so specialized that they cannot be replaced," Hoelz explains. "The cells that make us hear, along with other sensory cells, fall into this category. We have 37 trillion cells in our body, and only 16,000 of those are involved in hearing. When these cells die, our hearing is gone. And when it comes to inner ear hair cells, it's not a question of whether they will die, it's a question of when."

Inner ear hair cells (IHCs) perish for a variety of reasons, including viral infections, exposure to excessive noise, and normal aging processes. One cause of particularly devastating hearing loss is associated with cisplatin chemotherapy, a robust and taxing regimen of cancer treatment used to treat adult-onset cancers (testicular, head and neck, ovarian, cervical, endometrial, and lung, for example) and pediatric cancers (such as neuroblastoma, osteosarcoma, medulloblastoma, retinoblastoma, and Wilms tumor).

"Especially for pediatric patients, you want to kill as many cancer cells as possible. Children have another 80 years ahead of them, we hope. So, treatments for childhood cancers are aggressive," Hoelz explains. "Unfortunately, cisplatin chemotherapy may cause severe damage to the ear hairs we need in order to hear. A full 70% of patients that are treated with cisplatin will end up with some degree of hearing loss."

"There exist no ideal solutions to this toxicity," Friedman adds.

Hearing loss is particularly damaging for children who are still in the early phase of developing speech and communication. About 2,000 children are exposed to cisplatin each year in the United States. The only currently available treatment approved by the Food and Drug Administration to avoid hearing loss in patients being treated with cisplatin has a serious drawback: It inactivates cisplatin, thereby weakening the effectiveness of the chemotherapy. "This drug is basically an antidote for cisplatin," Hoelz says.

Cisplatin therapy saves lives that would otherwise be lost to cancer. If the choice comes down to losing one's hearing or dying, there is usually little debate.

Hoelz himself confronted a similar dilemma in 2015 when he experienced severe vertigo and temporary hearing loss. Doctors discovered that a very rare brain tumor was exerting pressure on his acoustic nerve, affecting his balance and hearing. Since Hoelz's symptoms came and went, he and his doctors chose to regularly monitor the tumor via MRI and periodically test his hearing. During this time, Hoelz began to see Dr. Friedman. "I had a very distinct feeling that eventually I would need to have surgery, and that Rick was the person to do it," Hoelz remembers. "But Rick told me I was not the best candidate for ear preservation, so I hesitated. I thought, 'I may not be lucky, but if not, at least I can keep my hearing for a while.'"

As Friedman monitored Hoelz's tumor, the two men began to talk science. "It was strange," Hoelz says. "I was debating whether or not to have the surgery, but alongside that, I was fascinated by Rick's data on protein complexes involved in hearing and I began to think about how the work I did in my lab could shed light on these processes."

When Hoelz's symptoms became markedly worse, he opted to have the surgery and lost hearing in his left ear. But at the same time, he began a collaboration with Friedman that has already shown promising results.

For his part, Friedman says, "Meeting and collaborating with Andre is the best thing that has happened in my scientific career."

Over the last five years, Hoelz, Friedman, and other scientists in the field have identified a gene that makes people more susceptible to hearing loss—whether from noise, cisplatin, or age—and started exploring ways to strengthen the inner ear hair cells to protect hearing.

Hoelz and Friedman first identified a gene, Prkag2, that encodes part of the AMPK (5' adenosine monophosphate-activated protein kinase) complex. AMPK is an enzyme that works throughout the body, from the liver to the brain to skeletal muscle, to regulate metabolism. IHCs are highly metabolically active. The synapses that connect IHCs to the auditory nerve rely on AMPK to deliver neurotransmitters—in this case, glutamate—when they are stimulated by sound. Without these deliveries from the AMPK complex, the IHCs cannot communicate auditory information to the brain.

Hoelz and Friedman have shown that they can in fact protect IHCs, and the hearing that relies on them, if an AMPK-activating drug is properly delivered prior to cisplatin treatment. With a grant from Curebound, a philanthropic organization based in San Diego that funds cancer research, they are now learning the correct dosage and timing required to protect the hearing of cisplatin-treated cancer patients. Efficacy is being assessed in murine models. Once an optimal therapy is designed, it will be tested in guinea pigs, whose auditory system is more similar to our own, and finally in humans.

"The hope is that it will be comparatively easy to recruit people for a study of these treatments," Hoelz says. "If you are being treated with cisplatin, you may lose your hearing anyway, so any chance to preserve at least some hearing should be attractive."

The possibilities for this therapy do not end there. "We hope that in the long run this will be a sort of ear vitamin that could work for everyone. The treatment would make IHCs sturdier and less susceptible to all sorts of damage, not only that from cisplatin. Just as you can put a veneer on teeth to protect them from cavities, you could use this therapy to boost the longevity of IHCs, potentially allowing them to survive for people's entire lifespans," Hoelz says.

"While mammals cannot regenerate IHCs, some fish and birds can," Hoelz explains. "Somehow as we evolved we lost this ability. Scientists are studying what developmental program might make it possible for humans to regenerate IHCs," he adds. "But in the meantime, it would be wonderful if we could develop a therapy to protect them. Working with Rick has been a thrilling dive into the world of hair cell biology, opening new scientific doors and sparking a deeply personal hope that this research might one day help preserve hearing—including my own."