How is a fish like an ear? It’s not a riddle — there’s something to be learned about human hearing by studying certain fish scales.
Like the inner ear, some sections of the fish body sport tiny hair cells that are exquisitely tuned to miniscule physical changes in their environment. These delicate cells dot the animals’ heads and run in a straight line down the fishes’ sides, known as the lateral line, and help the animals detect changes in water flow around their bodies.
Aside from just being cool, those hair cells make certain fish — namely, zebrafish, an animal commonly used in biology studies — a research model for understanding hearing loss and how to prevent it.
Fred Hutchinson Cancer Research Center medicinal chemist Dr. Julian Simon and his colleagues at the University of Washington used the tiny, silvery fish — many, many thousands of them — to find a drug that they think will prevent the hearing loss that often accompanies treatment with certain chemotherapies or antibiotics.
The chemotherapy cisplatin — commonly used to treat cancers such as breast, ovarian, and lung cancers — and a class of strong antibiotics known as aminoglycosides can cause irreversible hearing loss in approximately 20 to 40 percent of those who take the drugs. The drugs kill the ears’ hair cells, and, like most other types of hearing loss, there’s nothing to do about it once those cells are gone.
“We’re born with 15,000 hair cells in the left ear and 15,000 in the right ear, and that’s what we have for the duration of our lifetime. There’s no regeneration; there’s no way to replenish the cells,” Simon said. “This is why a lot of hearing loss is irreversible.”
The chemo and antibiotics also kill fish lateral line hair cells, and it’s easy to quickly check for the loss of those cells under the microscope, making these tiny animals a good starting ground for research to prevent that drug-associated hearing loss. Simon, an expert in screening large numbers of potential drugs in the laboratory, teamed up with UW zebrafish and hearing researchers Dr. David Raible and Dr. Edwin Rubel to screen different molecules that could, if given in the water that the fish are swimming in at the same time as the chemo or antibiotics, cancel out the associated hair cell-loss.
After 10,000 tests, they found one.
That compound, which the researchers termed PROTO-1, led to the creation of a spinoff company, Oricula Therapeutics, which is developing an optimized version of the drug for clinical trial testing. The company hopes to file for approval with the Food and Drug Administration this year, Simon said.
Denise Cutlip, a 64-year-old lung cancer survivor in Ypsilanti, Michigan, has suffered from hearing loss and tinnitus — ringing in the ear — for much of her life, having worked in a club when she was younger. But it was mild and didn’t bother her much, she said. That is, until she was diagnosed with stage 4 adenocarcinoma of the lung in 2010 and her doctor prescribed cisplatin treatment.
The tinnitus got worse along with more noticeable hearing loss, she said, but it wasn’t until a year into her treatment that Cutlip stumbled across an article describing the potential side effects of the chemo she was taking. Suddenly, she connected the dots. The ringing is now constant in one of her ears, she said, and can disrupt her sleep and her ability to concentrate on tasks like reading.
“The hearing loss can be isolating,” Cutlip said. “Sometimes I have to just tune out a conversation because I'm missing some of it. Other times my family and friends get tired of repeating themselves.”
Her doctors hadn’t told her about this possible side effect, and once she brought it up with them after the fact they said there was nothing they could do. But given the stage of her cancer when she was diagnosed, she’s not too surprised that nobody on her team focused on the long-term effects of her treatment, Cutlip said. Nobody expected she would live this long.
“They never thought in terms of survival,” she said. When she was diagnosed seven years ago, the 5-year survival rate for her cancer was 1 percent, she said. The hearing loss “was not considered an issue because you were going to be dead in a couple years anyhow,” she said.
Now, Cutlip said, she advises any friends who are treated with cisplatin to ask for hearing tests before and after their treatment.
If a patient is being treated with one of these drugs associated with “ototoxicity,” or hearing damage, and notices hearing loss, there’s nothing to do but stop the treatment to prevent the hearing loss from getting worse, Simon said. He pointed out that tinnitus has a different underlying biology than hearing loss and his research only focuses on the latter. But some patients, like Cutlip, don’t notice or aren’t tested for the damage until it’s too late. And for some, there might not be other treatment options.
“For cancer patients, obviously, getting rid of the tumor is a higher priority than hearing loss,” Simon said. But he and his colleagues started to wonder: “Wouldn’t it be great if we could administer drugs like cisplatin without worrying about affecting the quality of life, without hearing loss?”
To find such a drug, Simon, Raible, Rubel and their research teams screened 10,000 different molecular compounds on the tiny zebrafish in the presence of an aminoglycoside antibiotic (which causes hair-cell loss and thus hearing loss similarly to cisplatin). They used a fluorescent molecule to highlight the fishes’ hair cells under the microscope and looked for any molecules that prevented those tiny, lit-up cells from dying out in the presence of the antibiotic.
After six months, they found a compound that prevented antibiotic-related hair-cell loss — but not cell loss caused by cisplatin. Nevertheless, they decided to look into the compound, which they termed PROTO-1, further. Aminoglycoside antibiotics are not commonly used in the general population because they are such powerful drugs with potentially toxic side effects, but they are often used in people with cystic fibrosis who get certain chronic infections, Simon said. Preventing drug-related hearing loss in this population also seemed a worthy goal.
They knew the compound prevented hair-cell loss; their next step was to see if it could also prevent hearing loss. UW’s Rubel, who studies the ear and hearing, uses rodent models in his work — unlike zebrafish, you can tell if a rat is hearing something. His assays trace brain-stem function using tiny electrodes placed on the animals’ heads, much like the hearing tests commonly performed on newborn infants.
The compound worked to prevent antibiotic-induced hearing loss in the animals. The scientists went to work refining the drug, first in their own labs through a special drug development initiative from the National Institutes of Health and then, when that funding ran out, through their new start-up. The three scientists founded Oricula Therapeutics in Seattle in 2013. The drug that’s come out of all these studies, known as ORC-13661, is about 100 times more potent than PROTO-1 and actually works (in animals) to prevent both antibiotic- and cisplatin-related hair-cell loss.
Simon and his colleagues are working on the application for the FDA’s Investigational New Drug program, which will allow them to open a clinical trial. They’ll first test for safety in an early-phase trial with healthy volunteers, Simon said. He points out that ORC-13661 hasn’t shown any signs of side effects in their animal studies to date. They’ll likely then partner with Seattle Children’s cystic fibrosis researcher and physician Dr. Bonnie Ramsey in a clinical trial for patients with that disease who need aminoglycoside antibiotics. It’s too soon to say when that trial might launch.
In the meantime, Simon and his colleagues are trying to understand, biologically, how the drug works. They have no idea either how chemo and antibiotics kill the ear’s hair cells or how ORC-13661 prevents their loss.
Ultimately, the researchers hope to test the drug in other types of hearing loss, including age-related hearing loss, which affects nearly half of people over the age of 75. That would require fairly massive and lengthy clinical trials though, Simon said. But still, it’s a pressing concern.
“As we get an increasingly aging population, the ability to prevent any form of hearing loss becomes significant,” he said.
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.