It’s crucial, therefore, to find treatments to protect hearing from the harmful side-effects of these medicines. Researchers at the University of Sussex in the UK (who we’ve been supporting) have been working with a team at the University of Washington to study a new drug, ORC-13661, that shows promise as such a treatment.
Hair cells and zebrafish
Inside our ears are the sound-sensing hair cells, so-called because they have tiny projections that look like hairs at the top of the cells. These cells are involved in taking sound information from the outside world and turning it into an electrical signal that the brain can interpret. They’re absolutely crucial for hearing – and they’re also the cells that are damaged by ototoxic drugs.
It’s hard to study the hair cells inside the ear directly, as they’re hidden behind the bones of the skull. But it turns out that zebrafish, tiny tropical fish, also have hair cells, like the ones in our ears, on the outside of their bodies. They use these cells to sense movement in the water around them. As they’re on the surface of the fish, this makes it much easier to study them. It also makes it easier to treat the hair cells with drugs and look at their effects in real time. Because of this, zebrafish are widely used to screen drugs that might affect hair cells, either to repair them or to protect them from medicines like cisplatin.
ORC-13661 is the end result of such a screening process, looking for drugs to protect hearing.
Zebrafish have hair cells similar to the ones in our inner ear along the side of their bodies. They use them to sense movements in the water around them. Hearing researchers study these cells as a laboratory model of our own hair cells
Does ORC-13661 protect hair cells?The researchers at Sussex and Washington carried out an in-depth study of ORC-13661 and its protective effects on hair cells. They tested its ability to protect zebrafish (and mouse) hair cells against a range of different aminoglycoside antibiotics (such as gentamicin and amikacin, two of the more commonly used aminoglycosides) and cisplatin. They showed that it protected the hair cells from damage by all the ototoxic drugs it was tested against.
However, these initial tests were carried out, either on fish, which aren’t really very like us, or on mouse hair cells (which are more like us), but grown in a dish. That’s all well and good, but it doesn’t tell us whether the drug will work in real life, in the ear. ORC-13661 was designed to work effectively as a drug to protect hearing. That is, it should be able to get into the inner ear from the bloodstream when taken orally, and it should persist in the inner ear (and body as a whole) long enough to have an effect.
So the researchers went on to test whether this was the case in rats treated with the aminoglycoside amikacin. Some of the rats were also given ORC-16331 in their food. The rats treated with ORC-16331 and amikacin didn’t lose their hearing, whereas rats treated only with amikacin did. This suggests that ORC-13661 can get to where it’s needed in the body, and protect hair cells from damage caused by aminoglycoside antibiotics.
How does ORC-13661 work?
We know that aminoglycosides damage hair cells because they get into the cells through a special protein channel in the hair cell surface. This channel also happens to be how potassium enters the hair cell in response to sound to trigger a signal to the brain, so it’s quite important for our hearing! The problem is, once the antibiotic gets into the hair cell, it can’t get out. As a result, levels of the antibiotic in the hair cell build up. When those levels get too high, they become toxic and damage (and often kill) the hair cell.
The researchers investigated whether ORC-13661 might interfere with this process. They showed that ORC-13661 reversibly (that is, non-permanently) blocks the protein channel on hair cells. By doing this, it stops the aminoglycoside from getting into the hair cells and damaging them. More importantly, despite temporarily blocking the protein channel that’s crucial for allowing us to hear, it didn’t affect the hearing of rats treated with ORC-13661.
What does this mean?
We urgently need new treatments that can protect people’s hearing when they have to take these life-saving medications. This work suggests that ORC-13661 is an excellent candidate for such a treatment. The next stage of its development is for it to be tested in clinical trials in people – and that process has already begun; ORC-13661 is currently being tested in a Phase I trial (the first of three stages of clinical testing).
Although there’s still a long way to go before it can be approved for use to protect people’s hearing, we’re hopeful that it will be successful, and we’ll be following its progress and keeping you up to date.
Find out more
The research was published in the journal JCI Insight. You can read the original paper on the journal website: https://insight.jci.org/articles/view/126764
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