This is a Discovery Research Grant awarded to Professor Corné Kros at the University of Sussex in 2021.
Background
Hearing loss is an unfortunate side effect of certain important medicines that are used to treat life-threatening conditions, such as sepsis (blood poisoning) and cancer. The risk of developing hearing loss for patients treated with these drugs has to be weighed against the benefit of surviving a severe infection or cancer.
Aminoglycoside antibiotics, such as gentamicin, are used to treat patients at risk of severe infections. They’re often given to newborn babies in intensive care units and to older patients, such as those with cystic fibrosis or tuberculosis. Cisplatin is an anti-cancer drug used to treat solid tumours, with particularly high cure rates (~90%) for testicular cancer. Treatment with either of these drugs causes hearing loss by killing sensory hair cells. These are the cells in the inner ear that detect sounds and convert them into electrical signals that our brains perceive as, for example, speech or music.
The ultimate aim of the researchers is to deepen our understanding of how aminoglycosides and cisplatin kill hair cells. They aim to use this knowledge to find ways to reduce or prevent hearing loss in people treated with them.
They’ve identified a type of pore in the membrane of the hair cell that opens when cells are stressed and start to swell in response. These pores (Volume-Regulated Anion Channels, known as VRACs for short) help regulate the volume of most cells in the body by allowing water to leave the cell when it’s too swollen.
The researchers’ preliminary work suggests that these VRACs play a different role in hearing loss caused by aminoglycosides than their role in cisplatin-induced hearing loss. Aminoglycosides block the VRAC pores and, as a result, stop the hair cells from repairing damage caused by these antibiotics. Cisplatin, which is known to get into cancer cells through these pores, may also enter hair cells this way, going on to damage them and thereby cause hearing loss.
Aims
The team will investigate in more detail how the VRAC pores are involved in hearing loss caused by both aminoglycosides and cisplatin. They’ll study how VRACs are involved in repairing the damage caused by aminoglycosides, so that they can ultimately find ways to enhance this protective process. They will also investigate whether VRACs help cisplatin to enter the hair cells in the ear.
To do this, they’ll measure the tiny electrical currents that the VRACs make when they open in hair cells from mouse ears that are growing in a dish. They will test how hair cells and their VRACs are affected by both aminoglycosides and cisplatin. They’ll also test the hearing of mice which lack a key part of the VRAC pore, a component that’s specifically needed for cisplatin to enter cells. Cancer cells lacking this part of the pore are resistant to cisplatin treatment, and we predict that hair cells lacking this component will be likewise protected.
Benefit
This research will show how VRACs in hair cells contribute to the ototoxic side effects of aminoglycosides and cisplatin. This will then allow researchers to develop drugs or other treatments (such as gene therapy) to target VRACs to selectively protect hearing without affecting the antibiotic or anticancer effects of these medicines.