Scientists identify potential therapeutic targets to prevent hearing loss caused by some antibiotics

Some life saving antibiotics cause hearing loss, and now for the first time some researchers believe they know why, and are on the way to being able to prevent it.

Aminoglycosides (AGs), like Gentamycin, are potent, broad-spectrum antibiotics that are used to treat a wide variety of life-threatening infections.

However, they do come with a downside: they’re ototoxic – meaning a person taking them can develop hearing or balance problems because they cause irreversible damage to cochlear hair cells.

Until now, scientists have known very little about which molecular pathways critical to hair cell survival are affected by exposure to these antibiotics.

But in a new study in the journal Developmental Cell, US researchers have found that the dysfunction of a process within the cell, called autophagy, is linked.

By reducing the expression of a protein involved in autophagy in the cochlear hair cells, they were able to prevent hair cell death and subsequent hearing loss caused by systemic exposure to AGs.

“This work identifies multiple potential therapeutic targets for preventing hearing loss caused by aminoglycosides,” says senior author Bo Zhao, assistant professor of otolaryngology in the School of Medicine at Indiana University, US.

Read more: Hair cell loss may explain hearing loss.

What is autophagy?

Autophagy is the process by which cells “eat” bits of themselves – hence the name. It comes from the Greek “autos” meaning self and “phageîn” meaning to eat.

Through autophagy, unwanted or damaged molecules are removed and recycled from the cell. First, they are marked for removal, enveloped by a membrane (becoming an autophagosome) which then fuses with a lysosome (an acidic organelle filled with enzymes) that breaks them down into nutrients the cell can then re-use.

But when autophagy is abnormal, or triggered inappropriately, it can cause cell damage and death.

In a mouse inner ear cell line, the researchers found that AGs bind to and trigger the translocation of protein called RIPOR2.

Usually, this enzyme is found at the base of the tiny, hairlike structures called stereocilia of the cochlear hair cell. But all the AGs tested, and none of the other types of antibiotics examined, cause it to translocate to a different region – the pericuticular necklace – within the cell.

There, RIPOR2 interacts with GABARAP, a component of the autophagy pathway that has a major role in removing and recycling dysfunctional cellular components.

“As aminoglycosides specifically trigger a rapid localisation change of RIPOR2 in hair cells, we hypothesise that RIPOR2 is essential for aminoglycoside-induced hair cell death,” Zhao explains.

“We then discovered RIPOR2 regulates the autophagy pathway in hair cells. Knowing this, we developed other laboratory models without the expression of several key autophagy proteins that did not exhibit hair cell death or hearing loss when treated with the antibiotic,” adds Dr Jinan Li, postdoctoral fellow in the Zhao lab and first author of the paper.

Reducing RIPOR2 expression prevents hearing loss in mice

The team went on to inject AGs into mice that were genetically engineered to produce substantially lower levels of the RIPOR2 protein and, surprisingly, no significant hair cell loss occurred.

These results suggest that reducing RIPOR2 expression protects hair cells from AG-induced death.

Next, auditory brainstem response tests to ‘click stimuli’ were measured in normal and genetically engineered mice to determine whether reducing RIPOR2 expression could prevent AG-induced hearing loss.

And while normal mice were found to be profoundly deaf after treatment with an AG, remarkably, there was no significant change in the hearing thresholds of mice that produced less RIPOR2.

The authors say the proteins identified in this study could potentially be used as drug targets to prevent aminoglycoside-induced hearing loss in future studies.