If you know me, you know that I am passionate about antibacterial soap. Passionate about how much a hate it, that is. I know it has it's place, like in hospitals, or in the homes of immunocompromised people, probably. But you won't find it in my house because I happen to think of antimicrobial resistance (AMR) as a real life boogey man, and as a healthy enough individual I want to do my best to not contribute to that particular monster.
Development of, and access to novel antibiotics is a recognized unmet global public health need. That's one reason I found this study published last month so exciting. Ok, it was also because it overlaps with my interests in sensory neuroscience, but I won't be talking about that here.
The Indiana University authors of the linked paper are searching for a therapy that, when used prior to or in combination with aminoglycoside antibiotics, will prevent drug-induced hearing loss. You see, aminoglycosides (AGs for short) are a class of antibiotics that are extremely useful for treating all kinds of nasty bacterial infections that don't respond to other drugs. This makes the aminoglycosides, like gentamycin, kanamycin, and streptomycin, some of our best ammo against resistant bacterial strains, but with one huge caveat: tens of millions of people treated with AGs every year also develop irreversible, sometimes complete, hearing loss as a result of the treatment. That's right, AGs are great at killing drug-resistant bacteria, but they are great at damaging the cells in your inner ear too. Sadly, some infections are so severe and so resistant to alternative antibiotics that permanent hearing loss from treatment is a better outcome than the other options, of which there aren't many anyways.
In the linked study the authors describe a gene called GABARAP that appears to be required for AG-induced hearing loss to occur. The GABARAP gene codes for a protein involved in autophagy, which is basically our cells' internal recycling program. Usually autophagy cleans up and re-purposes old or broken molecules, but exposure to AG antibiotics kicks autophagy into overdrive and the exposed cells chew themselves to pieces.
The authors in the paper found that mice whose genomes were edited to remove the GABARAP gene were protected from hearing loss even after two weeks of high dose treatment with AG antibiotics. After learning this, the authors went on to design an injectable genetic therapy for normal mice that was effective at reducing GABARAP expression in their inner ears. After the same two week, high dose AG treatment, these mice, who had little to no GABARAP in their inner ears due to the gene therapy, had normal hearing after the AG treatment. Amazingly, the mice only had to receive one injection of the genetic treatment to be protected from AG-induced hearing loss a few weeks later.
The authors hope to develop a similar injectable gene therapy for humans to specifically reduce GABARAP expression in the inner ear. They believe this approach could prevent millions of cases of AG-induced hearing loss every year. They purposely designed the therapeutic molecule in this study to target both mouse and human GABARAP, which share about 95% of their nucleotide sequence in the protein coding region. This careful design means that any further preclinical animal studies can use the exact drug molecule that would eventually go into humans. If the results look good, this could be a strong candidate to enter human clinical trials, and ideally protect people across the world from needless side effects of the powerful aminoglycoside antibiotics.
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