Research in Hearing Protection
Oricula Therapeutics evolved from converging research into hearing loss and compounds that have potential to prevent it. Oricula’s scientists, working at the University of Washington, have studied compounds causing hearing loss in humans.
Understanding antibiotic-induced hearing loss
It has been long understood that the aminoglyosides class of antibiotics induce hearing loss by causing the death of sound-sensing mechanosensory hair cells in the inner ear; howver, the exact mechanism of this toxicity is not known. The inner ear of mammals is located in the hardest bone of the body and it is extremely difficult to directly observe the effects of various chemicals on the hair cells of the cochlea. Therefore, our early work focused on the lateral line hair cells of zebrafish.
Work by us and many colleagues worldwide has shown that zebrafish hair cells have many properties in common with the inner ear hair cells of humans and other mammals. We have shown that they share common genes with mammals and are affected by the same chemical compounds. Since the zebrafish lateral line hair cells are on the outside of the fish, they are exposed to the chemical milieu of the swimming fish. Also, using a variety of flourescent dyes, the health of the hair cells is directly observable.
Identifying compounds with potential to protect hair cells
Using zebrafish, we we able to accomplish two key things: demonstrate that known ototoxic chemicals killed lateral line hair cells and identify compounds that protected hair cells from damage. After screening libraries of thousands of compounds, we identified one (we called ORC-0001) that was effective at protecting zebrafish lateral hair cells from the toxic effects of aminoglycosides (see Zebrafish screening).
Testing in mammals
The next step in creating a drug that could protect human hearing from the toxicity of aminoglycosides was to show that our compound (ORC-0001) was effective in a mammalian model. We chose to test this in rats using an assay called auditory brainstem response (ABR). ABR is used both clinically in humans and in animals as a way to determine the threshold sound intensity necessary to produce a response in the brain using sound of varying frequencies. Treatment of rats for ten days with kanamycin, amikacin, or other aminoglycosides causes a loss of hearing as demonstrated by higher thresholds to evoke an ABR response. Morphologically, we were also able to show that the aminoglycoside treatment caused hair cell death in the cochlea of the rats. Concurrently administered ORC-0001 was effective at eliminating most of the hearing loss and hair cell death (see Mammalian Efficacy.)
Protecting the findings
Patents for Method of Use and Composition of Matter are exclusively licensed from University of Washington by Oricula Therapeutics.