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 and Fred Hutch Cancer Research Center, have studied compounds causing hearing loss in humans.

Understanding antibiotic-induced hearing loss 

It has been long understood that the aminoglyoside class of antibiotics induce hearing loss by causing the death of sound-sensing mechanosensory hair cells in the inner ear; however, the exact mechanism of this toxicity is not known. The inner ear of mammals is encased in the hardest bone of the body, making it extremely difficult to directly observe and manipulate. Therefore, early work focused on the lateral line hair cells of zebrafish.

Work at the University of Washington and by colleagues worldwide has shown that zebrafish lateral line hair cells have many properties conserved with inner ear hair cells of humans and other mammals. 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 directly accessible to visualization and manipulation.  

Identifying compounds with potential to protect hair cells in zebrafish

Work by Oricula's founders demonstrated that known ototoxic chemicals killed zebrafish lateral line hair cells, and could be used to identify compounds that protected hair cells from damage. Five-day-old zebrafish larvae can be placed in wells of a 96-well microplate. Each well contains normal zebrafish media, with additional compounds to test for potential toxic damage. In this way, hundreds or thousands of chemicals can be screened in a short time.  After screening libraries of thousands of compounds, one lead (ORC-0001; formerly called PROTO-1) was found to be effective at protecting zebrafish lateral hair cells from the toxic effects of aminoglycosides (Owens et al., 2008).


Developing a SAR

Oricula's ORC-13661 was developed through an iterative chemistry approach using ORC-0001 as the starting structure.  The new compound was over 25x more potent, with superior physiochemical, pharmacokinetic, and toxicologic properties (Chowdhury et al., 2018).


Testing in mammals

ORC-13661 (and ORC-0001) was shown to be effective in a mammalian model, testing for protection of rats against aminoglycoside damage using the auditory brainstem response (ABR) assay. 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.  Concurrently administered ORC-13661 was effective at eliminating most of the hearing loss and hair cell death.  

Hearing Protection by ORC-13661.jpg

Protecting the findings

ORC-13661 is a new chemical entity discovered and patented (US 9416141 and US 9493482 ) by University of Washington with funding from NIDCD, NINDS and the Life Sciences Discovery Fund, and exclusively licensed to Oricula Therapeutics LLC.