1. Academic Validation
  2. ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity

ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity

  • JCI Insight. 2019 Aug 8;4(15):e126764. doi: 10.1172/jci.insight.126764.
Siân R Kitcher 1 Nerissa K Kirkwood 1 Esra D Camci 2 Patricia Wu 2 3 Robin M Gibson 2 Van A Redila 2 Julian A Simon 4 Edwin W Rubel 2 David W Raible 2 3 Guy P Richardson 1 Corné J Kros 1
Affiliations

Affiliations

  • 1 Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
  • 2 Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, Washington, USA.
  • 3 Department of Biological Structure, University of Washington, Seattle, Washington, USA.
  • 4 Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Abstract

Aminoglycoside (AG) Antibiotics are widely used to prevent life-threatening infections, and cisplatin is used in the treatment of various cancers, but both are ototoxic and result in loss of sensory hair cells from the inner ear. ORC-13661 is a new drug that was derived from PROTO-1, a compound first identified as protective in a large-scale screen utilizing hair cells in the lateral line organs of zebrafish larvae. Here, we demonstrate, in zebrafish larvae and in mouse cochlear cultures, that ORC-13661 provides robust protection of hair cells against both ototoxins, the AGs and cisplatin. ORC-13661 also prevents both hearing loss in a dose-dependent manner in rats treated with amikacin and the loading of neomycin-Texas Red into lateral line hair cells. In addition, patch-clamp recordings in mouse cochlear cultures reveal that ORC-13661 is a high-affinity permeant blocker of the mechanoelectrical transducer (MET) channel in outer hair cells, suggesting that it may reduce the toxicity of AGs by directly competing for entry at the level of the MET channel and of cisplatin by a MET-dependent mechanism. ORC-13661 is therefore a promising and versatile protectant that reversibly blocks the hair cell MET channel and operates across multiple species and toxins.

Keywords

Drug screens; Drug therapy; Ion channels; Neuroscience; Therapeutics.

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