Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death

Kenyon, Emma J.; Kirkwood, Nerissa K.; Kitcher, Siân R.; O’Reilly, Molly; Derudas, Marco; Cantillon, Daire; Goodyear, Richard J.; Secker, Abigail; Baxendale, Sarah; Bull, James C.; Waddell, Simon J.; Whitfield, Tanya T.; Ward, Simon E.; Kros, Corné J.; Richardson, Guy P.

doi:10.1172/jci.insight.96773

Cited by 25 publications

(40 citation statements)

References 49 publications

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“…A higher throughput pipeline utilizes the zebrafish larva neuromast to study hair cell damage, protection and regeneration (Chiu et al, 2008;Stawicki et al, 2015). Large libraries of compounds can be tested in these models and 'hit' compounds can be re-validated in rodents (Kenyon et al, 2017;Ou et al, 2009;Owens et al, 2008). However, the transferability of the findings obtained in rodents or non-mammalian vertebrates to humans is uncertain.…”

Section: Drug Screensmentioning

confidence: 99%

Inner ear organoids: new tools to understand neurosensory cell development, degeneration and regeneration

Roccio

Edge

2019

Development

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The development of therapeutic interventions for hearing loss requires fundamental knowledge about the signaling pathways controlling tissue development as well as the establishment of human cell-based assays to validate therapeutic strategies ex vivo. Recent advances in the field of stem cell biology and organoid culture systems allow the expansion and differentiation of tissue-specific progenitors and pluripotent stem cells in vitro into functional hair cells and otic-like neurons. We discuss how inner ear organoids have been developed and how they offer for the first time the opportunity to validate drugbased therapies, gene-targeting approaches and cell replacement strategies.

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Section: Drug Screensmentioning

confidence: 99%

Inner ear organoids: new tools to understand neurosensory cell development, degeneration and regeneration

Roccio

Edge

2019

Development

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“…In progressing toward this goal, recent small molecule screens with zebrafish have been used to identify protective compounds that were also validated in mammalian systems. Starting with a zebrafish screen, Kenyon et al (2017) identified 13 compounds that also protected hair cells in mammalian cochlear cultures from the aminoglycoside antibiotic gentamicin. This study focused on compounds that block mechanotransduction, preventing aminoglycoside entry.…”

Section: Hair Cell Deathmentioning

confidence: 99%

Water Waves to Sound Waves: Using Zebrafish to Explore Hair Cell Biology

Pickett

Raible

2019

JARO

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Although perhaps best known for their use in developmental studies, over the last couple of decades, zebrafish have become increasingly popular model organisms for investigating auditory system function and disease. Like mammals, zebrafish possess inner ear mechanosensory hair cells required for hearing, as well as superficial hair cells of the lateral line sensory system, which mediate detection of directional water flow. Complementing mammalian studies, zebrafish have been used to gain significant insights into many facets of hair cell biology, including mechanotransduction and synaptic physiology as well as mechanisms of both hereditary and acquired hair cell dysfunction. Here, we provide an overview of this literature, highlighting some of the particular advantages of using zebrafish to investigate hearing and hearing loss.

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“…They identified four bisbenzylisoquinoline derivatives that protected HCs by preventing aminoglycoside uptake into HCs. Kenyon et al ( 2017 ) screened 160 ion-channel modulators for the ability to reduce gentamicin-induced HC death, block the HC MET channel or reduce gentamicin uptake. A total of 72 compounds affected one of these variables.…”

Section: Ototoxicity Screening Assaysmentioning

confidence: 99%

Screening Mammalian Cochlear Hair Cells to Identify Critical Processes in Aminoglycoside-Mediated Damage

Lim

Pak

Ryan

et al. 2018

Front. Cell. Neurosci.

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There is considerable interest in discovering drugs with the potential to protect inner ear hair cells (HCs) from damage. One means of discovery is to screen compound libraries. Excellent screening protocols have been developed employing cell lines derived from the cochlea and zebrafish larvae. However, these do not address the differentiated mammalian hair cell. We have developed a screening method employing micro-explants of the mammalian organ of Corti (oC) to identify compounds with the ability to influence aminoglycoside-induced HC loss. The assay is based on short segments of the neonatal mouse oC, containing ~80 HCs which selectively express green fluorescent protein (GFP). This allows the screening of hundreds of potential protectants in an assay that includes both inner and outer HCs. This review article describes various screening methods, including the micro-explant assay. In addition, two micro-explant screening studies in which antioxidant and kinase inhibitor libraries were evaluated are reviewed. The results from these screens are related to current models of HC damage and protection.

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Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death

Cited by 25 publications

References 49 publications

Inner ear organoids: new tools to understand neurosensory cell development, degeneration and regeneration

Inner ear organoids: new tools to understand neurosensory cell development, degeneration and regeneration

Water Waves to Sound Waves: Using Zebrafish to Explore Hair Cell Biology

Screening Mammalian Cochlear Hair Cells to Identify Critical Processes in Aminoglycoside-Mediated Damage

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