June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Hexafluoro-Honokiol improves visual function and photoreceptor survival in a zebrafish model of PCDH15 (USH1F)
Author Affiliations & Notes
  • Jennifer Phillips
    Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States
  • Jeremy Wegner
    Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States
  • Sara Buchner
    Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States
  • Siena Kulis
    Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States
  • Eric Fox
    Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States
  • Monte Westerfield
    Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States
  • Footnotes
    Commercial Relationships   Jennifer Phillips None; Jeremy Wegner None; Sara Buchner None; Siena Kulis None; Eric Fox None; Monte Westerfield None
  • Footnotes
    Support  Usher1F Collaborative, Usher Syndrome Society
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4892. doi:
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      Jennifer Phillips, Jeremy Wegner, Sara Buchner, Siena Kulis, Eric Fox, Monte Westerfield; Hexafluoro-Honokiol improves visual function and photoreceptor survival in a zebrafish model of PCDH15 (USH1F). Invest. Ophthalmol. Vis. Sci. 2023;64(8):4892.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Mutations in PCDH15 cause Usher type 1F, characterized by the onset of visual dysfunction in childhood along with profound congenital deafness and vestibular defects. Early intervention with cochlear implants can address the hearing deficit in USH1F but there are no current treatments to address progressive vision loss. Previous studies have implicated Reactive Oxygen Species (ROS) as contributors to Usher syndrome retinal symptoms, thus compounds with antioxidant properties could impact disesase progression.. Zebrafish models of USH1F exhibit early, severe defects in photoreceptor structure, function and survival, in addition to balance defects, and thus are well suited for preclinical testing of such therapies.

Methods : We delivered 0.11 uM hexafluoro-honokiol in DMSO to the growth medium of young zebrafish from 2 days post fertilization (dpf) until 7dpf. Controls were treated with an equal volume of DMSO only. At 5dpf we tested the optokinetic responses (OKR) and at 7dpf the experiment was terminated. Fixed 7dpf fish were embedded in resin, cut in 2µm sections, and stained with Toluidine Blue. Images of stained retinas were captured with a compound light microscope and analyzed in ImageJ. Statistical analysis was performed with GraphPad software.

Results : Treated mutants had significantly improved optokinetic responses compared to untreated mutants, although still significantly diminished compared to wild-type responses from treated or untreated fish. Total cell counts from representative regions of the outer nuclear layer in sectioned retinas showed a small but consistent increase in treated mutants compared to controls, but did not rise to the level of statistical significance. Photoreceptor morphology was similarly disturbed in treated vs. untreated mutants, and vestibular defects persisted in treated animals.

Conclusions : Hexafluoro-honokiol treatment improves visual function in treated zebrafish larvae, despite having no impact on photoreceptor morphological defects resulting from pcdh15b mutation, and only a small impact on cell death rate. We conclude that the antioxidant effect of hexafluoro-honokiol has a stabilizing effect on cell function, even when structural anomalies persist.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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