Large-scale phenotypic drug screen identifies neuroprotectants in zebrafish and mouse models of retinitis pigmentosa
- Johns Hopkins University, United States
- Johns Hopkins University School of Public Health, United States
- Johns Hopkins University School of Medicine, United States
- Victoria University of Wellington, New Zealand
- Medical University of South Carolina, United States
- University of Macau, Macao
Abstract
Retinitis pigmentosa (RP) and associated inherited retinal diseases (IRDs) are caused by rod photoreceptor degeneration, necessitating therapeutics promoting rod photoreceptor survival. To address this, we tested compounds for neuroprotective effects in multiple zebrafish and mouse RP models, reasoning drugs effective across species and/or independent of disease mutation may translate better clinically. We first performed a large-scale phenotypic drug screen for compounds promoting rod cell survival in a larval zebrafish model of inducible RP. We tested 2,934 compounds, mostly human-approved drugs, across six concentrations, resulting in 113 compounds being identified as hits. Secondary tests of 42 high-priority hits confirmed eleven lead candidates. Leads were then evaluated in a series of mouse RP models in an effort to identify compounds effective across species and RP models, i.e., potential pan-disease therapeutics. Nine of eleven leads exhibited neuroprotective effects in mouse primary photoreceptor cultures, and three promoted photoreceptor survival in mouse rd1 retinal explants. Both shared and complementary mechanisms of action were implicated across leads. Shared target tests implicated parp1-dependent cell death in our zebrafish RP model. Complementation tests revealed enhanced and additive/synergistic neuroprotective effects of paired drug combinations in mouse photoreceptor cultures and zebrafish, respectively. These results highlight the value of cross-species/multi-model phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for RP patients.
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Funding
Foundation Fighting Blindness (Wynn-Gund TRAP)
- Jeff S Mumm
National Institutes of Health (P30EY001765)
- Donald J Zack
National Institutes of Health (R01EY019320)
- Baerbel Rohrer
Department of Veterans Affairs (RX000444 and BX003050)
- Baerbel Rohrer
South Carolina SmartState Endowment
- Baerbel Rohrer
Flight Attendant Medical Research Institute
- Jun O Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal studies described herein were performed in accordance with both the Association for Research in Vision and Ophthalmology (ARVO) statement on the "Use of Animals in Ophthalmic and Vision Research" and the National Institutes of Health (NIH) Office of Laboratory Animal Welfare (OLAW) policies regarding studies conducted in vertebrate species. Animal protocols were approved by the Animal Care and Use Committees of the Johns Hopkins University School of Medicine (protocol # FI19M489 and #MO20M253) and Medical University of South Carolina (protocol #2018-00399).
Copyright
© 2021, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Large-scale phenotypic drug screen identifies neuroprotectants in zebrafish and mouse models of retinitis pigmentosa
eLife 10:e57245.
https://doi.org/10.7554/eLife.57245
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