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Large-scale phenotypic drug screen identifies neuroprotectants in zebrafish and mouse models of retinitis pigmentosa

Year: 2021
Type: article
Abstract: 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 zebrafish and mouse RP models, reasoning drugs effective across species may translate better clinically. We first performed a large-scale phenotypic drug screen using a larval zebrafish model of inducible RP. 2,934 compounds, mostly human-approved drugs, were tested across six concentrations. Statistically, 113 compounds achieved “hit” status. Secondary tests of 42 high-priority hits confirmed eleven lead compounds. Nine leads were then evaluated in mouse RP models, with six exhibiting neuroprotective effects. An analysis of potential mechanisms of action suggested complementary activities. Paired lead compound assays in zebrafish showed additive neuroprotective effects for the majority. These results highlight the value of cross-species phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for patients with RP and IRDs.
Source: eLife
DOI: 10.7554/elife.57245
Authors: Liyun Zhang, Conan Chen, Jie Fu, Brendan Lilley, Cynthia Berlinicke, Baranda Hansen, Ding Ding, Guohua Wang, Tao Wang, Daniel Shou, Ying Ye, Timothy Mulligan, Kevin Emmerich, Meera T Saxena, Kelsi R Hall, Abigail V Sharrock, Carlene Brandon, Hyejin Park, Tae-In Kam, Valina L Dawson, Ted M Dawson, Joong Sup Shim, Justin Hanes, Hongkai Ji, Jun O Liu, Jiang Qian, David F Ackerley, Baerbel Rohrer, Donald J Zack, Jeff S Mumm
Institutions: Johns Hopkins University, Nanjing Forestry University, Xuzhou College of Industrial Technology, Victoria University of Wellington, Medical University of South Carolina, University of Macau
Language: English
Open Access status: gold
Estimated APC paid: $2,500
Funders: U.S. Department of Veterans Affairs, Foundation Fighting Blindness, Flight Attendant Medical Research Institute, University of South Carolina, Instituto Tecnológico de Costa Rica, National Institutes of Health, National Eye Institute
Awards: G1364452740, Alternative Pathway of Complement Activation in Age-Related Macular Degeneration, G24192066, Improved Animal Models for Cell-Specific Regenerative Medicine Paradigms, G5346054153, P30 Wilmer Core Grant for Vision Research, Genetic and Chemical Screens for Factors Regulating Retinal Regeneration, G7358092887, G8684316755, G9000021709
OpenAlex ID: W3173973658
FWCI: 1.256
Cites: 182
Cited by: 31
Related to: 10