eLife (Jun 2021)
Large-scale phenotypic drug screen identifies neuroprotectants in zebrafish and mouse models of retinitis pigmentosa
- 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
Affiliations
- Liyun Zhang
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Conan Chen
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Jie Fu
- The Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Brendan Lilley
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Cynthia Berlinicke
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Baranda Hansen
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Ding Ding
- Department of Biostatistics, Johns Hopkins University, Baltimore, United States
- Guohua Wang
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Tao Wang
- The Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States; School of Chemistry, Xuzhou College of Industrial Technology, Xuzhou, China; College of Light Industry and Food Engineering, Nanjing Forestry University, Nanjing, China
- Daniel Shou
- The Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Ying Ye
- The Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Timothy Mulligan
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Kevin Emmerich
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States; Department of Genetic Medicine, Johns Hopkins University, Baltimore, United States
- Meera T Saxena
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Kelsi R Hall
- School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
- Abigail V Sharrock
- Department of Biostatistics, Johns Hopkins University, Baltimore, United States; School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
- Carlene Brandon
- Department of Ophthalmology, Medical University of South Carolina, Charleston, United States
- Hyejin Park
- Department of Neurology, Johns Hopkins University, Baltimore, United States
- Tae-In Kam
- Department of Neurology, Johns Hopkins University, Baltimore, United States; Institute for Cell Engineering, Johns Hopkins University, Baltimore, United States
- Valina L Dawson
- ORCiD
- Department of Neurology, Johns Hopkins University, Baltimore, United States; Institute for Cell Engineering, Johns Hopkins University, Baltimore, United States; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, United States; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, United States
- Ted M Dawson
- ORCiD
- Department of Neurology, Johns Hopkins University, Baltimore, United States; Institute for Cell Engineering, Johns Hopkins University, Baltimore, United States; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, United States; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, United States
- Joong Sup Shim
- Faculty of Health Sciences, University of Macau, Taipa, Macau, China
- Justin Hanes
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States; The Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- Hongkai Ji
- Department of Biostatistics, Johns Hopkins University, Baltimore, United States
- Jun O Liu
- ORCiD
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, United States; Department of Oncology, Johns Hopkins University, Baltimore, United States
- Jiang Qian
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
- David F Ackerley
- ORCiD
- School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
- Baerbel Rohrer
- Department of Ophthalmology, Medical University of South Carolina, Charleston, United States
- Donald J Zack
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States; The Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States; Department of Genetic Medicine, Johns Hopkins University, Baltimore, United States; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, United States; Department of Molecular Biology and Genetics, Johns Hopkins University, Baltimore, United States
- Jeff S Mumm
- ORCiD
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States; The Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States; Department of Genetic Medicine, Johns Hopkins University, Baltimore, United States; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, United States
- DOI
- https://doi.org/10.7554/eLife.57245
- Journal volume & issue
-
Vol. 10
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 2934 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, that is, potential pan-disease therapeutics. Nine of 11 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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