PUBLICATION

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

Authors
Zhang, L., Chen, C., Fu, J., Lilley, B., Berlinicke, C., Hansen, B., Ding, D., Wang, G., Wang, T., Shou, D., Ye, Y., Mulligan, T., Emmerich, K., Saxena, M.T., Hall, K.R., Sharrock, A.V., Brandon, C., Park, H., Kam, T.I., Dawson, V.L., Dawson, T.M., Shim, J.S., Hanes, J., Ji, H., Liu, J.O., Qian, J., Ackerley, D.F., Rohrer, B., Zack, D.J., Mumm, J.S.
ID
ZDB-PUB-210630-8
Date
2021
Source
eLIFE   10: (Journal)
Registered Authors
Mumm, Jeff
Keywords
developmental biology, neuroscience, zebrafish
MeSH Terms
  • Dose-Response Relationship, Drug
  • Poly (ADP-Ribose) Polymerase-1/genetics
  • Poly (ADP-Ribose) Polymerase-1/metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 6/genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 6/metabolism
  • Drug Evaluation, Preclinical
  • Cells, Cultured/drug effects
  • Mice
  • Retinal Rod Photoreceptor Cells/drug effects
  • Gene Expression Regulation/drug effects
  • Retinitis Pigmentosa/drug therapy*
  • Zebrafish
  • Disease Models, Animal
  • Neuroprotective Agents/pharmacology*
  • Animals
  • Animals, Genetically Modified
  • Mutation
(all 17)
PubMed
34184634 Full text @ Elife
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.
Genes / Markers
Figures
Figure Gallery (11 images) / 2
Show all Figures
Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
YFPmpv17a9; gmc500Tgchemical treatment by environment: metronidazoleDays 7-13IFL
YFPmpv17a9; gmc500Tgchemical treatment by environment: metronidazole, chemical treatment by environment: dihydroartemisininDays 7-13IFL
YFPmpv17a9; gmc500Tgchemical treatment by environment: miconazole, chemical treatment by environment: metronidazoleDays 7-13IFL
YFPmpv17a9; gmc500Tgchemical treatment by environment: warfarin, chemical treatment by environment: metronidazoleDays 7-13IFL
YFPmpv17a9; gmc500Tgchemical treatment by environment: zinc pyrithione, chemical treatment by environment: metronidazoleDays 7-13IFL
YFPmpv17a9; gmc500Tgchemical treatment by environment: cloxiquine, chemical treatment by environment: metronidazoleDays 7-13IFL
YFPmpv17a9; gmc500Tgchemical treatment by environment: (+)-artemisinin, chemical treatment by environment: metronidazoleDays 7-13IFL
YFPmpv17a9; gmc500Tgchemical treatment by environment: Calcimycin, chemical treatment by environment: metronidazoleDays 7-13IFL
YFPmpv17a9; gmc500Tgchemical treatment by environment: chloroxine, chemical treatment by environment: metronidazoleDays 7-13IFL
YFPmpv17a9; gmc500Tgchemical treatment by environment: metronidazole, chemical treatment by environment: cortexoloneDays 7-13IFL
1 - 10 of 17
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Phenotype
Fish Conditions Stage Phenotype Figure
mpv17a9; gmc500Tgchemical treatment by environment: (+)-artemisinin, chemical treatment by environment: metronidazole, chemical treatment by environment: cortexoloneDays 7-13
mpv17a9; gmc500Tgchemical treatment by environment: (+)-artemisinin, chemical treatment by environment: metronidazoleDays 7-13
mpv17a9; gmc500Tgchemical treatment by environment: (+)-artemisinin, chemical treatment by environment: metronidazoleDays 7-13
mpv17a9; gmc500Tgchemical treatment by environment: (+)-artemisinin, chemical treatment by environment: metronidazoleDays 7-13
mpv17a9; gmc500Tgchemical treatment by environment: Calcimycin, chemical treatment by environment: metronidazole, chemical treatment by environment: cortexoloneDays 7-13
mpv17a9; gmc500Tgchemical treatment by environment: Calcimycin, chemical treatment by environment: metronidazoleDays 7-13
mpv17a9; gmc500Tgchemical treatment by environment: Calcimycin, chemical treatment by environment: metronidazoleDays 7-13
mpv17a9; gmc500Tgchemical treatment by environment: Calcimycin, chemical treatment by environment: metronidazoleDays 7-13
mpv17a9; gmc500Tgchemical treatment by environment: metronidazole, chemical treatment: EC 3.4.22.56 (caspase-3) inhibitorDays 7-13
mpv17a9; gmc500Tgchemical treatment by environment: chloroxine, chemical treatment by environment: metronidazoleDays 7-13
1 - 10 of 84
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a9
    		Complex
    gmc500TgTransgenic Insertion
      jh405TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        Human Disease Fish Conditions Evidence
        retinitis pigmentosampv17a9; gmc500Tgchemical treatment by environment: metronidazoleTAS
        retinitis pigmentosampv17a9; jh405Tgchemical treatment by environment: metronidazoleTAS
        1 - 2 of 2
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        Sequence Targeting Reagents
        Target Reagent Reagent Type
        casp3aCRISPR3-casp3aCRISPR
        casp3aCRISPR4-casp3aCRISPR
        casp3aCRISPR6-casp3aCRISPR
        casp3aCRISPR8-casp3aCRISPR
        casp3bCRISPR1-casp3bCRISPR
        casp3bCRISPR2-casp3bCRISPR
        casp3bCRISPR3-casp3bCRISPR
        casp3bCRISPR4-casp3bCRISPR
        parp1CRISPR4-parp1CRISPR
        parp1CRISPR5-parp1CRISPR
        1 - 10 of 20
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        Fish
        Fish
        mpv17a9; gmc500Tg
        mpv17a9; gmc500Tg + CRISPR1-casp3b + CRISPR2-casp3b + CRISPR3-casp3a + CRISPR3-casp3b + CRISPR4-casp3a + CRISPR4-casp3b + CRISPR6-casp3a + CRISPR8-casp3a
        mpv17a9; gmc500Tg + CRISPR2-ripk1l + CRISPR3-ripk1l + CRISPR4-ripk1l + CRISPR5-ripk1l
        mpv17a9; gmc500Tg + CRISPR3-tdp1 + CRISPR4-tdp1 + CRISPR5-tdp1 + CRISPR6-tdp1
        mpv17a9; gmc500Tg + CRISPR4-parp1 + CRISPR5-parp1 + CRISPR6-parp1 + CRISPR7-parp1
        mpv17a9; jh405Tg
        1 - 6 of 6
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        Antibodies
        Orthology
        Engineered Foreign Genes
        Marker Marker Type Name
        NTREFGNTR
        TagYFPEFGTagYFP
        YFPEFGYFP
        1 - 3 of 3
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        Mapping
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        Citation
        Zhang, L., Chen, C., Fu, J., Lilley, B., Berlinicke, C., Hansen, B., Ding, D., Wang, G., Wang, T., Shou, D., Ye, Y., Mulligan, T., Emmerich, K., Saxena, M.T., Hall, K.R., Sharrock, A.V., Brandon, C., Park, H., Kam, T.I., Dawson, V.L., Dawson, T.M., Shim, J.S., Hanes, J., Ji, H., Liu, J.O., Qian, J., Ackerley, D.F., Rohrer, B., Zack, D.J., Mumm, J.S. (2021) Large-scale phenotypic drug screen identifies neuroprotectants in zebrafish and mouse models of retinitis pigmentosa. eLIFE. 10:.