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

  1. Liyun Zhang
  2. Conan Chen
  3. Jie Fu
  4. Brendan Lilley
  5. Cynthia Berlinicke
  6. Baranda Hansen
  7. Ding Ding
  8. Guohua Wang
  9. Tao Wang
  10. Daniel Shou
  11. Ying Ye
  12. Timothy Mulligan
  13. Kevin Emmerich
  14. Meera T Saxena
  15. Kelsi R Hall
  16. Abigail V Sharrock
  17. Carlene Brandon
  18. Hyejin Park
  19. Tae-In Kam
  20. Valina L Dawson
  21. Ted M Dawson
  22. Joong Sup Shim
  23. Justin Hanes
  24. Hongkai Ji
  25. Jun O Liu
  26. Jiang Qian
  27. David F Ackerley
  28. Baerbel Rohrer
  29. Donald J Zack
  30. Jeff S Mumm  Is a corresponding author
  1. Johns Hopkins University, United States
  2. Johns Hopkins University School of Public Health, United States
  3. Johns Hopkins University School of Medicine, United States
  4. Victoria University of Wellington, New Zealand
  5. Medical University of South Carolina, United States
  6. Seoul National University, Republic of Korea
  7. 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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The following previously published data sets were used

Article and author information

Author details

  1. Liyun Zhang

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    Liyun Zhang, has filed a provisional patent for the discoveries described herein..
  2. Conan Chen

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  3. Jie Fu

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  4. Brendan Lilley

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  5. Cynthia Berlinicke

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  6. Baranda Hansen

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  7. Ding Ding

    Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, United States
    Competing interests
    No competing interests declared.
  8. Guohua Wang

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  9. Tao Wang

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  10. Daniel Shou

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  11. Ying Ye

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  12. Timothy Mulligan

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  13. Kevin Emmerich

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  14. Meera T Saxena

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  15. Kelsi R Hall

    Victoria University of Wellington, Wellington, New Zealand
    Competing interests
    No competing interests declared.
  16. Abigail V Sharrock

    Victoria University of Wellington, Wellington, New Zealand
    Competing interests
    No competing interests declared.
  17. Carlene Brandon

    Ophthalmology, Medical University of South Carolina, Charleston, United States
    Competing interests
    No competing interests declared.
  18. Hyejin Park

    School of Biological Science, Seoul National University, Seoul, Republic of Korea
    Competing interests
    No competing interests declared.
  19. Tae-In Kam

    School of Biological Science, Seoul National University, Seoul, Republic of Korea
    Competing interests
    No competing interests declared.
  20. Valina L Dawson

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2915-3970
  21. Ted M Dawson

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6459-0893
  22. Joong Sup Shim

    Faculty of Health Sciences, University of Macau, Taipa, Macao
    Competing interests
    No competing interests declared.
  23. Justin Hanes

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  24. Hongkai Ji

    Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, United States
    Competing interests
    No competing interests declared.
  25. Jun O Liu

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3842-9841
  26. Jiang Qian

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  27. David F Ackerley

    Victoria University of Wellington, Wellington, New Zealand
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6188-9902
  28. Baerbel Rohrer

    Ophthalmology, Medical University of South Carolina, Charleston, United States
    Competing interests
    No competing interests declared.
  29. Donald J Zack

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  30. Jeff S Mumm

    Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States
    For correspondence
    jmumm3@jhmi.edu
    Competing interests
    Jeff S Mumm, holds patents for the NTR inducible cell ablation system (US #7,514,595) and uses thereof (US #8,071,838 and US#8431768). Has filed a provisional patent for the discoveries described herein. All other authors have no commercial relationships..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2575-287X

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).

Reviewing Editor

  1. James J Dowling, The Hospital for Sick Children, Canada

Publication history

  1. Received: March 26, 2020
  2. Accepted: June 28, 2021
  3. Accepted Manuscript published: June 29, 2021 (version 1)
  4. Accepted Manuscript updated: July 9, 2021 (version 2)
  5. Version of Record published: September 8, 2021 (version 3)
  6. Version of Record updated: September 15, 2021 (version 4)

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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  1. Liyun Zhang
  2. Conan Chen
  3. Jie Fu
  4. Brendan Lilley
  5. Cynthia Berlinicke
  6. Baranda Hansen
  7. Ding Ding
  8. Guohua Wang
  9. Tao Wang
  10. Daniel Shou
  11. Ying Ye
  12. Timothy Mulligan
  13. Kevin Emmerich
  14. Meera T Saxena
  15. Kelsi R Hall
  16. Abigail V Sharrock
  17. Carlene Brandon
  18. Hyejin Park
  19. Tae-In Kam
  20. Valina L Dawson
  21. Ted M Dawson
  22. Joong Sup Shim
  23. Justin Hanes
  24. Hongkai Ji
  25. Jun O Liu
  26. Jiang Qian
  27. David F Ackerley
  28. Baerbel Rohrer
  29. Donald J Zack
  30. Jeff S Mumm
(2021)
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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