July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
The FDA-approved Drug Carvedilol Improves Vision and Retinal Morphology in a Zebrafish Model of Retinitis Pigmentosa
Author Affiliations & Notes
  • Logan Ganzen
    Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States
    Interdisciplinary Life Sciences Program, Purdue University, West Lafayette, Indiana, United States
  • Rebecca Marie James
    Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States
  • Calvin C P Pang
    Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, Kowloon, Hong Kong
  • Mingzhi Zhang
    Joint Shantou International Eye Center, Shantou University & the Chinese University of Hong Kong, Shantou, China
  • Motokazu Tsujikawa
    Department of Opthalmology, Osaka University Graduate School of Medicine, Osaka, Japan
  • Yuk Fai Leung
    Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States
    Institute for Integrative Neuroscience, Purdue University, West Lafayette, Indiana, United States
  • Footnotes
    Commercial Relationships   Logan Ganzen, None; Rebecca James, None; Calvin Pang, None; Mingzhi Zhang, None; Motokazu Tsujikawa, None; Yuk Fai Leung, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5711. doi:https://doi.org/
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      Logan Ganzen, Rebecca Marie James, Calvin C P Pang, Mingzhi Zhang, Motokazu Tsujikawa, Yuk Fai Leung; The FDA-approved Drug Carvedilol Improves Vision and Retinal Morphology in a Zebrafish Model of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5711. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Retinitis Pigmentosa (RP) is an incurable retinal degeneration disease, and the purpose of our work is to discover drugs for patients suffering from the disease. To accomplish this goal, we utilized a visual-motor-response (VMR) assay to assess the diminished vision of a transgenic zebrafish RP model carrying a human Rhodposin transgene with Q344X truncation mutation (Ganzen et al., ARVO 2018), and used this line to screen compound libraries. Here, we report the visual function and retinal morphology of the Q344X zebrafish model was improved by an FDA-approved drug Carvedilol.

Methods : In our screen that identified Carvedilol, we treated the Q344X mutant with 10 μM drug from 5 days post-fertilization (dpf) to 7 dpf. This line experiences significant rod death and diminished VMR by 7 dpf (Ganzen et al. ARVO 2018). In this study, the Q344X line was treated with the same protocol, and the rescuing effects on rod number and morphology was evaluated through fluorescent imaging and in situ hybridization. The presence of rods and their precursors was determined by rod-EGFP reporter and in situ hybridization of rhodopsin and nr2e3. Since individual rods cannot be easily resolved well in a whole retina, we measured the area containing EGFP signal as a surrogate of rod numbers and quantified that using ImageJ.

Results : Carvedilol-treated Q344X zebrafish had a significant increase in rod-positive area on 7 dpf. Treated larvae had a larger average area of fluorescent signal near the marginal zone (3610±2841 μm2; N = 24) compared to the untreated larvae (1112±1305 μm2; N = 24) (Welch’s Two-sample T-test, T=3.9; df=32.3; p-value = 0.0004). Treated larvae also had a larger average area of fluorescent signal in the ventral patch (2728±2468 μm2; N = 24) compared to untreated larvae (529±537 μm2; N = 24) (Welch’s Two-sample T-test; T=4.2; df=25.2; p-value = 0.0002). Similarly, in situ hybridization revealed that Carvedilol increased staining of nr2e3 and rhodopsin near the Q344X ventral patch and marginal zone.

Conclusions : We conclude that Carvedilol is a beneficial drug to the Q344X RP model. Fluorescent imaging and in situ hybridization indicate that rod-positive area near the marginal zone area and ventral patch were expanded by the drug treatment. This finding implies that the drug potentially increased rod numbers and in turn improved the vision of the Q344X RP model.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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