Drug screening with zebrafish visual behavior identifies carvedilol as a potential treatment for an autosomal dominant form of retinitis pigmentosa

Logan Ganzen; Mee Jung Ko; Mengrui Zhang; Rui Xie; Yongkai Chen; Liyun Zhang; Rebecca James; Jeff Mumm; Richard M van Rijn; Wenxuan Zhong; Chi Pui Pang; Mingzhi Zhang; Motokazu Tsujikawa; Yuk Fai Leung

doi:10.1038/s41598-021-89482-z

Drug screening with zebrafish visual behavior identifies carvedilol as a potential treatment for an autosomal dominant form of retinitis pigmentosa

Sci Rep. 2021 Jun 1;11(1):11432. doi: 10.1038/s41598-021-89482-z.

Authors

Logan Ganzen^{1

2}, Mee Jung Ko^{2

3}, Mengrui Zhang⁴, Rui Xie⁵, Yongkai Chen⁴, Liyun Zhang⁶, Rebecca James¹, Jeff Mumm⁶, Richard M van Rijn^{2

3

7

8}, Wenxuan Zhong⁴, Chi Pui Pang^{9

10}, Mingzhi Zhang¹¹, Motokazu Tsujikawa^{12

13}, Yuk Fai Leung^{14

15

16

17}

Affiliations

¹ Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA.
² Purdue University Life Sciences Program, Purdue University, West Lafayette, IN, 47907, USA.
³ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
⁴ Department of Statistics, University of Georgia, Athens, GA, 30602, USA.
⁵ Department of Statistics and Data Science, University of Central Florida, Orlando, FL, 32816, USA.
⁶ Wilmer Eye Institute, John Hopkins School of Medicine, Baltimore, MD, 21205, USA.
⁷ Purdue Institute for Integrative Neuroscience, Purdue University, 610 Purdue Mall, West Lafayette, IN, 47907, USA.
⁸ Purdue Institute for Drug Discovery, Purdue University, 610 Purdue Mall, West Lafayette, IN, 47907, USA.
⁹ Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, China.
¹⁰ Joint Shantou International Eye Center, Shantou University and the Chinese University of Hong Kong, Shantou, China.
¹¹ Joint Shantou International Eye Center, Shantou University and the Chinese University of Hong Kong, Shantou, China. zmz@jsiec.org.
¹² Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan. moto@ophthal.med.osaka-u.ac.jp.
¹³ Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan. moto@ophthal.med.osaka-u.ac.jp.
¹⁴ Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA. yfleung@purdue.edu.
¹⁵ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine Lafayette, 625 Harrison Street, West Lafayette, IN, 47907, USA. yfleung@purdue.edu.
¹⁶ Purdue Institute for Integrative Neuroscience, Purdue University, 610 Purdue Mall, West Lafayette, IN, 47907, USA. yfleung@purdue.edu.
¹⁷ Purdue Institute for Drug Discovery, Purdue University, 610 Purdue Mall, West Lafayette, IN, 47907, USA. yfleung@purdue.edu.

Abstract

Retinitis Pigmentosa (RP) is a mostly incurable inherited retinal degeneration affecting approximately 1 in 4000 individuals globally. The goal of this work was to identify drugs that can help patients suffering from the disease. To accomplish this, we screened drugs on a zebrafish autosomal dominant RP model. This model expresses a truncated human rhodopsin transgene (Q344X) causing significant rod degeneration by 7 days post-fertilization (dpf). Consequently, the larvae displayed a deficit in visual motor response (VMR) under scotopic condition. The diminished VMR was leveraged to screen an ENZO SCREEN-WELL REDOX library since oxidative stress is postulated to play a role in RP progression. Our screening identified a beta-blocker, carvedilol, that ameliorated the deficient VMR of the RP larvae and increased their rod number. Carvedilol may directly on rods as it affected the adrenergic pathway in the photoreceptor-like human Y79 cell line. Since carvedilol is an FDA-approved drug, our findings suggest that carvedilol can potentially be repurposed to treat autosomal dominant RP patients.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified* / genetics
Animals, Genetically Modified* / metabolism
Behavior, Animal / drug effects*
Cell Line
Drug Evaluation, Preclinical
Genetic Diseases, Inborn* / drug therapy
Genetic Diseases, Inborn* / genetics
Genetic Diseases, Inborn* / metabolism
Humans
Mutation
Retinal Rod Photoreceptor Cells
Retinitis Pigmentosa* / drug therapy
Retinitis Pigmentosa* / genetics
Retinitis Pigmentosa* / metabolism
Rhodopsin* / genetics
Rhodopsin* / metabolism
Transgenes
Vision, Ocular* / drug effects
Vision, Ocular* / immunology
Zebrafish* / genetics
Zebrafish* / metabolism

Substances

Rhodopsin

Abstract

Publication types

MeSH terms

Substances

Grants and funding