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

Ganzen, Logan; Ko, Mee Jung; Zhang, Mengrui; Xie, Rui; Chen, Yongkai; Zhang, Liyun; James, Rebecca; Mumm, Jeff S.; Rijn, Richard M. van; Zhong, Wenxuan; Pang, Chi Pui; Zhang, Mingzhi; Tsujikawa, Motokazu; Leung, Yiu-Wing

doi:10.1038/s41598-021-89482-z

Cited by 15 publications

(11 citation statements)

References 79 publications

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“…Larvae can be placed in 96-well plates and exposed to chemical compounds in the medium. Many such high-throughput chemical screens have been performed using zebrafish ( Cassar et al, 2020 ; Zhang and Peterson, 2020 ), including drug screenings in kidney disease ( Gehrig et al, 2018 ) and retinal degeneration ( Ganzen et al, 2021 ), yielding interesting candidate molecules. Given the large number of JBTS zebrafish models available, these can now be used for identifying compounds that improve ciliopathy phenotypes as a first step for developing therapeutic strategies for JBTS patients.…”

Section: Future Directionsmentioning

confidence: 99%

Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome

2022

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Cilia are quasi-ubiquitous microtubule-based sensory organelles, which play vital roles in signal transduction during development and cell homeostasis. Dysfunction of cilia leads to a group of Mendelian disorders called ciliopathies, divided into different diagnoses according to clinical phenotype constellation and genetic causes. Joubert syndrome (JBTS) is a prototypical ciliopathy defined by a diagnostic cerebellar and brain stem malformation termed the “Molar Tooth Sign” (MTS), in addition to which patients display variable combinations of typical ciliopathy phenotypes such as retinal dystrophy, fibrocystic renal disease, polydactyly or skeletal dystrophy. Like most ciliopathies, JBTS is genetically highly heterogeneous with ∼40 associated genes. Zebrafish are widely used to model ciliopathies given the high conservation of ciliary genes and the variety of specialized cilia types similar to humans. In this review, we compare different existing JBTS zebrafish models with each other and describe their contributions to our understanding of JBTS pathomechanism. We find that retinal dystrophy, which is the most investigated ciliopathy phenotype in zebrafish ciliopathy models, is caused by distinct mechanisms according to the affected gene. Beyond this, differences in phenotypes in other organs observed between different JBTS-mutant models suggest tissue-specific roles for proteins implicated in JBTS. Unfortunately, the lack of systematic assessment of ciliopathy phenotypes in the mutants described in the literature currently limits the conclusions that can be drawn from these comparisons. In the future, the numerous existing JBTS zebrafish models represent a valuable resource that can be leveraged in order to gain further insights into ciliary function, pathomechanisms underlying ciliopathy phenotypes and to develop treatment strategies using small molecules.

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Section: Future Directionsmentioning

confidence: 99%

Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome

2022

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“…Zebrafish can be utilized as phenotypes in screening neuroactive compounds for photoreceptor degeneration [145][146][147]. An ENZO SCREEN-WELL REDOX library on a zebrafish autosomal dominant RP model finds that carvedilol, a beta-blocker, can increase the rod number and improve visual function [148]. Schisandrin B, an active component isolated from the traditional Chinese medicine (Fructus Schisandrae), is observed to improve light sensation in the pde6c zebrafish model of retinal degeneration [149].…”

Section: Neuroprotective Drugsmentioning

confidence: 99%

Zebrafish Model in Ophthalmology to Study Disease Mechanism and Drug Discovery

Hong

Luo

2021

Pharmaceuticals

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Visual impairment and blindness are common and seriously affect people’s work and quality of life in the world. Therefore, the effective therapies for eye diseases are of high priority. Zebrafish (Danio rerio) is an alternative vertebrate model as a useful tool for the mechanism elucidation and drug discovery of various eye disorders, such as cataracts, glaucoma, diabetic retinopathy, age-related macular degeneration, photoreceptor degeneration, etc. The genetic and embryonic accessibility of zebrafish in combination with a behavioral assessment of visual function has made it a very popular model in ophthalmology. Zebrafish has also been widely used in ocular drug discovery, such as the screening of new anti-angiogenic compounds or neuroprotective drugs, and the oculotoxicity test. In this review, we summarized the applications of zebrafish as the models of eye disorders to study disease mechanism and investigate novel drug treatments.

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“…The larvae movement in both dark and light periods is recorded and quantified in a high-throughput manner generating reliable data [ 86 , 87 ] through automated systems such as ZebraBox™ apparatus [ 84 ] or DanioVision™ [ 88 ]. VMR is a useful tool to assess oculotoxicity and visual disorders, as well as to verify the physiological integrity of neurocircuits promoted by therapeutic compounds in a noninvasively way [ 83 , 89 , 90 , 91 ].…”

Section: Neurological Functions and Behavior Models Toward Pre-clinic...mentioning

confidence: 99%

“…In phenotypes-based screenings, the visual system is a powerful tool to assess drug effects since it presents a rapid development [ 102 ]. Robust visually guided responses such as VMR can be used to identify new therapeutic molecules or to reposition already approved drugs [ 83 ].…”

Section: Neurological Functions and Behavior Models Toward Pre-clinic...mentioning

confidence: 99%

Zebrafish Larvae Behavior Models as a Tool for Drug Screenings and Pre-Clinical Trials: A Review

Rosa

Lima

Lopes-Ferreira

2022

IJMS

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To discover new molecules or review the biological activity and toxicity of therapeutic substances, drug development, and research relies on robust biological systems to obtain reliable results. Phenotype-based screenings can transpose the organism’s compensatory pathways by adopting multi-target strategies for treating complex diseases, and zebrafish emerged as an important model for biomedical research and drug screenings. Zebrafish’s clear correlation between neuro-anatomical and physiological features and behavior is very similar to that verified in mammals, enabling the construction of reliable and relevant experimental models for neurological disorders research. Zebrafish presents highly conserved physiological pathways that are found in higher vertebrates, including mammals, along with a robust behavioral repertoire. Moreover, it is very sensitive to pharmacological/environmental manipulations, and these behavioral phenotypes are detected in both larvae and adults. These advantages align with the 3Rs concept and qualify the zebrafish as a powerful tool for drug screenings and pre-clinical trials. This review highlights important behavioral domains studied in zebrafish larvae and their neurotransmitter systems and summarizes currently used techniques to evaluate and quantify zebrafish larvae behavior in laboratory studies.

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

Cited by 15 publications

References 79 publications

Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome

Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome

Zebrafish Model in Ophthalmology to Study Disease Mechanism and Drug Discovery

Zebrafish Larvae Behavior Models as a Tool for Drug Screenings and Pre-Clinical Trials: A Review

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