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

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

doi:10.1038/s41598-021-89482-z

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.

Highlights

Retinitis Pigmentosa (RP) is a mostly incurable inherited retinal degeneration affecting approximately 1 in 4000 individuals globally
We utilized the visual motor response (VMR) assay to screen drugs with the Q344X zebrafish model using a scotopic light stimulus. This fish model was selected for our drug screening as its rods begin to degenerate at 5 dpf, and the rod degeneration becomes severe by 7 dpf[15]
To address this unmet need, we have utilized the Q344X autosomal dominant cases of RP (adRP) zebrafish model to establish a drug screening platform that can be expanded into other subtypes of RP

Summary

Introduction

Retinitis Pigmentosa (RP) is a mostly incurable inherited retinal degeneration affecting approximately 1 in 4000 individuals globally. 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). The Luxturna treatment strategy aims to replace a deficient enzyme in an autosomal recessive case of RP, this will not work in autosomal dominant cases of RP (adRP) This highlights an urgent need for RP therapeutics that are effective and inexpensive. The zebrafish can provide a powerful system to model RP, and they have been used to model a number of human retinal-degenerative d iseases[11,12,13,14,15] These models include transgenic zebrafish expressing human rhodopsin (RHO) with autosomal dominant mutations found in RP patients[16]. We utilized this Q344X zebrafish model to develop an in vivo drug-screening platform for identifying drugs that may treat adRP

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