Author:
Zhang Liyun,Chen Conan,Fu Jie,Lilley Brendan,Berlinicke Cynthia,Hansen Baranda,Ding Ding,Wang Guohua,Wang Tao,Shou Daniel,Ye Ying,Saxena Meera T.,Hall Kelsi R.,Sharrock Abigail V.,Brandon Carlene,Shim Joong Sup,Hanes Justin,Ji Hongkai,Liu Jun O.,Qian Jiang,Ackerley David F.,Rohrer Baerbel,Zack Donald J.,Mumm Jeff S.
Abstract
ABSTRACTRetinitis 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 zebrafish and mouse RP models, reasoning drugs effective across species may translate better clinically. We first performed a large-scale phenotypic drug screen using a larval zebrafish model of inducible RP. 2,934 compounds, mostly human-approved drugs, were tested across six concentrations. Statistically, 113 compounds achieved “hit” status. Secondary tests of 42 high-priority hits confirmed eleven lead compounds. Nine leads were then evaluated in mouse RP models, with six exhibiting neuroprotective effects. An analysis of potential mechanisms of action suggested complementary activities. Paired lead compound assays in zebrafish showed additive neuroprotective effects for the majority. These results highlight the value of cross-species phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for patients with RP and IRDs.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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