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Eupatilin Improves Cilia Defects in Human CEP290 Ciliopathy Models

Corral-Serrano, Julio C; Sladen, Paul E; Ottaviani, Daniele; Rezek, Olivia F; Athanasiou, Dimitra; Jovanovic, Katarina; Van der Spuy, Jacqueline; ... Cheetham, Michael E; + view all (2023) Eupatilin Improves Cilia Defects in Human CEP290 Ciliopathy Models. Cells , 12 (12) , Article 1575. 10.3390/cells12121575. Green open access

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Abstract

The photoreceptor outer segment is a highly specialized primary cilium that is essential for phototransduction and vision. Biallelic pathogenic variants in the cilia-associated gene CEP290 cause non-syndromic Leber congenital amaurosis 10 (LCA10) and syndromic diseases, where the retina is also affected. While RNA antisense oligonucleotides and gene editing are potential treatment options for the common deep intronic variant c.2991+1655A>G in CEP290, there is a need for variant-independent approaches that could be applied to a broader spectrum of ciliopathies. Here, we generated several distinct human models of CEP290-related retinal disease and investigated the effects of the flavonoid eupatilin as a potential treatment. Eupatilin improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, in gene-edited CEP290 knockout (CEP290 KO) RPE1 cells, and in both CEP290 LCA10 and CEP290 KO iPSCs-derived retinal organoids. Furthermore, eupatilin reduced rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids. Eupatilin altered gene transcription in retinal organoids by modulating the expression of rhodopsin and by targeting cilia and synaptic plasticity pathways. This work sheds light on the mechanism of action of eupatilin and supports its potential as a variant-independent approach for CEP290-associated ciliopathies.

Type: Article
Title: Eupatilin Improves Cilia Defects in Human CEP290 Ciliopathy Models
Open access status: An open access version is available from UCL Discovery
DOI: 10.3390/cells12121575
Publisher version: https://doi.org/10.3390/cells12121575
Language: English
Additional information: Copyright © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Keywords: CEP290; Leber congenital amaurosis (LCA); retina; ciliopathy; photoreceptor; cilium; eupatilin; retinal organoid
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10172581
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