Dorgau, Birthe, Georgiou, Maria, Chaudhary, Alexander, Moya-Molina, Marina, Collin, Joseph, Queen , Rachel, Hilgen, Gerrit, Davies, Tracey, Hewitt, Philip, Schmitt, Michael, Kusterman, Stefan, Pognan, Francois, Steel, David, Sernagor, Evelyne, Armstrong, Lyle and Lako, Majlinda (2021) Human iPSC-derived retinal organoid model for in vitro toxicity screening. Toxicology letters, 350. ISSN 1879-3169; 0378-4274

Abstract

Drug toxicity screening on retina is essential for the development of safe therapies for a large number of diseases, whilst preserving visual acuity and function. To this end, retinal organoids derived from human pluripotent stem cells (hPSCs) provide a suitable screening platform due to their similarity to human retina and the ease of generation in large-scale formats. In this study, two hPSC cell lines were differrentiated to retinal organoids, which comprised all key retinal cell types in multiple nuclear and synaptic layers. Single cell RNA-Seq of retinal organoids at day 200 of differentiation indicated the maintenance of retinal ganglion cells and development of bipolar cells: both cell types segregated into several subtypes. Ketorolac, Digoxin, Thioridazine, Sildenafil, Ethanol and Methanol were selected as key drugs to screen on retinal organoids because of the retinotoxic effects described in literature. Exposure of the hPSC-derived retinal organoids to Diogxin, Thioridazine and Sildenafil exposure resulted in photoreceptor cell death, while Digoxin and Thioridazine additionally affected all other cell types, including Müller glia cells. Ethanol and Methanol exposure caused an increase in the fraction of retinal ganglion cells. All drug treatments caused activation of astrocytes, indicated by dendrites sprouting into neuroepithelium The ability to resond to light was preserved in organoids although the number of active retinal ganglion cells decreased after drug exposure. These data indicate similar drug effects in organoids to those reported in in vivo models and/or in humans, thus providing the first robust experimental evidence of their suitability for toxicological studies.

Item Type:	Article
Date Deposited:	01 Feb 2022 00:45
Last Modified:	01 Feb 2022 00:45
URI:	https://oak.novartis.com/id/eprint/44981