Spirig, Stefan, Arteaga Moreta, Valeria, Raics, Zoltan, Posada, Susana, Chreng, Stephanie, Galuba, Olaf, Galuba, Inga, Claerr, Isabelle, Renner, Steffen, Kleindienst, Timo, Volak, Adrienn, Imbach, Jannick, Malysheva, Svitlana, Siwicki, Rebecca, Hahaut, Vincent, Hou, Yanyan, Picelli, Simone, Cattaneo, Marco, Juettner, Josephine, Cowan, Cameron, Duckely, Myriam, Baeschlin, Daniel, Renner, Magdalena, Unterreiner, Vincent and Roska, Botond (2026) Cell type–focused compound screen in human organoids reveals CK1 inhibition protects cone photoreceptors from death. Neuron.

Abstract

Human organoids that mirror their corresponding organs in cell-type diversity present an opportunity to perform large-scale screens for compounds that protect disease-affected or damage healthy cell types. Here, we generated 20,000 human retinal organoids with GFP-labeled cone photoreceptors. Since degeneration of cones is a leading cause of blindness, we induced cone death and screened 2,707 compounds with known targets, for those that saved cones or those that further damaged cones. We identified inhibitors of CK1 that protected cones, HSP90 inhibitors that saved cones in the short term but damaged them in the longer term, and broad HDAC inhibition by many compounds that significantly damaged cones. Finally, we confirmed the protective effects of identified compounds in a mouse model of photoreceptor degeneration. This work provides a database for cone-damaging compounds and describes compounds and targets that can be starting points to develop neuroprotection for cones in diseases such as macular degeneration.

Item Type:	Article
Keywords:	Human organoids, compound screen, retinal organoids, photoreceptor, rod, cone, cone degeneration, rod degeneration, retinitis pigmentosa, age related macular degeneration, macular degeneration, glucose starvation, selective vulnerability, mode of action library, kinase inhibitors, HDAC inhibition, HSP90 inhibition
Date Deposited:	14 Apr 2026 00:45
Last Modified:	14 Apr 2026 00:45
URI:	https://oak.novartis.com/id/eprint/59888