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 damaged healthy cell types. Here, we generated 20,000 human retinal organoids with green fluorescent protein (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 casein kinase 1 (CK1) that protected cones, heat shock protein 90 (HSP90) inhibitors that saved cones in the short term but damaged them in the longer term, and broad histone deacetylase (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.

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