Cell type-focused compound screen in human organoids reveals molecules and pathways controlling cone photoreceptor death

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. However, such screens have not yet been performed. 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 kinase inhibitors that protected cones in both the short and
longer term, 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. This resource provides a database for cone-damaging compounds, and it describes
compounds that can be starting points to develop neuroprotection for cones in diseases such
as macular degeneration.