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Cell-type-focused compound screen in human organoids reveals CK1 inhibition protects cone photoreceptors from death
Stefan E Spirig1, Álvaro Herrero-Navarro2, Larissa Utz2
1Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; Department of Ophthalmology, University of Basel, 4031 Basel, Switzerland.
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.
Insights
Researchers screened 2,707 compounds using human retinal organoids to find treatments for cone degeneration, a cause of blindness. They identified casein kinase 1 (CK1) inhibitors that protected cone photoreceptors, offering potential neuroprotection strategies.
Area of Science:
- Biomedical Science
- Neuroscience
- Ophthalmology
Background:
- Cone photoreceptor degeneration is a primary cause of blindness.
- Human organoids offer a model for studying disease and screening compounds.
- Developing neuroprotective strategies for retinal diseases is crucial.
Purpose of the Study:
- To screen a large library of compounds for their ability to protect cone photoreceptors from degeneration.
- To identify specific compounds and molecular targets involved in cone protection or damage.
- To validate findings in a preclinical animal model.
Main Methods:
- Generation of 20,000 human retinal organoids with labeled cone photoreceptors.
- Induction of cone death and screening of 2,707 compounds.
- Confirmation of protective effects in a mouse model of photoreceptor degeneration.
Main Results:
- Casein kinase 1 (CK1) inhibitors demonstrated cone-protective effects.
- Heat shock protein 90 (HSP90) inhibitors provided short-term protection but long-term damage.
- Histone deacetylase (HDAC) inhibition by multiple compounds significantly damaged cones.
Conclusions:
- CK1 inhibitors are promising starting points for developing cone neuroprotection.
- HSP90 and HDAC inhibitors warrant further investigation regarding their complex effects on cones.
- This study provides a valuable database of cone-damaging and protective compounds for retinal disease research.
