Cell-type-focused compound screen in human organoids reveals CK1 inhibition protects cone photoreceptors from death

  • Neuron. 2026 Jul 1;114(13):2347-2366.e12. doi: 10.1016/j.neuron.2026.02.024.
Stefan E Spirig  1 ,  Álvaro Herrero-Navarro  2 ,  Larissa Utz  2 ,  Valeria J Arteaga-Moreta  2 ,  Zoltan Raics  2 ,  Susana Posada-Céspedes  2 ,  Stephanie Chreng  3 ,  Olaf Galuba  3 ,  Inga Galuba  3 ,  Isabelle Claerr  3 ,  Steffen Renner  3 ,  Miklos Boldogkoi  1 ,  Verónica Moreno-Juan  2 ,  P Timo Kleindienst  2 ,  Adrienn Volak  2 ,  Jannick Imbach  2 ,  Svitlana Malysheva  4 ,  Rebecca A Siwicki  2 ,  Vincent Hahaut  2 ,  Yanyan Hou  2 ,  Tiago M Rodrigues  1 ,  Simone Picelli  2 ,  Marco Cattaneo  5 ,  Josephine Jüttner  2 ,  Cameron S Cowan  2 ,  Myriam Duckely  3 ,  Daniel K Baeschlin  3 ,  Magdalena Renner  2 ,  Vincent Unterreiner  3 ,  Botond Roska  6
Affiliations
  • 1. Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; Department of Ophthalmology, University of Basel, 4031 Basel, Switzerland.
  • 2. Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland.
  • 3. Novartis Biomedical Research, 4056 Basel, Switzerland.
  • 4. Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; Biozentrum, University of Basel, 4056 Basel, Switzerland.
  • 5. Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; Department of Clinical Research, University of Basel, 4031 Basel, Switzerland.
  • 6. Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; Department of Ophthalmology, University of Basel, 4031 Basel, Switzerland. Electronic address: [email protected].
PMID: 41916277 DOI: 10.1016/j.neuron.2026.02.024
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.

Keywords
CK1; CK1 inhibition; CSNK1G1; MAPK11; MAPK11 inhibition; compound screen; cone; cone degeneration; human organoid; macular degeneration; photoreceptor; rd10 mice; retinal organoid; retinitis pigmentosa; rod; rod degeneration; selective vulnerability.
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