Chemical Induction and Reversal of Photoreceptor Dystrophy in Retinal Organoids

ABSTRACT: Activating Transcription Factor 6 (ATF6) controls a signal transduction pathway of the Unfolded Protein Response (UPR) to alleviate endoplasmic reticulum (ER) stress. Loss-of-function ATF6 mutations in people cause inherited photoreceptor diseases like achromatopsia and cone-rod dystrophy. Ceapin-A7 is a cell-permeable, non-toxic small molecule that selectively binds and inhibits ATF6. We tested the role of ATF6 in retinal cell maintenance by treating wild-type human embryonic stem cell (hESC)-derived retinal organoids with Ceapin-A7 starting at D230 and evaluated the effects via snRNA-Seq and confocal microscopy at D290. Ceapin-A7 administration effectively suppressed ATF6-targeted and proteostasis-related gene expression in mature, wild-type retinal organoids without causing cell death. Inhibition of ATF6 in mature organoids caused a suppression of ATF6-targeted and proteostasis genes and led to a reduction in rod and cone inner/outer segment quantity, altered cone segment morphology, and Muller gliosis; however, the outer limiting membrane (OLM) remained intact. Additionally, we removed Ceapin-A7 from mature retinal organoid growth media after a period of treatment to determine if photoreceptors could recover from ATF6 inhibition. Under removal conditions, photoreceptor segment quantity was significantly improved compared to the sustained treatment group, indicating that photoreceptors were able to restore segments when ATF6 function returned. These findings demonstrate that ATF6 is essential for maintaining photoreceptor integrity, and that modulating ATF6 activity can alter this structure, suggesting its potential as a target in future studies of photoreceptor-related diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317151 | GEO | 2026/08/31

REPOSITORIES: GEO