Phototoxicity avoidance is a potential therapeutic approach for retinal dystrophy caused by EYS dysfunction

Area of Science:

• Ophthalmology
• Genetics
• Cell Biology

Background:

• Inherited retinal dystrophies (IRDs) cause progressive vision loss.
• Mutations in the eyes shut homolog (EYS) gene are a frequent cause of IRDs.
• The precise mechanism of photoreceptor degeneration in EYS-associated retinal dystrophy (EYS-RD) remains unclear.

Purpose of the Study:

• To investigate the mechanism of photoreceptor cell degeneration in EYS-RD.
• To utilize patient-derived induced pluripotent stem cells (iPSCs) to create retinal organoids for studying EYS-RD.
• To explore the role of EYS and phototoxicity in the disease pathology.

Main Methods:

• Generated retinal organoids from iPSCs of patients with EYS-RD.
• Examined the localization of EYS and GRK7 in photoreceptor cells of the organoids.
• Assessed the vulnerability of photoreceptor cells to light stimuli, particularly blue light.
• Investigated the effect of EYS gene delivery on photoreceptor function.

Main Results:

• Photoreceptor cells in EYS-RD organoids showed mislocalization of EYS and GRK7 from the outer segment.
• These photoreceptor cells exhibited increased vulnerability to light, especially blue light.
• Mislocalization of GRK7 was also observed in eys-knockout zebrafish models.
• Restoring EYS in RD organoid photoreceptor cells corrected GRK7 mislocalization.

Conclusions:

• EYS mutations lead to photoreceptor outer segment dysfunction and light sensitivity in EYS-RD.
• Mislocalization of GRK7 contributes to phototoxicity in EYS-RD.
• Targeting phototoxicity represents a potential therapeutic strategy for EYS-RD.