Eupatilin Improves Cilia Defects in Human CEP290 Ciliopathy Models

Area of Science:

• Ophthalmology
• Genetics
• Cell Biology

Background:

• Photoreceptor outer segments are specialized cilia crucial for vision.
• Pathogenic variants in the cilia-associated gene CEP290 cause Leber congenital amaurosis 10 (LCA10) and other retinal ciliopathies.
• Current treatments for CEP290 variants are variant-specific, highlighting the need for broader approaches.

Purpose of the Study:

• To investigate the therapeutic potential of the flavonoid eupatilin for CEP290-related retinal diseases.
• To explore eupatilin's effects on cilia structure and function in human disease models.
• To elucidate eupatilin's mechanism of action in the context of CEP290 ciliopathies.

Main Methods:

• Generated human cell and organoid models of CEP290-related retinal disease, including patient-derived fibroblasts, CEP290 knockout RPE1 cells, and iPSC-derived retinal organoids.
• Assessed the impact of eupatilin on cilium formation, length, and rhodopsin localization.
• Analyzed gene expression changes in response to eupatilin treatment using RNA sequencing.

Main Results:

• Eupatilin significantly improved cilium formation and length in various CEP290-deficient cellular and organoid models.
• Eupatilin treatment reduced aberrant rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids.
• Eupatilin modulated gene transcription, affecting rhodopsin expression and targeting pathways related to cilia function and synaptic plasticity.

Conclusions:

• Eupatilin demonstrates efficacy in restoring cilia structure and function in models of CEP290-related retinal disease.
• Eupatilin acts as a variant-independent therapeutic agent, addressing a broad range of CEP290-associated ciliopathies.
• This study supports eupatilin as a promising therapeutic candidate for treating retinal ciliopathies linked to CEP290 dysfunction.