Related Experiment Video
Updated: Jan 6, 2026
Generation of Retinal Organoids from Healthy and Retinal Disease-Specific Human-Induced Pluripotent Stem Cells
Published on: December 9, 2022
USH2A-Mutated Human Retinal Organoids Model Rod-Cone Dystrophy
Kristen E Ashworth1,2, Jiajie Zhang2,3, Cassandra D'Amata2
1Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Purpose:
USH2A mutations are the leading cause of autosomal recessive retinitis pigmentosa (RP), a progressive blinding disease marked by photoreceptor degeneration. Animal models fail to recapitulate the features of USH2A RP seen in humans, and its earliest pathogenic events remain unknown. Here, we established a human model of USH2A RP using retinal organoids derived from patient induced pluripotent stem cells and CRISPR-Cas9-engineered isogenic-USH2A-/- induced pluripotent stem cells.
Methods:
We assessed organoids for cellular, molecular, and morphological defects using serial live imaging and whole organoid and fixed section analyses.
Results:
Both patient-derived and isogenic-USH2A-/- organoids showed preferential rod photoreceptor loss followed by widespread degeneration, consistent with the clinical phenotype. Additionally, isogenic-USH2A-/- organoids showed early defects in proliferation and structure.
Conclusions:
Our findings suggest that molecular changes precede overt photoreceptor loss in USH2A RP, and pathogenesis may begin before clinical symptoms emerge. By defining early and late disease features, we provide new insight on the developmental origins of USH2A RP to guide therapeutic strategies.
