Orphanet Journal of Rare Diseases | Advances of iPSC-Derived Retinal Organoids in Inherited Retinal Disease Research

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This systematic review summarizes the application of iPSC-derived retinal organoids in modeling retinal development and inherited retinal disease mechanisms, highlighting their potential in disease modeling and drug screening to provide novel in vitro model strategies for rare retinal disease research.

 

Literature Overview
This article 'Progress of iPSC-Derived Retinal Organoids in the Study of Inherited Retinal Diseases', published in the Orphanet Journal of Rare Diseases, reviews the latest advancements of iPSC-derived retinal organoids (RO) in studying inherited retinal diseases (IRDs). The study indicates traditional 2D cell models and animal models have significant limitations in IRD research, while retinal organoids (RO) can effectively simulate three-dimensional retinal structures, cellular composition, and physiological functions, providing powerful tools for disease mechanism analysis and precision therapy exploration. The article also systematically compares RO's similarity to in vivo retinal development and discusses their applications in various IRD models (e.g., RP, Rb, LCA, XLRS).

Background Knowledge
Inherited retinal diseases (IRDs) are rare ocular disorders caused by mutations in over 280 disease-causing genes, often leading to photoreceptor cell degeneration and vision loss. Due to lack of appropriate preclinical models, IRD research and therapeutic development face significant challenges. Recent advances in retinal organoid (RO) technology, particularly iPSC-derived ROs, enable simulation of retinal development processes and recreation of retinal cellular hierarchy and functional characteristics such as phototransduction and synaptic connections. These models demonstrate excellent phenotypic recapitulation capabilities in RP, Rb, LCA, and XLRS disease research, and can be applied to high-throughput drug screening and mechanism exploration. However, organoid maturity, structural consistency, and operational complexity remain major technical challenges in current research. This article comprehensively analyzes RO's advantages in IRD mechanism studies, disease modeling, and therapeutic development, while discussing their future clinical translation potential.

 

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Research Methods and Experiments
The study employs a 3D culture system for iPSC differentiation into ROs, combined with 2D/3D hybrid culture to enhance differentiation efficiency. By modulating Wnt, Nodal, Notch, TGF-β, and Shh signaling pathways, culture conditions are optimized through additions of DAPT, Wnt inhibitors, retinoic acid, taurine, BMP4, and IGF-1 factors. Additionally, researchers use single-cell RNA sequencing, electrophysiological recordings, and calcium imaging to verify the maturity and functionality of retinal cells in ROs, including phototransduction, synaptic connections, and cellular polarity. The experiments further utilize patient-derived iPSCs to construct disease-specific RO models combined with CRISPR/Cas9 gene editing technology for molecular mechanism studies of pathogenic mutations.

Key Conclusions and Perspectives

• ROs can simulate three major stages of retinal development: optic vesicle formation, optic cup formation, and photoreceptor differentiation, with structural and functional similarities to in vivo retinas.
• In disease models of RP, Rb, LCA, and XLRS, ROs successfully recapitulate pathogenic features caused by relevant gene mutations (e.g., USH2A, RHO, CEP290, RS1), including developmental abnormalities, phototransduction defects, and increased apoptosis.
• Pharmacological interventions (e.g., Topotecan, TW-37) or gene repairs (e.g., CRISPR/Cas9-mediated RS1 correction) can partially restore retinal functions in ROs, suggesting their application potential in drug screening and personalized therapy.
• RO technology has achieved differentiation from iPSCs to multiple retinal cell types including retinal ganglion cells, horizontal cells, bipolar cells, and Müller glial cells, with stable expression of key phototransduction proteins (e.g., rhodopsin, opsin).
• Although ROs demonstrate excellent retinal development simulation, challenges remain including low differentiation efficiency, insufficient maturity, and complex operations requiring further optimization of culture conditions and standardization of protocols.

Research Significance and Prospects
ROs provide manipulatable human-derived models for IRD research, helping reveal disease mechanisms and advance precision therapies. Future studies should focus on improving RO reproducibility and functionality to promote their applications in preclinical trials and regenerative medicine. Combining organoids with bioreactors and co-culture systems may further enhance physiological relevance, offering a more reliable platform for gene therapy, cell transplantation, and drug development.

 

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Conclusion
Retinal organoid technology represents a significant breakthrough in retinal disease research, with iPSC-based RO models effectively recapitulating human retinal development processes and cellular composition. This technology provides powerful tools for analyzing molecular mechanisms of inherited retinal diseases, screening potential therapeutic drugs, and developing personalized treatment strategies. Despite challenges in maturity and efficiency, successful applications in RP, Rb, LCA, and XLRS disease models have significantly accelerated translational research in retinal diseases. Looking forward, with optimized culture systems, integration of gene editing technologies, and deeper multi-omics analyses, ROs are expected to become core platforms for IRD research and therapeutic development, establishing a solid foundation for precision medicine and regenerative therapies.

 

Bochen Liu, Yi Liu, Haiyan Zhang, Jing Huang, and Guohua Liu. Progress of iPSC-derived retinal organoids in the study of inherited retinal diseases. Orphanet Journal of Rare Diseases.