Abstract
Inherited retinal diseases (IRDs) cause progressive loss of light-sensitive photoreceptors in the eye and can lead to blindness. Gene-based therapies for IRDs have shown remarkable progress in the past decade, but the vast majority of forms remain untreatable. In the era of personalised medicine, induced pluripotent stem cells (iPSCs) emerge as a valuable system for cell replacement and to model IRD because they retain the specific patient genome and can differentiate into any adult cell type. Three-dimensional (3D) iPSCs-derived retina-like tissue called retinal organoid contains all major retina-specific cell types: amacrine, bipolar, horizontal, retinal ganglion cells, Müller glia, as well as rod and cone photoreceptors. Here, we describe the main applications of retinal organoids and provide a comprehensive overview of the state-of-art analysis methods that apply to this model system. Finally, we will discuss the outlook for improvements that would bring the cellular model a step closer to become an established system in research and treatment development of IRDs.
Highlights
Inherited retinal diseases (IRDs) comprise a genetically and clinically heterogeneous subgroup of vision disorders with over 270 different causative genes identified so far [1]
With the notable example of the FDA approval of a gene augmentation therapy for RPE65-associated IRD, recent success in the field of gene augmentation therapies is largely driven by preclinical studies performed in animal models [2–4]
The levels of aberrant splicing and pseudoexon inclusion associated with a deep-intronic variant in CEP290, which causes Leber congenital amaurosis 10 (LCA10), were higher in patient-derived retinal organoids compared to retinal pigment epithelium (RPE) or other cell types [78]
Summary
Inherited retinal diseases (IRDs) comprise a genetically and clinically heterogeneous subgroup of vision disorders with over 270 different causative genes identified so far [1]. In human ESC-derived retinal organoids, electron microscopy (EM) analysis of the photoreceptor cell layer showed mitochondria and rudimentary connecting cilia with basal bodies, only lacking obvious OS [24].
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