Retinal organoids provide unique insights into molecular signatures of inherited retinal disease throughout retinogenesis

• Published in: Journal of anatomy Vol. 243; no. 2; pp. 186 - 203
• Main Authors: Watson, Avril, Lako, Majlinda
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.08.2023; John Wiley and Sons Inc
• Subjects: Animal models; Animals; Cell culture; Disease; disease modelling; Drug screening; Epithelium; Gene therapy; Humans; Induced Pluripotent Stem Cells; inherited retinal disease; Mutation; Organoids; Phenotypes; Pluripotency; Retina; Retinal Diseases - genetics; Retinal Diseases - pathology; retinal organoids; Retinal pigment epithelium; Retinal Pigment Epithelium - pathology; Retinitis pigmentosa; Retinoblastoma; Retinogenesis; Review; Special Section: Mini‐symposium on Vision and Visualisation; Stargardt disease; Stem cells; stem cells; disease modelling; retinoblastoma; retinitis pigmentosa; Stargardt disease; retinal pigment epithelium; retinal organoids; inherited retinal disease
• ISSN: 0021-8782; 1469-7580
• DOI: 10.1111/joa.13768

The demand for induced pluripotent stem cells (iPSC)‐derived retinal organoid and retinal pigment epithelium (RPE) models for the modelling of inherited retinopathies has increased significantly in the last decade. These models are comparable with foetal retinas up until the later stages of retinogenesis, expressing all of the key neuronal markers necessary for retinal function. These models have proven to be invaluable in the understanding of retinogenesis, particular in the context of patient‐specific diseases. Inherited retinopathies are infamously described as clinically and phenotypically heterogeneous, such that developing gene/mutation‐specific animal models in each instance of retinal disease is not financially or ethically feasible. Further to this, many animal models are insufficient in the study of disease pathogenesis due to anatomical differences and failure to recapitulate human disease phenotypes. In contrast, iPSC‐derived retinal models provide a high throughput platform which is physiologically relevant for studying human health and disease. They also serve as a platform for drug screening, gene therapy approaches and in vitro toxicology of novel therapeutics in pre‐clinical studies. One unique characteristic of stem cell‐derived retinal models is the ability to mimic in vivo retinogenesis, providing unparalleled insights into the effects of pathogenic mutations in cells of the developing retina, in a highly accessible way. This review aims to give the reader an overview of iPSC‐derived retinal organoids and/or RPE in the context of disease modelling of several inherited retinopathies including Retinitis Pigmentosa, Stargardt disease and Retinoblastoma. We describe the ability of each model to recapitulate in vivo disease phenotypes, validate previous findings from animal models and identify novel pathomechanisms that underpin individual IRDs. Retinal organoids have become an exceedingly useful tool in recent years for understanding retinogenesis, particularly in the context of retinal disease. Pluripotent stem cells (PSCs) can be derived directly from somatic cells of affected patients, or alternatively, existing pluripotent lines can undergo gene editing to harbour mutations of interest. These PSCs can then undertake a directed differentiation to retinal tissues in vitro, specifically retinal organoids and retinal pigment epithelium (RPE), giving the investigator an abundance of disease‐relevant tissue to assay. There are several applications for the use of retinal organoids and RPE in the scientific study including disease modelling, understanding retinogenesis, drug screening and toxicological screening. This review aims to serve as a primer in the utility of retinal organoids and RPE, derived from PSCs, in the study of inherited retinopathies. Using retinal diseases, such as Retinitis pigmentosa, Stargardt disease and Retinoblastoma, we discuss how PSC‐derived retinal tissues can corroborate results from animal models and uncover novel molecular signatures of disease that may be crucial in developing therapies against inherited blindness.