Abstract
Approximately one-third of childhood blindness is attributed to developmental eye disorders, of which 80% have a genetic cause. Eye morphogenesis is tightly regulated by a highly conserved network of transcription factors when disrupted by genetic mutations can result in severe ocular malformation. Human-induced pluripotent stem cells (hiPSCs) are an attractive tool to study early eye development as they are more physiologically relevant than animal models, can be patient-specific and their use does not elicit the ethical concerns associated with human embryonic stem cells. The generation of self-organizing hiPSC-derived optic cups is a major advancement to understanding mechanisms of ocular development and disease. Their development in vitro has been found to mirror that of the human eye and these early organoids have been used to effectively model microphthalmia caused by a VSX2 variant. hiPSC-derived optic cups, retina, and cornea organoids are powerful tools for future modeling of disease phenotypes and will enable a greater understanding of the pathophysiology of many other developmental eye disorders. These models will also provide an effective platform for identifying molecular therapeutic targets and for future clinical applications.
Highlights
Developmental eye disorders are amongst the most common cause of severe visual impairment in children, with a combined incidence of 1–2 per 10,000 births (Nedelec et al, 2019)
One of the major earlyonset disease groups arising between weeks 4–7 of gestation is the microphthalmia/anophthalmia/coloboma (MAC) spectrum, which varies in severity and includes the complete absence of an eye, a small underdeveloped eye and incomplete fusion of the optic fissure leading to a persistent cleft in the inferior aspect of the eye spanning one or more of the following tissues: iris, ciliary body, retina, RPE, choroid and optic nerve
Ocular maldevelopment accounts for a third of congenital blindness worldwide, and a genetic component is responsible for the majority of cases. Human-induced pluripotent stem cells (hiPSCs) modeling of early eye development has advanced greatly in recent years and omics studies reveal a close cellular and molecular similarity with human fetal tissue (HFT) of similar development stage
Summary
Developmental eye disorders are amongst the most common cause of severe visual impairment in children, with a combined incidence of 1–2 per 10,000 births (Nedelec et al, 2019). One of the major earlyonset disease groups arising between weeks 4–7 of gestation is the microphthalmia/anophthalmia/coloboma (MAC) spectrum, which varies in severity and includes the complete absence of an eye (anophthalmia), a small underdeveloped eye (microphthalmia) and incomplete fusion of the optic fissure leading to a persistent cleft in the inferior aspect of the eye spanning one or more of the following tissues: iris, ciliary body, retina, RPE, choroid and optic nerve (coloboma; Harding and Moosajee, 2019) All these disorders are caused by disruption to key regulatory genes, including numerous transcription factors, that are essential for normal eye development (Moosajee et al, 2018). By understanding the roles of these genes in development, the pathological mechanisms and phenotypic variation can be better understood, improving diagnosis and management
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