Pluripotent stem cell-derived retinal organoids for disease modeling and development of therapies

Abstract

Retinal diseases constitute a genetically and phenotypically diverse group of clinical conditions leading to vision impairment or blindness with limited treatment options. Advances in reprogramming of somatic cells to induced pluripotent stem cells and generation of three-dimensional organoids resembling the native retina offer promising tools to interrogate disease mechanisms and evaluate potential therapies for currently incurable retinal neurodegeneration. Next-generation sequencing, singlecell analysis, advanced electrophysiology, and high-throughput screening approaches are expected to greatly expand the utility of stem cell-derived retinal cells and organoids for developing personalized treatments. In this review, we discuss the current status and future potential of combining retinal organoids as human models with recent technologies to advance the development of gene, cell, and drug therapies for retinopathies.

Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution

“…Human retinal organoids have been used to study retinal development and disease (Foltz and Clegg, 2019;Kruczek and Swaroop, 2020) but, unlike the real human retina, currently used organoids are not five-layered and have not been shown capable of rapidly transmitting light responses synaptically to inner retinal layers. Additional barriers to modeling genetic diseases of the retina are the difficulty of producing organoids in large quantities and the lack of a comprehensive quantitative comparison of gene expression between cell types in organoids and adult human retinas (Collin et al, 2019;Kim et al, 2019;Lu et al, 2020).…”

Gene Therapy of Dominant CRX-Leber Congenital Amaurosis using Patient Stem Cell-Derived Retinal Organoids

“…Directed differentiation of iPSCs into three-dimensional (3D) retinal organoids has enabled the modeling of retinopathies in patient-specific genetic background ( Kruczek and Swaroop, 2020 ). Next generation sequencing technologies have provided a detailed comparison of developing retinal organoids with human retina ( Collin et al., 2019 ; Cowan et al., 2020 ; Hoshino et al., 2017 ; Kaya et al., 2019 ; Kim et al., 2019 ) and permit evaluation of major retinal cell types in a disease context.…”

Retinal organoids: a window into human retinal development

“…The requisite of well-characterised models is essential to fully understand how well current models are mimicking normal development. Retinal organoids represent unique platforms for modelling human disease, therapies (reviewed by Kruczek and Swaroop, 2020 ) and development, but studies must take into account that disease phenotypes might be an experimental artefact due to artificial culture conditions. As a human model, the expression of key ECM components and cell-surface markers are recapitulated in hPSC-derived retinal organoids more faithfully than in animal models ( Felemban et al, 2018 ).…”