Modeling of early-onset retinal dystrophy development in optic vesicle containing-brain organoids

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Congenital retinal disorders, including Leber Congenital Amaurosis (LCA) /early-onset severe retinal dystrophy and Oculocutaneous Albinism (OCA), are genetically inherited retinal disorders affecting ~150 live births every year. These congenital retinal disorders occur at the early onset of retinal development, for which the mechanisms of disease development remain unknown. Therefore, underpinning the defective cellular mechanisms that trigger the disease development in a disease-relevant experimental system is a prerequisite to designing therapeutic strategies. A significant limiting factor for this is the lack of an experimental system that physiologically recapitulates the early retinogenesis from the developing forebrain. The first funding period of this priority prograhas supported us to generate 3D brain organoids developing bilaterally symmetric optic vesicles in a topographically restricted manner (OVB-organoids). The OVB-organoid culturing method is robust as we could generate numerous OVB-organoids from five independent iPSCs donors. In the current funding period, we will model the developmental disease mechanisms of LCA and OCA using patient-specific OVB-organoids and test if pharmacological agents and gene augmentation strategies can mitigate the disease phenotypes.To this end, via collaborating with human geneticists, we have identified patients carrying mutations in SPATA7, Cep290 (causing LCA), and HPS1 (causing OCA). Notably, these patient mutations are non-syndromic, meaning that the mutations do not affect the brain developmental process but only the retina.This research program combines our interdisciplinary expertise to dissect the deregulated cellular pathways that elicit disease development in patient-specific OVB-organoids and evaluate potential gene-based therapies. To accomplish this ultimate goal, we will1. Generate vascularized OVB-organoids (v-OVB-organoids) for an extended period of viability to generate mature retinal cell types.2. Generate patient-specific v-OVB-organoids to dissect developmental pathophysiology of LCA and OCA due to SPATA7, Cep290, and HPS1 mutations.3. Determine the impact of translational read-through agents and AAV-gene augmentations in mitigating the disease phenotypes. Overall, with our interdisciplinary expertise that uses novel types of 3D brain-retinal hybrid organoids, we will identify deregulated cellular pathways of retinal developmental disorders causing LCA and OCA and offer novel therapeutic options.