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Single-cell Sequencing of ABCA4-Mutant Human Retinal Organoids Reveals Organoids Application in Modeling Inherited Retinal Diseases

ABSTRACT: In the studies of Inherited Retinal Diseases (IRDs), the knockout of traditional animal models like mice often fails to accurately replicate human phenotypes due to genetic and anatomical differences. Human retinal organoids (ROs) derived from stem cells have emerged as promising developmental models in retinal studies to delineate cell growth, but their ability to represent the characteristics of late-onset IRDs remains unclear. This study aims to validate ROs as a disease model for Stargardt's Disease (STGD) caused by Abca4 mutations. Using single-cell RNA sequencing, ROs from 2 STGD patients were compared with unaffected ROs at two developmental stages on both the cellular and transcriptomic levels. The results from gene-level comparisons show promising evidence that ROs successfully capture the underlying molecular variations between patient and control samples even at the early developmental stage, providing the potential of applying ROs to facilitate the study of IRDs and late-onset neurodegenerative diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266191 | GEO | 2025/09/01

REPOSITORIES: GEO

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Project description:Stargardt disease (STGD1) is an inherited retinopathy affecting approximately 1:8,000 individuals. It is characterised by biallelic mutations in ABCA4, and encodes a vital protein for the recycling of retinaldehyde in the retina. Despite its prevalence and impact, there are currently no treatments available for this condition. Furthermore, 35% of STGD1 cases remain genetically unsolved. Efforts have been directed towards comprehending the fundamental disease mechanisms and identifying all disease-causing variants in the extensive 150kb gene, to better aid with the development of effective therapeutic strategies. In this study, we generated iPSC lines from two monoallelic (PT1 & PT2), late onset STGD1 cases with the heterozygous complex allele - c.[5461-10T>C;5603A>T]. We differentiated these cells alongside a biallelic affected control (AC) - c.4892T>C, and c.4539+2001G>A, to retinal organoids (ROs) allowing us to investigate cellular and molecular characteristics associated with STGD1. We hypothesized that the missing inheritance in our monoallelic cases is due to an RNA defect. Consequently, we utilised a myriad of sequencing strategies including WGS, single-cell RNA sequencing (scRNAseq) and long-read RNA sequencing (LRS) to address this. ROs were grown for 230 days and developed all key retinal neurons with photoreceptor outer segments capable of ABCA4 expression. We observed patient-specific disruption to lamination with OPN1MW/LW+ cone photoreceptor retention in the RO centre during differentiation. Retention was more severe in the AC case affecting both cones and rods, suggesting a genotype/phenotype correlation. scRNAseq suggests retention may be due to the induction of apoptosis in photoreceptors. WGS successfully identified the missing alleles in both cases; PT1 reported c. 5603A>T in homozygous state and PT2 uncovered a rare hypomorph - c.4865T>C. Furthermore, ROs were able to recapitulate the retina-specific splicing defect in PT1 as shown by LRS data. Collectively, these results highlight the suitability of ROs in STGD1 modelling. Their ability to display genotype-phenotype correlations enhances their utility as a platform for therapeutic development. Importantly, both PT1 and PT2 cases were genetically resolved in this study, providing two more individuals their confirmed genetic diagnosis.

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Single-cell Sequencing of ABCA4-Mutant Human Retinal Organoids Reveals Organoids Application in Modeling Inherited Retinal Diseases

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