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Autosomal recessive RDH12-Leber congenital amaurosis retinal organoids display reduced photoreceptor length and phospholipid dysregulation

ABSTRACT: NADPH-dependent retinol dehydrogenase 12 (RDH12) reduces all-trans-retinal in photoreceptor inner segments to regulate the phototransduction cascade and control the concentration of retinoids in the retina. Biallelic variants in RDH12 have been reported to cause autosomal recessive (AR) Leber congenital amaurosis (LCA), a severe cause of childhood blindness. Animal models have failed to recapitulate the clinical phenotype, hence, we generated human induced pluripotent stem cell (hiPSC) derived retinal organoids (RO) from the dermal fibroblasts of a female patient with homozygous missense variant c.619A>G p.(Asn207Asp) in RDH12 (RDH12-AR), and an unrelated healthy control (WT). RDH12-AR RO develop shortened rod and cone photoreceptors (from the outer limiting membrane to the tip of the outer segment), which lack RDH12 localisation in the inner segment. Bulk transcriptomic analysis revealed cone marker and apoptosis dysregulation in RDH12-AR RO compared to WT; but phospholipid transport is perturbed in RDH12-AR RO compared to an autosomal dominant hiPSC-derived RDH12-retinitis pigmentosa RO model. Our study helps to decipher the distinct disease pathways involved in RDH12 retinopathies, however, further modelling from additional patients with isogenic controls will strengthen the findings and aid identification of targets for therapeutic approaches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283720 | GEO | 2025/12/06

REPOSITORIES: GEO

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Project description:The loss of cone photoreceptor cells, which are critical for optimal daylight vision, have the great impact on vision during retinal degenerations. Retinal differentiation of human induced pluripotent stem cell (hiPSC) sources could provide a renewable source of cone photoreceptors towards developing a cone cell replacement therapy to treat blindness. Demonstration of comparable gene expression profiles between human foetal and stem cell-derived cones at equivalent stages is required to progress the cell transplantation approach into the patient, as it is hypothesised stem cell-derived cones are required to show high levels of developmental recapitulation of the in vivo generated cones. In this study, the AAV2/9.pR2.1.GFP reporter was used to specifically label L/M-opsin cone photoreceptors in human foetal retinal samples, obtained from the MRC-Wellcome Trust Human Developmental Biology Resource, at a range of developmental stages. The L/M-opsin cone population represent the majority cone cell types in the adult human retina and are the only photoreceptors present within the fovea. Using fluorescence activated cell sorting, L/M-opsin GFP+ cones and GFP- retinal populations, alongside total foetal retinal samples containing all retinal cell tytpes, were isolated and processed for bulk RNA sequencing and downstream comparative analysis. Using DESeq2 differential gene expression analyses, statistically significant genes enriched within the GFP+ human foetal LM-opsin cone populations were determined which led to the identification of a cone enriched gene signature of human L/M-opsin cone photoreceptors. The AAV2/9.pR2.1.GFP reporter was applied to hiPSC-derived retinal cultures to isolate and process cone-like cell populations for RNA sequencing using the same strategy developed within the human foetal retina. Applying the cone enriched gene signature to the transcriptome of hiPSC-derived GFP+ samples at equivalent developmental stages revealed some expression similarities in genes found to be enriched within the late foetal L/M-opsin cone photoreceptors. This analysis overall revealed an intermediate stage of cone differentiation was achieved within the hiPSC-derived samples and the comparison to human foetal L/M-opsin gene express profiles suggesting further differentiation of hiPSC-derived sample is required.

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Autosomal recessive RDH12-Leber congenital amaurosis retinal organoids display reduced photoreceptor length and phospholipid dysregulation

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