Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids.

Stem Cell Reports
Amelia LaneMichael E Cheetham

Abstract

RP2 mutations cause a severe form of X-linked retinitis pigmentosa (XLRP). The mechanism of RP2-associated retinal degeneration in humans is unclear, and animal models of RP2 XLRP do not recapitulate this severe phenotype. Here, we developed gene-edited isogenic RP2 knockout (RP2 KO) induced pluripotent stem cells (iPSCs) and RP2 patient-derived iPSC to produce 3D retinal organoids as a human retinal disease model. Strikingly, the RP2 KO and RP2 patient-derived organoids showed a peak in rod photoreceptor cell death at day 150 (D150) with subsequent thinning of the organoid outer nuclear layer (ONL) by D180 of culture. Adeno-associated virus-mediated gene augmentation with human RP2 rescued the degeneration phenotype of the RP2 KO organoids, to prevent ONL thinning and restore rhodopsin expression. Notably, these data show that 3D retinal organoids can be used to model photoreceptor degeneration and test potential therapies to prevent photoreceptor cell death.

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Datasets Mentioned

BETA
GSE148300

Methods Mentioned

BETA
nucleotide exchange
light microscopy
RNA-seq
biopsy
PCR
transfection
dissecting

Software Mentioned

Enricher
DESeq2
Spotter Spotter
sva
STAR
Zen imaging
Adobe Photoshop
Ensembl
GeNorm
Off

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