Abstract
Purpose :
Choroideremia (CHM) is a rare X-linked recessive chorioretinal dystrophy, marked by degeneration of the RPE, photoreceptors and choroid. CHM is caused by loss-of-function variants in the CHM gene, but the pathogenic mechanism is not yet fully characterised. We aim to use patient-derived iPSC-RPE (induced pluripotent stem cell-derived retinal pigment epithelium) to identify novel disrupted pathways and therapeutic targets.
Methods :
We generated iPSC-RPE from a CHMS190X patient-derived fibroblast line (n=3), and two wildtype control lines (n=3). Samples were sent off for paired-end RNAseq. Differential gene expression and enrichment analysis were performed (using threshold cut off for the adjusted p value of < 0.05, log2fold change > 1).
Results :
In the CHMS190X iPSC-RPE, key retinal genes were dysregulated such as BEST1, PRNP, TYRP1, MYRIP. Disruption in cytokine pathways such as NLRP1 inflammasome, chemokine receptor CXCR binding and IL-7 signalling were seen. Cellular senescence, oxidative stress, and ion transport pathways were also dysregulated, suggesting inflammatory pathomechanisms. Disruption of cell adhesion pathways was highlighted, which may be causative of lymphocyte migration into the retina, as has been previously described in CHM patients.
Conclusions :
This study interrogates the CHM iPSC-RPE transcriptome using RNA-seq. We identify increased cell death and a heightened inflammatory state with novel pathways implicated including NLRP1 inflammasome activation, and dysregulated CXCR-binding. This draws a parallel mechanisms with other retinal degenerative conditions such as age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR). Identifying common mechanisms underlying rare retinal diseases is essential for accessible treatments.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.