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Targeted antisense oligonucleotide therapy rescues PRPF31 expression in retinitis pigmentosa caused by a splicing mutation

ABSTRACT: Pathogenic variants in splicing factors are the second most common cause of autosomal dominant retinitis pigmentosa (RP), with mutations in PRPF31 being the most prevalent. Here, we characterize a novel intronic variant in PRPF31 (c.1074-11C>G) that creates a cryptic 3′ splice site, resulting in an aberrantly spliced transcript predicted to encode a protein with an altered C-terminus. However, the pathogenic protein was not detected in patient-derived induced pluripotent stem cells (iPSCs). In addition, expression of PRPF31 protein was reduced in patient iPSC-derived retinal pigment epithelium (RPE). To correct the splicing defect, we designed a panel of antisense oligonucleotides (ASOs) targeting putative RNA-binding sites in exon 10 and intron 10 and identified a candidate that corrects PRPF31 splicing in a minigene reporter system as well as in patient-derived iPSCs and RPE. Finally, we showed that ASO treatment enhances PRPF31 protein expression in patient iPSC-derived RPE, supporting its potential as a therapeutic approach to restore PRPF31 expression in RP patients.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Retinitis Pigmentosa

SUBMITTER: Marek Vrbacky

LAB HEAD: David Stanek

PROVIDER: PXD071251 | Pride | 2026-06-12

REPOSITORIES: Pride

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			Action	DRS
	PLK303_OE480_250516_IMG16_iPSC-CX5_2-3uL_DIA-FAIMS_120M_90G.raw	Raw
	PLK303_OE480_250516_IMG16_iPSC-K_1-4uL_DIA-FAIMS_120M_90G.raw	Raw
	PLK303_OE480_25cm_250717_IMG16_SC_1-7uL_DIA-FAIMS_120M_90G.raw	Raw
	PLK303_OE480_25cm_250717_IMG16_SWT_1-4uL_DIA-FAIMS_120M_90G.raw	Raw
	PLK303_Stanek_hu_4x_iPSC_PRPF31_mut_SN20-1_250806_Report_Peptide.tsv	Tabular

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