{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Grainok J"],"funding":["Murdoch Strategic Scholarship, Australia and the Dual-PhD Program Scholarship, Mahidol University, Thailand","National Health and Medical Research Council"],"pagination":["3391"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10970544"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["25(6)"],"pubmed_abstract":["Retinitis pigmentosa 11 is an untreatable, dominantly inherited retinal disease caused by heterozygous mutations in pre-mRNA processing factor 31 <i>PRPF31</i>. The expression level of <i>PRPF31</i> is linked to incomplete penetrance in affected families; mutation carriers with higher PRPF31 expression can remain asymptomatic. The current study explores an antisense oligonucleotide exon skipping strategy to treat RP11 caused by truncating mutations within <i>PRPF31</i> exon 12 since it does not appear to encode any domains essential for PRPF31 protein function. Cells derived from a patient carrying a <i>PRPF31</i> 1205C>A nonsense mutation were investigated; <i>PRPF31</i> transcripts encoded by the 1205C>A allele were undetectable due to nonsense-mediated mRNA decay, resulting in a 46% reduction in <i>PRPF31</i> mRNA, relative to healthy donor cells. Antisense oligonucleotide-induced skipping of exon 12 rescued the open reading frame with consequent 1.7-fold <i>PRPF31</i> mRNA upregulation in the RP11 patient fibroblasts. The level of <i>PRPF31</i> upregulation met the predicted therapeutic threshold of expression inferred in a non-penetrant carrier family member harbouring the same mutation. This study demonstrated increased <i>PRPF31</i> expression and retention of the nuclear translocation capability for the induced PRPF31 isoform. Future studies should evaluate the function of the induced PRPF31 protein on pre-mRNA splicing in retinal cells to validate the therapeutic approach for amenable RP11-causing mutations."],"journal":["International journal of molecular sciences"],"pubmed_title":["A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31."],"pmcid":["PMC10970544"],"funding_grant_id":["GNT1116360; GNT1188694; GNT1054712; MRF1142962","PhD Stipend"],"pubmed_authors":["Pitout IL","Mitrpant C","McLenachan S","Chen FK","Fletcher S","Grainok J","Heath Jeffery RC"],"additional_accession":[]},"is_claimable":false,"name":"A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31.","description":"Retinitis pigmentosa 11 is an untreatable, dominantly inherited retinal disease caused by heterozygous mutations in pre-mRNA processing factor 31 <i>PRPF31</i>. The expression level of <i>PRPF31</i> is linked to incomplete penetrance in affected families; mutation carriers with higher PRPF31 expression can remain asymptomatic. The current study explores an antisense oligonucleotide exon skipping strategy to treat RP11 caused by truncating mutations within <i>PRPF31</i> exon 12 since it does not appear to encode any domains essential for PRPF31 protein function. Cells derived from a patient carrying a <i>PRPF31</i> 1205C>A nonsense mutation were investigated; <i>PRPF31</i> transcripts encoded by the 1205C>A allele were undetectable due to nonsense-mediated mRNA decay, resulting in a 46% reduction in <i>PRPF31</i> mRNA, relative to healthy donor cells. Antisense oligonucleotide-induced skipping of exon 12 rescued the open reading frame with consequent 1.7-fold <i>PRPF31</i> mRNA upregulation in the RP11 patient fibroblasts. The level of <i>PRPF31</i> upregulation met the predicted therapeutic threshold of expression inferred in a non-penetrant carrier family member harbouring the same mutation. This study demonstrated increased <i>PRPF31</i> expression and retention of the nuclear translocation capability for the induced PRPF31 isoform. Future studies should evaluate the function of the induced PRPF31 protein on pre-mRNA splicing in retinal cells to validate the therapeutic approach for amenable RP11-causing mutations.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2025-04-21T21:31:57Z","creation":"2025-04-05T18:22:51.235Z"},"accession":"S-EPMC10970544","cross_references":{"pubmed":["38542364"],"doi":["10.3390/ijms25063391"]}}