دورية أكاديمية
A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31
| العنوان: | A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31 |
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| المؤلفون: | Grainok, Janya, Pitout, Ianthe L, Chen, Fred K, McLenachan, Samuel, Heath Jeffery, Rachael C, Mitrpant, Chalermchai, Fletcher, Sue |
| بيانات النشر: | MDPI |
| سنة النشر: | 2024 |
| مصطلحات موضوعية: | Codon, Nonsense, Eye Proteins - genetics, Eye Proteins - metabolism, Humans, Mutation, Oligonucleotides, Antisense - genetics, Antisense - therapeutic use, Open Reading Frames, Pedigree, Retinitis Pigmentosa, RNA Precursors - genetics |
| الوصف: | Retinitis pigmentosa 11 is an untreatable, dominantly inherited retinal disease caused by heterozygous mutations in pre-mRNA processing factor 31 PRPF31. The expression level of PRPF31 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 PRPF31 exon 12 since it does not appear to encode any domains essential for PRPF31 protein function. Cells derived from a patient carrying a PRPF31 1205C>A nonsense mutation were investigated; PRPF31 transcripts encoded by the 1205C>A allele were undetectable due to nonsense-mediated mRNA decay, resulting in a 46% reduction in PRPF31 mRNA, relative to healthy donor cells. Antisense oligonucleotide-induced skipping of exon 12 rescued the open reading frame with consequent 1.7-fold PRPF31 mRNA upregulation in the RP11 patient fibroblasts. The level of PRPF31 upregulation met the predicted therapeutic threshold of expression inferred in a non-penetrant carrier family member harbouring the same mutation. This study demonstrated increased PRPF31 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | |
| اللغة: | English |
| تدمد: | 1422-0067 |
| العلاقة: | ispartof: International journal of molecular sciences issue 6 vol 25; WOS:001193446500001; 991005652870007891; https://researchportal.murdoch.edu.au/esploro/outputs/journalArticle/A-Precision-Therapy-Approach-for-Retinitis/991005652870007891Test; https://researchportal.murdoch.edu.au/view/delivery/61MUN_INST/12160737560007891/13160737550007891Test; alma:61MUN_INST/bibs/991005652870007891 |
| DOI: | 10.3390/ijms25063391 |
| الإتاحة: | https://doi.org/10.3390/ijms25063391Test https://researchportal.murdoch.edu.au/esploro/outputs/journalArticle/A-Precision-Therapy-Approach-for-Retinitis/991005652870007891Test https://researchportal.murdoch.edu.au/view/delivery/61MUN_INST/12160737560007891/13160737550007891Test |
| حقوق: | © 2024 by the authors. ; Open ; CC BY V4.0 |
| رقم الانضمام: | edsbas.B36590BC |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 14220067 |
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| DOI: | 10.3390/ijms25063391 |