A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31

Janya Grainok; Ianthe L Pitout; Fred K Chen; Samuel McLenachan; Rachael C Heath Jeffery; Chalermchai Mitrpant; Sue Fletcher

doi:10.3390/ijms25063391

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A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31

Journal article

Open access

Peer reviewed

A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31

Janya Grainok, Ianthe L Pitout, Fred K Chen, Samuel McLenachan, Rachael C Heath Jeffery, Chalermchai Mitrpant and Sue Fletcher

International journal of molecular sciences, Vol.25(6), 3391

2024

DOI: https://doi.org/10.3390/ijms25063391

PMID: 38542364

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Abstract

Codon, Nonsense

Eye Proteins - genetics

Eye Proteins - metabolism

Humans

Mutation

Oligonucleotides, Antisense - genetics

Oligonucleotides, Antisense - therapeutic use

Open Reading Frames

Pedigree

Retinitis Pigmentosa

RNA Precursors - genetics

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.

Details

Title: A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31
Authors/Creators: Janya Grainok - Siriraj Hospital
Ianthe L Pitout - Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics
Fred K Chen - The University of Western Australia
Samuel McLenachan - The University of Western Australia
Rachael C Heath Jeffery - Lions Eye Institute
Chalermchai Mitrpant - Siriraj Hospital
Sue Fletcher - Murdoch University, Health Futures Institute
Publication Details: International journal of molecular sciences, Vol.25(6), 3391
Publisher: MDPI
Grant note: GNT1116360; GNT1188694; GNT1054712; MRF1142962 / National Health and Medical Research Council PhD Stipend / Murdoch Strategic Scholarship, Australia and the Dual-PhD Program Scholarship, Mahidol University, Thailand
Identifiers: 991005652870007891
Murdoch Affiliation: Health Futures Institute
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.36 Ophthalmology; 1.36.212 Genetic Retinopathies
Web Of Science research areas: Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
ESI research areas: Chemistry