PRPF31-retinitis pigmentosa: Challenges and opportunities for clinical translation

Aweidah, Hamzah; Xi, Zhouhuan; Sahel, José-Alain; Byrne, Leah C.

doi:10.1016/j.visres.2023.108315

Cited by 2 publications

(1 citation statement)

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“…Haploinsufficiency diseases, while dominantly inherited, are potentially treatable by various gene augmentation strategies. Approaches to the treatment of RP11 include boosting PRPF31 expression from the healthy allele, gene editing, and gene replacement, (for review see Aweidah 2023 [ 45 ]). Significant improvements in gene expression and enhanced cellular characteristics in patient-derived models are reported [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

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

Grainok,

Pitout,

Chen

et al. 2024

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%