Modeling PRPF31 retinitis pigmentosa using retinal pigment epithelium and organoids combined with gene augmentation rescue
Mutations in the ubiquitously expressed pre-mRNA processing factor ( PRPF ) 31 gene, one of the most common causes of dominant form of Retinitis Pigmentosa (RP), lead to a retina-specific phenotype. It is uncertain which retinal cell types are affected and animal models do not clearly present the RP...
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Published in | npj Regenerative medicine Vol. 7; no. 1; p. 39 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
16.08.2022
Nature Publishing Group Springer Nature Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | Mutations in the ubiquitously expressed
pre-mRNA processing factor
(
PRPF
)
31
gene, one of the most common causes of dominant form of Retinitis Pigmentosa (RP), lead to a retina-specific phenotype. It is uncertain which retinal cell types are affected and animal models do not clearly present the RP phenotype observed in
PRPF31
patients. Retinal organoids and retinal pigment epithelial (RPE) cells derived from human-induced pluripotent stem cells (iPSCs) provide potential opportunities for studying human
PRPF31
-related RP. We demonstrate here that RPE cells carrying
PRPF31
mutations present important morphological and functional changes and that
PRPF31
-mutated retinal organoids recapitulate the human RP phenotype, with a rod photoreceptor cell death followed by a loss of cones. The low level of
PRPF31
expression may explain the defective phenotypes of
PRPF31
-mutated RPE and photoreceptor cells, which were not observed in cells derived from asymptomatic patients or after correction of the pathogenic mutation by CRISPR/Cas9. Transcriptome profiles revealed differentially expressed and mis-spliced genes belonging to pathways in line with the observed defective phenotypes. The rescue of RPE and photoreceptor defective phenotypes by
PRPF31
gene augmentation provide the proof of concept for future therapeutic strategies. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2057-3995 2057-3995 |
DOI: | 10.1038/s41536-022-00235-6 |