scholarly journals In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa

2016 ◽  
Vol 24 (3) ◽  
pp. 556-563 ◽  
Author(s):  
Benjamin Bakondi ◽  
Wenjian Lv ◽  
Bin Lu ◽  
Melissa K Jones ◽  
Yuchun Tsai ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Rat Model ◽  
Gene Editing ◽  
Autosomal Dominant ◽  
Retinal Dystrophy ◽  
Autosomal Dominant Retinitis Pigmentosa

scholarly journals Human iPSC-derived RPE and retinal organoids reveal impaired alternative splicing of genes involved in pre-mRNA splicing in PRPF31 autosomal dominant retinitis pigmentosa

2017 ◽  
Author(s):  
Adriana Buskin ◽  
Lili Zhu ◽  
Valeria Chichagova ◽  
Basudha Basu ◽  
Sina Mozaffari-Jovin ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Retinitis Pigmentosa ◽  
Gene Editing ◽  
Autosomal Dominant ◽  
Mrna Processing ◽  
Mrna Splicing ◽  
Patient Specific ◽  
Rpe Cells ◽  
Autosomal Dominant Retinitis Pigmentosa

SummaryMutations in pre-mRNA processing factors (PRPFs) cause 40% of autosomal dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed PRPFs cause retinal disease. To understand the molecular basis of this phenotype, we have generated RP type 11 (PRPF31-mutated) patient-specific retinal organoids and retinal pigment epithelium (RPE) from induced pluripotent stem cells (iPSC). Impaired alternative splicing of genes encoding pre-mRNA splicing proteins occurred in patient-specific retinal cells and Prpf31+/− mouse retinae, but not fibroblasts and iPSCs, providing mechanistic insights into retinal-specific phenotypes of PRPFs. RPE was the most affected, characterised by loss of apical-basal polarity, reduced trans-epithelial resistance, phagocytic capacity, microvilli, and cilia length and incidence. Disrupted cilia morphology was observed in patient-derived-photoreceptors that displayed progressive features associated with degeneration and cell stress. In situ gene-editing of a pathogenic mutation rescued key structural and functional phenotypes in RPE and photoreceptors, providing proof-of-concept for future therapeutic strategies.eTOCPRPF31 is a ubiquitously expressed pre-mRNA processing factor that when mutated causes autosomal dominant RP. Using a patient-specific iPSC approach, Buskin and Zhu et al. show that retinal-specific defects result from altered splicing of genes involved in the splicing process itself, leading to impaired splicing, loss of RPE polarity and diminished phagocytic ability as well as reduced cilia incidence and length in both photoreceptors and RPE.HighlightsSuccessful generation of iPSC-derived RPE and photoreceptors from four RP type 11 patientsRPE cells express the mutant PRPF31 protein and show the lowest expression of wildtype proteinPRPF31 mutations result in altered splicing of genes involved in pre-mRNA splicing in RPE and retinal organoidsPrpf31 haploinsufficiency results in altered splicing of genes involved in pre-mRNA splicing in mouse retinaRPE cells display loss of polarity, reduced barrier function and phagocytosisPhotoreceptors display shorter and fewer cilia and degenerative featuresRPE cells display most abnormalities suggesting they might be the primary site of pathogenesisIn situ gene editing corrects the mutation and rescues key phenotypes

scholarly journals Erratum: Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa

10.1038/2077 ◽  
1998 ◽  
Vol 4 (9) ◽  
pp. 1081-1081 ◽  
Author(s):  
Alfred Lewin ◽  
Kimberly Drenser ◽  
William Hauswirth ◽  
Shimpei Nishikawa ◽  
Douglas Yasumura ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Rat Model ◽  
Autosomal Dominant ◽  
Photoreceptor Cells ◽  
Transgenic Rat ◽  
Autosomal Dominant Retinitis Pigmentosa ◽  
Transgenic Rat Model

Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa

1998 ◽  
Vol 4 (8) ◽  
pp. 967-971 ◽  
Author(s):  
Alfred S. Lewin ◽  
Kimberly A. Drenser ◽  
William W. Hauswirth ◽  
Shimpei Nishikawa ◽  
Douglas Yasumura ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Rat Model ◽  
Autosomal Dominant ◽  
Photoreceptor Cells ◽  
Transgenic Rat ◽  
Autosomal Dominant Retinitis Pigmentosa ◽  
Transgenic Rat Model

Further Screening of the Rhodopsin Gene in Patients with Autosomal Dominant Retinitis Pigmentosa

Genomics ◽  
1994 ◽  
Vol 21 (2) ◽  
pp. 461-463 ◽  
Author(s):  
Rajani Vaithinathan ◽  
Eliot L. Berson ◽  
Thaddeus P. Dryja
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Dominant ◽  
Autosomal Dominant Retinitis Pigmentosa ◽  
Rhodopsin Gene
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