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Modelling and rescue of RP2 Retinitis Pigmentosa using iPSC Derived Retinal Organoids

ABSTRACT: Modelling and rescue of RP2 Retinitis Pigmentosa using iPSC Derived Retinal Organoids

PROVIDER: PRJNA623855 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11510107_1.fastq.gz	Fastqsanger.gz
	SRR11510107_2.fastq.gz	Fastqsanger.gz
	SRR11510108_1.fastq.gz	Fastqsanger.gz
	SRR11510108_2.fastq.gz	Fastqsanger.gz
	SRR11510109_1.fastq.gz	Fastqsanger.gz

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Modelling and rescue of RP2 Retinitis Pigmentosa using iPSC Derived Retinal Organoids

Project description:Mutations in RP2 lead to a severe form of X-linked retinitis pigmentosa (XLRP). RP2 functions as a GTPase activating protein (GAP) for the small GTPase ARL3, which is essential for cilia function and for photoreceptor development and maintenance. The mechanisms of RP2 associated retinal degeneration in humans are poorly understood, and genetically engineered animal models of RP2 XLRP present with differing retinal phenotypes and slow degeneration suggesting potential species differences. Here, we developed CRISPR gene edited isogenic RP2 knock-out (RP2 KO) induced pluripotent stem cells (iPSC) and RP2 patient derived iPSC to produce 3D retinal organoids as a human retinal disease model. The isogenic RP2 KO retinal organoids and two unrelated RP2 patient iPSC lines produced retinal organoids with a defined photoreceptor cell layer (ONL) containing rod and cone photoreceptors. Strikingly the RP2 KO and RP2 patient derived organoids showed a thinning of the ONL by 180 days (D180) of culture, which was associated with a spike in cell death in the ONL at D150 of differentiation. RNA sequencing confirmed induction of cell death pathways in the RP2 null organoids at this stage. Photoreceptor cell death and ONL thinning was attributed to cells undergoing terminal rod cell differentiation characterized by reduced RHO expression and fewer rhodopsin immunoreactive photoreceptors. Gene augmentation with a human RP2 transgene in an AAV2/5 vector efficiently transduced RP2 KO organoids and led to high levels of RP2 expression in both rods and cones. Importantly, the viral transduction significantly increased ONL thickness and restored rhodopsin expression, suggesting rescue of the RP2 degeneration phenotype. These data show that 3D retinal organoids can be used to model molecular defects associated with inherited retinal disease, photoreceptor cell death and also to test potential therapies targeted to prevent photoreceptor degeneration.

2020-07-08 | GSE148300 | GEO

Inhibition of JNK ameliorates rod photoreceptor degeneration in a mouse model of retinitis pigmentosa

Project description:Retinitis pigmentosa (RP) is an inherited eye disease that causes progressive vision loss.To investigate the biological processes and molecular changes that occur in different cell types in the retinas in rd1 mice, a mouse model of retinitis pigmentosa, we performed single-cell RNA-seq to examine the transcriptomes of various retinal cells.

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Search for recessive retinitis pigmentosa genes using RNA expression analysis in lymphoblasts

Project description:Recessive retinitis pigmentosa (RP) is often caused by nonsense mutations that lead to low mRNA levels as a result of nonsense-mediated decay. Some RP genes are expressed at detectable levels in leukocytes as well as in the retina. We designed a microarray-based method to find recessive RP genes based on low lymphoblast mRNA expression levels Keywords: Recessive mutations; mRNA expression; nonsense mediated-decay; retinitis pigmentosa; lymphocyte; Affymetrix genechip Human Genome U133Plus2.0.

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Mutations in the Drosophila splicing regulator Prp31 as a model for Retinitis pigmentosa 11

Project description:A Drosophila mutant for the splicing factor Prp31 was generated and characterized as a model for Retinitis pigmentosa 11. The transcriptome of the mutant was compared to the genetic control white.

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MicroRNA profiling of mouse wild type (C57) retina and a retina from a mouse model of retinitis pigmentosa (Pro347Ser)

Project description:Experiment to examine the miRNA profiles in the retina compared to the brain and other body regions. A comparison of a wild type C57 mouse retina versus a retina from a mouse model of retinitis pigmentosa (Pro347Ser) was under taken.

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Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids.

Project description:RP2 mutations cause a severe form of X-linked retinitis pigmentosa (XLRP). The mechanism of RP2-associated retinal degeneration in humans is unclear, and animal models of RP2 XLRP do not recapitulate this severe phenotype. Here, we developed gene-edited isogenic RP2 knockout (RP2 KO) induced pluripotent stem cells (iPSCs) and RP2 patient-derived iPSC to produce 3D retinal organoids as a human retinal disease model. Strikingly, the RP2 KO and RP2 patient-derived organoids showed a peak in rod photoreceptor cell death at day 150 (D150) with subsequent thinning of the organoid outer nuclear layer (ONL) by D180 of culture. Adeno-associated virus-mediated gene augmentation with human RP2 rescued the degeneration phenotype of the RP2 KO organoids, to prevent ONL thinning and restore rhodopsin expression. Notably, these data show that 3D retinal organoids can be used to model photoreceptor degeneration and test potential therapies to prevent photoreceptor cell death.

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Modeling PRPF31 retinitis pigmentosa using iPSC-derived retinal organoids and retinal pigmented epithelium and rescue by gene augmentation strategy

Project description:Mutations in the ubiquitously expressed pre-mRNA processing factor (PRPF) 31, one of the most common cause of dominant form of Retinitis Pigmentosa (RP), lead to 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 pigmented epithelial (RPE) cells derived from human induced pluripotent stem cells (iPSCs) provide potential opportunities for studying human PRPF31-related RP. We demonstrated 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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Inhibition of epigenetic modifiers LSD1 and HDAC1 blocks rod photoreceptor death in mouse models of Retinitis Pigmentosa.

Project description:In retinitis pigmentosa mouse models inhibitors of histone modification enzymes LSD1and HDAC1 blocked rod degeneration, preserved vision and affected the expression of multiple genes including maintenance of rod-specific transcripts and downregulation those involved in inflammation, gliosis and cell death.

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Retinitis pigmentosa (RP) mouse cone transcriptom change with Txnip treatment

Project description:Purpose: To identifiy mRNA changes in retinitis pigmentosa (RP) cone photoreceptors with Txnip overexpression treatment, which improved RP cone survival and visual acuity. Methods: two RP mouse strains, rd1 and Rho-/-, were injected with AAV-Txnip or AAV-H2BGFP control subretinally at P0. Retinas were dissected out at P21 for rd1 and P90 for Rho-/-. 1,000 H2BGFP labeled cones per retina sample were FACS sorted out, and subject for RNA-sequencing. Results: >1,400 genes in P21 rd1 and >700 genes in Rho-/- were found differentially expressed with Txnip treatment. Conclusions: 25 genes are in common between P21 rd1 and P90 Rho-/- with Txnip treatment. On this list, notably, three mitochondrial Electron Transport Chain (ETC) genes were up-regulated.

2021-01-20 | GSE161622 | GEO

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Project description:HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

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