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AAV-mediated gene augmentation therapy of CRB1-patient derived retinal organoids restores the histological and transcriptional retinal phenotype

ABSTRACT: AAV-mediated gene augmentation therapy of CRB1-patient derived retinal organoids restores the histological and transcriptional retinal phenotype

PROVIDER: PRJNA876116 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21397817_1.fastq.gz	Fastqsanger.gz
	SRR21397817_2.fastq.gz	Fastqsanger.gz
	SRR21397818_1.fastq.gz	Fastqsanger.gz
	SRR21397818_2.fastq.gz	Fastqsanger.gz
	SRR21397819_1.fastq.gz	Fastqsanger.gz

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AAV-mediated gene augmentation therapy of CRB1-patient derived retinal organoids restores the histological and transcriptional retinal phenotype

Project description:Retinitis pigmentosa (RP) and Leber congenital amaurosis are inherited retinal dystrophies caused by mutations in, among others, the Crumbs homologue 1 (CRB1) gene. CRB1 is required for organizing apical-basal polarity and adhesion between photoreceptors and Müller glial cells. Using human CRB1 patient induced pluripotent stem cells from RP patients we derived CRB1 retinal organoids, with diminished expression of variant CRB1 protein with immunohistochemical analysis. Single cell RNA-sequencing revealed impact on, among others, the endosomal pathway and cell adhesion and migration in CRB1 patient derived retinal organoids compared to isogenic controls. Adeno-associated viral (AAV) vector-mediated hCRB2 or hCRB1 gene augmentation in Müller glial and photoreceptor cells partially restored the histological and differentially expressed genes phenotype. Altogether, we show proof-of-concept that AAV.hCRB1 or AAV.hCRB2 treatment improved the phenotype of CRB1 patient derived retinal organoids, providing essential information for future gene therapy approaches for patients with mutations in the CRB1 gene.

2023-04-20 | GSE212582 | GEO

Retinal organoids with X-linked retinoschisis RS1 (E72K) mutation exhibit a photoreceptor developmental delay and are rescued by gene augmentation therapy

Project description:Background X-linked juvenile retinoschisis (XLRS) is an inherited disease caused by RS1 gene mutation, which leads to retinal splitting and visual impairment. The mechanism of RS1-associated retinal degeneration is not fully understood. Besides, animal models of XLRS have limitations in the study of XLRS. Here, we used human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) to investigate the disease mechanisms and potential treatments for XLRS. Methods hiPSCs reprogrammed from peripheral blood mononuclear cells of two RS1 mutant (E72K) XLRS patients were differentiated into ROs. Subsequently, we explored whether RS1 mutation could affect RO development and explore the effectiveness of RS1 gene augmentation therapy. Results ROs derived from RS1 (E72K) mutation hiPSCs exhibited a developmental delay in the photoreceptor, retinoschisin (RS1) deficiency, and altered spontaneous activity compared with control ROs. Furthermore, the delays in development were associated with decreased expression of rod-specific precursor markers (NRL) and photoreceptor-specific markers (RCVRN). Adeno-associated virus (AAV)-mediated gene augmentation with RS1 at the photoreceptor immature stage rescued the rod photoreceptor developmental delay in ROs with the RS1 (E72K) mutation. Conclusions The RS1 (E72K) mutation results in the photoreceptor development delay in ROs and can be partially rescued by the RS1 gene augmentation therapy.

2024-05-17 | GSE267405 | GEO

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.

2022-08-01 | GSE206529 | GEO

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

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

| PRJNA851279 | ENA

Quantitative single-cell transcriptome-based ranking of engineered AAVs in human retinal explants

Project description:Gene therapy is a rapidly developing field, and adeno-associated virus (AAV) is a leading viral vector candidate for therapeutic gene delivery. Newly engineered AAVs with improved abilities are now entering the clinic. It has proven challenging, however, to predict the translational potential of gene therapies developed in animal models, due to cross-species differences. Human retinal explants are the only available model of fully developed human retinal tissue, and are thus important for the validation of candidate AAV vectors. In this study, we evaluated 18 wildtype and engineered AAV capsids in human retinal explants using a recently developed single-cell RNA-Seq AAV engineering pipeline (scAAVengr). Human retinal explants retain the same major cell types as fresh retina, with similar expression of cell-specific markers, except for a photoreceptor population with altered expression of photoreceptor-specific genes. The efficiency and tropism of AAVs in human explants was quantified, with single cell resolution. The top performing serotypes, K91, K912, and 7m8, were further validated in non-human primate and human retinal explants. Together, this study provides detailed information about the transcriptome profiles of retinal explants, and quantifies the infectivity of leading AAV serotypes in human retina, accelerating the translation of retinal gene therapies to the clinic.

2022-04-28 | GSE199840 | GEO

VLDL Proteome in Control-AAV and PSS1(Q353R)-AAV

Project description:Fractionated VLDL from Control-AAV and PSS1(Q353R)-AAV.

2024-10-21 | PXD047916 | Pride

Modifications in Retinal Microvascularization With Targeted Anti-angiogenic Therapy in Colorectal Cancer

Project description:Retinal microvascularization can provide important informations to systemic vascular phenomena. The non-invasive quantitative description of the retinal vascularization is now possible by performing OCT-angiography and their image analysis software (vascular density and retinal perfusion). Systemic microvacular changes during the establishment of oncological treatment by targeted antiangiogenic therapy are little described in the literature. The objective of this pilot study is to describe the evolution of the retinal vascular density of patients with antiangiogenic drugs. In addition, the evolution of the retinal vascular density of patients on antiangiogenic drugs will study as a function of the response to the treatment and the toxicity of these treatments.

| 2382594 | ecrin-mdr-crc

AAV-Mediated Gene Augmentation Therapy Restores Critical Functions in Mutant PRPF31+/- iPSC-Derived RPE Cells.

Project description:Retinitis pigmentosa (RP) is the most common form of inherited vision loss and is characterized by degeneration of retinal photoreceptor cells and the retinal pigment epithelium (RPE). Mutations in pre-mRNA processing factor 31 (PRPF31) cause dominant RP via haploinsufficiency with incomplete penetrance. There is good evidence that the diverse severity of this disease is a result of differing levels of expression of the wild-type allele among patients. Thus, we hypothesize that PRPF31-related RP will be amenable to treatment by adeno-associated virus (AAV)-mediated gene augmentation therapy. To test this hypothesis, we used induced pluripotent stem cells (iPSCs) with mutations in PRPF31 and differentiated them into RPE cells. The mutant PRPF31 iPSC-RPE cells recapitulate the cellular phenotype associated with the PRPF31 pathology, including defective cell structure, diminished phagocytic function, defects in ciliogenesis, and compromised barrier function. Treatment of the mutant PRPF31 iPSC-RPE cells with AAV-PRPF31 restored normal phagocytosis and cilia formation, and it partially restored structure and barrier function. These results suggest that AAV-based gene therapy targeting RPE cells holds therapeutic promise for patients with PRPF31-related RP.

| S-EPMC6909184 | biostudies-literature

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

Project description:Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in C. elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WRN syndrome is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

2020-01-13 | PXD015644 | Pride

Proteomic Analysis of Retinal Degeneration in the Rd10 Mouse

Project description:To explore the mechanism associated with retinal degeneration and adeno-associated virus (AAV)-mediated gene therapy in rd10 mouse, a model of autosomal recessive retinitis pigmentosa (arRP) containing mutation of β subunit of the rod cGMP phosphodiesterase 6 (PDE6).

2022-04-29 | PXD033560 |

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