Interactions of the choroid, Bruch's membrane, retinal pigment epithelium, and neurosensory retina collaborate to form the outer blood-retinal-barrier

Progress in Retinal and Eye Research, Journal Year: 2019, Volume and Issue: 76, P. 100803 - 100803

Published: Nov. 5, 2019

Language: Английский

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The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies

Progress in Retinal and Eye Research, Journal Year: 2020, Volume and Issue: 82, P. 100898 - 100898

Published: Aug. 26, 2020

X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with without syndromic features. Many are recessive, but several exhibit phenotype in female carriers, which can help establish diagnosis yield insights into disease mechanisms. The presence affected carriers misleadingly suggest autosomal dominant inheritance. Some disorders (such as RPGR-associated retinopathy) show diverse phenotypes from variants the same gene also highlight limitations current genetic sequencing methods. frequently arises loss function, implying potential for benefit replacement strategies. We review X-inactivation inheritance, explore burden attributable to genes our clinically genetically characterised cohort, finding correlation between transcript length numbers families. list relevant discuss key clinical features, mechanisms, carrier novel experimental therapies. consider detail following: RPGR (associated retinitis pigmentosa, cone cone-rod dystrophy), RP2 (retinitis pigmentosa), CHM (choroideremia), RS1 (X-linked retinoschisis), NYX (complete congenital night blindness (CSNB)), CACNA1F (incomplete CSNB), OPN1LW/OPN1MW (blue monochromacy, Bornholm eye disease, GPR143 (ocular albinism), COL4A5 (Alport syndrome), NDP (Norrie familial exudative vitreoretinopathy (FEVR)). use recently published transcriptome analysis expression by cell-type electrophysiology. In final section, we present an algorithm diagnosing males non-syndromic retinopathy, summarise therapeutic approaches, questions future research.

Language: Английский

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Human embryonic stem cell-derived organoid retinoblastoma reveals a cancerous origin

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(52), P. 33628 - 33638

Published: Dec. 14, 2020

Significance As a genetic malignancy, retinoblastoma (Rb) is caused by RB1 mutations; however, its developmental origin and drug agents for human Rb remain largely unexplored. Here we describe an innovative organoid model derived from embryonic stem cells with biallelic mutagenesis of the gene. We identify tumorigenic growth in organoids, as well properties consistent primary Rb. confirm that cell stemmed ARR3 + maturing cone precursor SYK inhibitors displaying significant therapeutic response. Our elegant in-dish can be used to efficiently effectively dissect mechanisms tumorigenesis, screen novel therapies.

Language: Английский

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The primate model for understanding and restoring vision

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(52), P. 26280 - 26287

Published: Dec. 23, 2019

Retinal degenerative diseases caused by photoreceptor cell death are major causes of irreversible vision loss. As only primates have a macula, the nonhuman primate (NHP) models crucial role not in revealing biological mechanisms underlying high-acuity but also development therapies. Successful translation basic research findings into clinical trials and, moreover, approval first therapies for blinding inherited and age-related retinal dystrophies has been reported recent years. This article explores value NHP understanding human reviews their contribution to innovative therapeutic strategies save restore vision.

Language: Английский

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COCO enhances the efficiency of photoreceptor precursor differentiation in early human embryonic stem cell-derived retinal organoids

Stem Cell Research & Therapy, Journal Year: 2020, Volume and Issue: 11(1)

Published: Aug. 24, 2020

Language: Английский

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Patient-Specific Retinal Organoids Recapitulate Disease Features of Late-Onset Retinitis Pigmentosa

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: March 6, 2020

Although an increasing number of disease genes have been identified, the exact cellular mechanisms retinitis pigmentosa (RP) remain largely unclear. Retinal organoids (ROs) derived from induced pluripotent stem cells (iPSCs) patients provide a potential but unvalidated platform for deciphering and advantageous tool preclinical testing new treatments. Notably, early-onset RP has extensively recapitulated by patient-iPSC-derived ROs. However, it remains challenge to model late-onset in dish due its chronicity, complexity instability. Here, we generated ROs proband-derived iPSCs harboring PDE6B mutation. Transcriptome analysis revealed remarkably distinct gene expression profile patient at differentiation day (D) 230. Changes regulating cGMP hydrolysis prompted elevation levels, which was verified enzyme-linked immunosorbent assay (ELISA) Furthermore, significantly higher levels than control D193 D230 might lead impaired formation synaptic connections connecting cilium photoreceptor cells. In this study, established first with consistent phenotype using vitro cell culture system provided insights into PDE6B-related mechanism RP.

Language: Английский

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Therapeutic Options in Hereditary Optic Neuropathies

Drugs, Journal Year: 2020, Volume and Issue: 81(1), P. 57 - 86

Published: Nov. 7, 2020

Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch antioxidant idebenone Leber's Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially variety mitochondrial such as dominant atrophy (DOA), are needed, and number pharmaceutical agents, acting on different molecular pathways, currently under development. These include gene therapy, which has reached Phase III development LHON, but is expected to be developed also DOA, whilst most agents (other antioxidants, anti-apoptotic drugs, activators mitobiogenesis, etc.) almost all at II or preclinical stage research. Here, we review proposed target mechanisms, evidence, available trials with primary endpoints results, wide range tested molecules, give overview field, providing landscape future scenarios, including editing, reproductive options prevent transmission DNA mutations.

Language: Английский

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Mesenchymal Stem Cell-Based Therapy for Retinal Degenerative Diseases: Experimental Models and Clinical Trials

Cells, Journal Year: 2021, Volume and Issue: 10(3), P. 588 - 588

Published: March 7, 2021

Retinal degenerative diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy or glaucoma, represent the main causes of a decreased quality vision even blindness worldwide. However, despite considerable efforts, treatment possibilities for these disorders remain very limited. A perspective is offered by cell therapy using mesenchymal stem cells (MSCs). These can be obtained from bone marrow adipose tissue particular patient, expanded in vitro and used autologous cells. MSCs possess potent immunoregulatory properties inhibit harmful inflammatory reaction diseased retina. By production numerous growth neurotrophic factors, they support survival retinal In addition, protect antiapoptotic could contribute to regeneration retina their ability differentiate into various types, including All indicate potential retinas. This view supported recent results experimental studies different preclinical models. Here we provide an overview therapeutic MSCs, use models diseases clinical trials.

Language: Английский

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3D and organoid culture in research: physiology, hereditary genetic diseases and cancer

Cell & Bioscience, Journal Year: 2022, Volume and Issue: 12(1)

Published: April 1, 2022

Abstract In nature, cells reside in tissues subject to complex cell–cell interactions, signals from extracellular molecules and niche soluble mechanical signaling. These microenvironment interactions are responsible for cellular phenotypes functions, especially normal settings. However, 2D cultures, where limited the horizontal plane, exposed uniformly factors or drugs; therefore, this model does not reconstitute of a natural microenvironment. 3D culture systems more closely resemble architectural functional properties vivo tissues. these different concentrations nutrients, growth factors, oxygen cytotoxic agents depending on their localization communication. The architecture also differentially alters physiological, biochemical, biomechanical that can affect cell growth, survival, differentiation morphogenesis, migration EMT properties, responses therapy resistance. This latter point may, part, explain failure current therapies drug discovery research. Organoids promising system between cultures models allow manipulation signaling pathways genome editing body-like environment but lack many disadvantages living system. review, we will focus role stem establishment organoids possible therapeutic applications model, field cancer

Language: Английский

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Immunological aspects of RPE cell transplantation

Progress in Retinal and Eye Research, Journal Year: 2021, Volume and Issue: 84, P. 100950 - 100950

Published: Jan. 19, 2021

Retinal pigment epithelial (RPE) cells have several functions, including support of the neural retina and choroid in eye immunosuppression. Cultured human RPE directly suppress inflammatory immune cells. For instance, they activation T vitro. In contrast, transplanted allogeneic are rejected by bystander such as vivo. Recently, embryonic stem cell-derived been used clinical trials, induced pluripotent cell (iPSC)-RPE also tested our study patients with retinal degeneration. Major safety concerns after cell-based transplantation surgery include hyper-proliferation, tumorigenicity, or ectopic tissue formation, but these events currently not seen any patients. However, if allogeneic, there about rejection issues that raised previous trials. We therefore performed a preclinical iPSC-RPE animal models. then conducted autogenic studies age-related macular this review, we focus on immunological cells, iPSC-derived unique (immunosuppressive immunogenic) characteristics like primary cultured The purpose review is to summarize current findings obtained from (basic research) transplantation, especially aspects.

Language: Английский

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