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European Journal of Pharmaceutical... Aug 2022Dry eye disease (DED), keratoconjunctivitis sicca or dysfunctional tear syndrome, is the most prevalent ophthalmic disease which affects a substantial segment of people... (Review)
Review
Dry eye disease (DED), keratoconjunctivitis sicca or dysfunctional tear syndrome, is the most prevalent ophthalmic disease which affects a substantial segment of people worldwide with increasing frequency. It is considered a multifactorial disease of the ocular surface and tear film, characterized by a variation of signs and symptoms. The symptoms range from mild to severe itching, burning, irritation, eye fatigue, and ocular inflammation that may lead to potential damage to the cornea, conjunctiva and even vision loss. Correspondingly, depending on the different manifestations and pathophysiology, the treatment must be tailored specifically to each patient by targeting the specific mechanisms implicated in their disease. Currently, there are several medical products and techniques available or under investigation for the treatment of DED. The present article focused on the pathophysiology of DED, the new diagnostic approach and the recently developed drug delivery systems or devices reducing the progress of the disease and treating the causes.
Topics: Conjunctiva; Cornea; Dry Eye Syndromes; Humans; Inflammation; Pharmaceutical Preparations; Tears
PubMed: 35568107
DOI: 10.1016/j.ejps.2022.106206 -
Current Gene Therapy 2022This review provides comprehensive information about the advances in gene therapy in the anterior segment of the eye, including cornea, conjunctiva, lacrimal gland, and... (Review)
Review
This review provides comprehensive information about the advances in gene therapy in the anterior segment of the eye, including cornea, conjunctiva, lacrimal gland, and trabecular meshwork. We discuss gene delivery systems, including viral and non-viral vectors as well as gene editing techniques, mainly CRISPR-Cas9, and epigenetic treatments, including antisense and siRNA therapeutics. We also provide a detailed analysis of various anterior segment diseases where gene therapy has been tested with corresponding outcomes. Disease conditions include corneal and conjunctival fibrosis and scarring, corneal epithelial wound healing, corneal graft survival, corneal neovascularization, genetic corneal dystrophies, herpetic keratitis, glaucoma, dry eye disease, and other ocular surface diseases. Although most of the analyzed results on the use and validity of gene therapy at the ocular surface have been obtained in vitro or using animal models, we also discuss the available human studies. Gene therapy approaches are currently considered very promising as emerging future treatments of various diseases, and this field is rapidly expanding.
Topics: Animals; Anterior Eye Segment; Cornea; Gene Editing; Gene Transfer Techniques; Genetic Therapy
PubMed: 33902406
DOI: 10.2174/1566523221666210423084233 -
Cells Mar 2021The extracellular matrix (ECM) plays a crucial role in all parts of the eye, from maintaining clarity and hydration of the cornea and vitreous to regulating... (Review)
Review
The extracellular matrix (ECM) plays a crucial role in all parts of the eye, from maintaining clarity and hydration of the cornea and vitreous to regulating angiogenesis, intraocular pressure maintenance, and vascular signaling. This review focuses on the interactions of the ECM for homeostasis of normal physiologic functions of the cornea, vitreous, retina, retinal pigment epithelium, Bruch's membrane, and choroid as well as trabecular meshwork, optic nerve, conjunctiva and tenon's layer as it relates to glaucoma. A variety of pathways and key factors related to ECM in the eye are discussed, including but not limited to those related to transforming growth factor-β, vascular endothelial growth factor, basic-fibroblastic growth factor, connective tissue growth factor, matrix metalloproteinases (including MMP-2 and MMP-9, and MMP-14), collagen IV, fibronectin, elastin, canonical signaling, integrins, and endothelial morphogenesis consistent of cellular activation-tubulogenesis and cellular differentiation-stabilization. Alterations contributing to disease states such as wound healing, diabetes-related complications, Fuchs endothelial corneal dystrophy, angiogenesis, fibrosis, age-related macular degeneration, retinal detachment, and posteriorly inserted vitreous base are also reviewed.
Topics: Bruch Membrane; Choroid; Cornea; Extracellular Matrix; Humans; Macular Degeneration; Neovascularization, Pathologic; Retina; Retinal Pigment Epithelium
PubMed: 33804633
DOI: 10.3390/cells10030687 -
Molecules (Basel, Switzerland) Aug 2022Age-related macular degeneration (AMD) was described for the first time in the 1840s and is currently the leading cause of blindness for patients over 65 years in... (Review)
Review
Age-related macular degeneration (AMD) was described for the first time in the 1840s and is currently the leading cause of blindness for patients over 65 years in Western Countries. This disease impacts the eye's posterior segment and damages the macula, a retina section with high levels of photoreceptor cells and responsible for the central vision. Advanced AMD stages are divided into the atrophic (dry) form and the exudative (wet) form. Atrophic AMD consists in the progressive atrophy of the retinal pigment epithelium (RPE) and the outer retinal layers, while the exudative form results in the anarchic invasion by choroidal neo-vessels of RPE and the retina. This invasion is responsible for fluid accumulation in the intra/sub-retinal spaces and for a progressive dysfunction of the photoreceptor cells. To date, the few existing anti-AMD therapies may only delay or suspend its progression, without providing cure to patients. However, in the last decade, an outstanding number of research programs targeting its different aspects have been initiated by academics and industrials. This review aims to bring together the most recent advances and insights into the mechanisms underlying AMD pathogenicity and disease evolution, and to highlight the current hypotheses towards the development of new treatments, i.e., symptomatic vs. curative. The therapeutic options and drugs proposed to tackle these mechanisms are analyzed and critically compared. A particular emphasis has been given to the therapeutic agents currently tested in clinical trials, whose results have been carefully collected and discussed whenever possible.
Topics: Aged; Aging; Humans; Macular Degeneration; Photoreceptor Cells; Retina; Retinal Pigment Epithelium
PubMed: 36014339
DOI: 10.3390/molecules27165089 -
Investigative Ophthalmology & Visual... May 2023The choroid is the richly vascular layer of the eye located between the sclera and Bruch's membrane. Early studies in animals, as well as more recent studies in humans,... (Review)
Review
The choroid is the richly vascular layer of the eye located between the sclera and Bruch's membrane. Early studies in animals, as well as more recent studies in humans, have demonstrated that the choroid is a dynamic, multifunctional structure, with its thickness directly and indirectly subject to modulation by a variety of physiologic and visual stimuli. In this review, the anatomy and function of the choroid are summarized and links between the choroid, eye growth regulation, and myopia, as demonstrated in animal models, discussed. Methods for quantifying choroidal thickness in the human eye and associated challenges are described, the literature examining choroidal changes in response to various visual stimuli and refractive error-related differences are summarized, and the potential implications of the latter for myopia are considered. This review also allowed for the reexamination of the hypothesis that short-term changes in choroidal thickness induced by pharmacologic, optical, or environmental stimuli are predictive of future long-term changes in axial elongation, and the speculation that short-term choroidal thickening can be used as a biomarker of treatment efficacy for myopia control therapies, with the general conclusion that current evidence is not sufficient.
Topics: Animals; Humans; Axial Length, Eye; Choroid; Bruch Membrane; Myopia; Models, Animal; Tomography, Optical Coherence
PubMed: 37126359
DOI: 10.1167/iovs.64.6.4 -
Progress in Retinal and Eye Research Jul 2021Diabetic retinopathy (DR) is a leading cause of blindness. It has long been regarded as vascular disease, but work in the past years has shown abnormalities also in the... (Review)
Review
Diabetic retinopathy (DR) is a leading cause of blindness. It has long been regarded as vascular disease, but work in the past years has shown abnormalities also in the neural retina. Unfortunately, research on the vascular and neural abnormalities have remained largely separate, instead of being integrated into a comprehensive view of DR that includes both the neural and vascular components. Recent evidence suggests that the most predominant neural cell in the retina (photoreceptors) and the adjacent retinal pigment epithelium (RPE) play an important role in the development of vascular lesions characteristic of DR. This review summarizes evidence that the outer retina is altered in diabetes, and that photoreceptors and RPE contribute to retinal vascular alterations in the early stages of the retinopathy. The possible molecular mechanisms by which cells of the outer retina might contribute to retinal vascular damage in diabetes also are discussed. Diabetes-induced alterations in the outer retina represent a novel therapeutic target to inhibit DR.
Topics: Diabetes Mellitus; Diabetic Retinopathy; Humans; Photoreceptor Cells; Retina; Retinal Pigment Epithelium
PubMed: 33188897
DOI: 10.1016/j.preteyeres.2020.100919 -
The Ocular Surface Jul 2021Single cell (sc) analyses of key embryonic, fetal and adult stages were performed to generate a comprehensive single cell atlas of all the corneal and adjacent...
PURPOSE
Single cell (sc) analyses of key embryonic, fetal and adult stages were performed to generate a comprehensive single cell atlas of all the corneal and adjacent conjunctival cell types from development to adulthood.
METHODS
Four human adult and seventeen embryonic and fetal corneas from 10 to 21 post conception week (PCW) specimens were dissociated to single cells and subjected to scRNA- and/or ATAC-Seq using the 10x Genomics platform. These were embedded using Uniform Manifold Approximation and Projection (UMAP) and clustered using Seurat graph-based clustering. Cluster identification was performed based on marker gene expression, bioinformatic data mining and immunofluorescence (IF) analysis. RNA interference, IF, colony forming efficiency and clonal assays were performed on cultured limbal epithelial cells (LECs).
RESULTS
scRNA-Seq analysis of 21,343 cells from four adult human corneas and adjacent conjunctivas revealed the presence of 21 cell clusters, representing the progenitor and differentiated cells in all layers of cornea and conjunctiva as well as immune cells, melanocytes, fibroblasts, and blood/lymphatic vessels. A small cell cluster with high expression of limbal progenitor cell (LPC) markers was identified and shown via pseudotime analysis to give rise to five other cell types representing all the subtypes of differentiated limbal and corneal epithelial cells. A novel putative LPCs surface marker, GPHA2, expressed on the surface of 0.41% ± 0.21 of the cultured LECs, was identified, based on predominant expression in the limbal crypts of adult and developing cornea and RNAi validation in cultured LECs. Combining scRNA- and ATAC-Seq analyses, we identified multiple upstream regulators for LPCs and demonstrated a close interaction between the immune cells and limbal progenitor cells. RNA-Seq analysis indicated the loss of GPHA2 expression and acquisition of proliferative limbal basal epithelial cell markers during ex vivo LEC expansion, independently of the culture method used. Extending the single cell analyses to keratoconus, we were able to reveal activation of collagenase in the corneal stroma and a reduced pool of limbal suprabasal cells as two key changes underlying the disease phenotype. Single cell RNA-Seq of 89,897 cells obtained from embryonic and fetal cornea indicated that during development, the conjunctival epithelium is the first to be specified from the ocular surface epithelium, followed by the corneal epithelium and the establishment of LPCs, which predate the formation of limbal niche by a few weeks.
CONCLUSIONS
Our scRNA-and ATAC-Seq data of developing and adult cornea in steady state and disease conditions provide a unique resource for defining genes/pathways that can lead to improvement in ex vivo LPCs expansion, stem cell differentiation methods and better understanding and treatment of ocular surface disorders.
Topics: Adult; Cell Differentiation; Cells, Cultured; Cornea; Epithelial Cells; Epithelium, Corneal; Humans; Limbus Corneae; Stem Cells
PubMed: 33865984
DOI: 10.1016/j.jtos.2021.03.010 -
Contact Lens & Anterior Eye : the... Apr 2023To evaluate the benefits on the eyes of taking breaks based on the 20-20-20 rule.
PURPOSE
To evaluate the benefits on the eyes of taking breaks based on the 20-20-20 rule.
METHODS
Bespoke computer software using the laptop webcam to assess user breaks, eye gaze and blinking, and emitting personalized reminders of breaks based on the 20-20-20 rule, was downloaded onto the laptops of 29 symptomatic computer users. Digital eye strain (DES), binocular vision and dry eye were assessed before and after two weeks of using the reminders and one week after the discontinuation of the strategy. Binocular measurements included visual acuity, accommodative posture, stereopsis, fixation disparity, ocular alignment, accommodative facility, positive/negative vergences and near point of convergence. Symptoms were evaluated using the computer vision syndrome questionnaire, ocular surface disease index (OSDI), and symptom assessment in dry eye questionnaire (SANDE) versions one and two. Dry eye signs were assessed by measuring tear meniscus height, conjunctival redness, blink rate and incomplete blinking, lipid layer thickness, non-invasive keratograph break-up time, corneal and conjunctival staining and lid wiper epitheliopathy.
RESULTS
A decrease in the duration of computer work and the duration of breaks, along with an increase in the number of breaks taken per day was observed as a result of the 20-20-20 rule reminders (p ≤ 0.015). No changes on any binocular parameter were observed after the management period (p ≥ 0.051), except for an increase in accommodative facility (p = 0.010). Dry eye symptoms and DES decreased with the rule reminders (p ≤ 0.045), although this improvement was not maintained one week after discontinuation (p > 0.05). No changes on any ocular surface and tear film parameter were observed with the rule reminders (p ≥ 0.089).
CONCLUSIONS
The 20-20-20 rule is an effective strategy for reducing DES and dry eye symptoms, although 2 weeks was not enough to considerably improve binocular vision or dry eye signs.
Topics: Humans; Vision, Binocular; Dry Eye Syndromes; Tears; Cornea; Conjunctiva
PubMed: 35963776
DOI: 10.1016/j.clae.2022.101744 -
Molecular Neurodegeneration Sep 2023Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited... (Review)
Review
Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium's efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.
Topics: Animals; Humans; Retinal Ganglion Cells; Optic Nerve Diseases; Retina; Brain; Cell Differentiation; Mammals
PubMed: 37735444
DOI: 10.1186/s13024-023-00655-y -
Proceedings of the National Academy of... Jul 2022The anterior segment of the eye consists of the cornea, iris, ciliary body, crystalline lens, and aqueous humor outflow pathways. Together, these tissues are essential...
The anterior segment of the eye consists of the cornea, iris, ciliary body, crystalline lens, and aqueous humor outflow pathways. Together, these tissues are essential for the proper functioning of the eye. Disorders of vision have been ascribed to defects in all of them; some disorders, including glaucoma and cataract, are among the most prevalent causes of blindness in the world. To characterize the cell types that compose these tissues, we generated an anterior segment cell atlas of the human eye using high-throughput single-nucleus RNA sequencing (snRNAseq). We profiled 195,248 nuclei from nondiseased anterior segment tissues of six human donors, identifying >60 cell types. Many of these cell types were discrete, whereas others, especially in the lens and cornea, formed continua corresponding to known developmental transitions that persist in adulthood. Having profiled each tissue separately, we performed an integrated analysis of the entire anterior segment, revealing that some cell types are unique to a single structure, whereas others are shared across tissues. The integrated cell atlas was then used to investigate cell type-specific expression patterns of more than 900 human ocular disease genes identified through either Mendelian inheritance patterns or genome-wide association studies.
Topics: Adult; Anterior Eye Segment; Aqueous Humor; Atlases as Topic; Ciliary Body; Eye Diseases; Genome-Wide Association Study; Humans; Iris; Organ Specificity
PubMed: 35858321
DOI: 10.1073/pnas.2200914119