RESUMEN
Glaucoma is a group of optic neuropathies characterized by the degeneration of retinal ganglion cells and the loss of their axons in the optic nerve. The only approved therapies for the treatment of glaucoma are topical medications and surgical procedures aimed at lowering intraocular pressure. Gene therapy involves the insertion, removal, or modification of genetic material within cells to repair or compensate for the loss of a gene's function. It describes a process or technology that enables the genetic modification of cells to produce a therapeutic effect. However, changing the genetic material alone does not extend the duration of overexpression of proteins that combat disease, nor does it facilitate the production of new proteins for this purpose. We reviewed the literature concerning the use of gene therapy in the treatment of glaucoma and explored the future directions that this innovation may offer. Three genes associated with glaucoma have been identified within these loci: myocilin/trabecular meshwork glucocorticoid response (TIGR) (GLC1A), optineurin (GLC1E), and WDR36 (GLC1G). Among these, the most extensively studied glaucoma gene is myocilin (a TM-inducible glucocorticoid response gene). Building on previous successes, researchers have begun to apply genetic therapeutic approaches to alleviate or reduce symptoms associated with ocular hypertension (OHT) and glaucoma-like optic neuropathy (GON). It is evident that several therapeutic strategies exist that modulate aqueous humor production and flow, thereby regulating intraocular pressure (IOP) and protecting retinal ganglion cells (RGCs) from apoptosis. With the emergence of gene therapy as a potentially viable approach to preserving vision, new methods for managing glaucoma may soon become available. Genomic therapy is a promising treatment option for glaucoma patients and has significant potential for widespread clinical application.
Asunto(s)
Terapia Genética , Glaucoma , Humanos , Terapia Genética/métodos , Glaucoma/terapia , Glaucoma/genética , Animales , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Proteínas del Citoesqueleto/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Proteínas de Transporte de MembranaRESUMEN
Purpose: To characterize early trabecular meshwork (TM) morphologic abnormalities in a feline model of human primary congenital glaucoma (PCG) caused by mutation in LTBP2. Methods: Eyes from 41 cats, including 19 normal and 22 homozygous for LTBP2 mutation, across various postnatal stages (birth, 2 weeks, 5 weeks, and 12 weeks) were paraformaldehyde fixed, anterior segments dissected, post-fixed in glutaraldehyde, osmicated, and processed and sectioned for transmission electron microscopy. Cell morphology, nuclear shape, and intertrabecular space (ITS) were quantitatively assessed, and the structure of the fibrillar extracellular matrix in the TM was systematically evaluated. Results: The earliest differences in TM morphology between PCG and normal cats were identified at 2 weeks postnatally. Elastic fibers in the TM were discontinuous and disorganized (P = 0.0122), and by 5 weeks of age PCG cats presented significantly less ITS (P = 0.0076) and morphologically rounder TM cells than normal cats (P = 0.0293). By 12 weeks of age, the ITS was further collapsed (P < 0.0001), and the TM cells were morphologically elongated and attenuated in PCG compared to controls (P = 0.0028). Conclusions: In this feline model of PCG due to LTBP2 mutation, development of ultrastructural TM extracellular matrix abnormalities are first observed by 2 weeks and cellular abnormalities by 5 weeks of age. By 12 weeks of age, when intraocular pressure becomes significantly elevated, the TM morphologic abnormalities are already well established. These findings suggest that the postnatal period between 0 and 5 weeks of age is critical for TM and PCG development and progression in cats.
Asunto(s)
Modelos Animales de Enfermedad , Presión Intraocular , Mutación , Malla Trabecular , Animales , Malla Trabecular/ultraestructura , Malla Trabecular/patología , Gatos , Presión Intraocular/fisiología , Glaucoma/genética , Glaucoma/patología , Microscopía Electrónica de Transmisión , Proteínas de Unión a TGF-beta Latente/genética , Animales Recién NacidosRESUMEN
Purpose: The optic nerve head (ONH) is well known to be the initial site of glaucomatous damage; however, the molecular mechanisms initiating this pathology are not fully understood. To further understand the initiating factors in glaucomatous damage we utilized a novel mouse model of glaucoma, B6.EDA+/+ mice, which constitutively express fibronectin containing the extra domain A (FN+EDA). FN+EDA is a known damage-associated molecular pattern (DAMP) that activates Toll-like receptor 4 and elicits a fibro-inflammatory response. Methods: Eyes from B6.EDA+/+ and C57BL/6J mice were evaluated for retinal ganglion cell (RGC) death, retinal nerve fiber layer (RNFL) thickness, and optic nerve (ON) damage at 12 months and 22 months of age. ONH sections were isolated using laser capture microdissection for subsequent RNA-sequencing and Gene Set Enrichment Analysis (GSEA). GSEA results were confirmed using immunohistochemical (IHC) staining. Results: B6.EDA+/+ mice exhibit significantly higher intraocular pressure, loss of RGCs, thinning of the RNFL, and progressive levels of ON damage at 12 months and 22 months of age compared to C57BL/6J controls. Protein expression of DAMPs FN+EDA and biglycan was significantly increased in B6.EDA+/+ mice compared to C57BL/6J controls. GSEA analysis identified significantly up- and downregulated gene groupings at both 12 months and 22 months of age, and IHC staining at 12 and 18 months of age demonstrated significant increases of IFNα, IFNß, and pSTAT1 expression in B6.EDA+/+ mice compared to C57BL/6J controls. Conclusions: Our study characterizes glaucomatous changes to the retina, ON, and ONH over the course of 2 years and identifies novel molecular pathways associated with these pathophysiological changes. These data illustrate the effects of FN+EDA on the fibro-inflammatory response in the aging ONH in a novel mouse model of glaucoma.
Asunto(s)
Modelos Animales de Enfermedad , Fibronectinas , Glaucoma , Presión Intraocular , Ratones Endogámicos C57BL , Disco Óptico , Células Ganglionares de la Retina , Animales , Ratones , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Disco Óptico/patología , Disco Óptico/metabolismo , Presión Intraocular/fisiología , Glaucoma/metabolismo , Glaucoma/genética , Fibronectinas/metabolismo , Fibronectinas/genética , Fibras Nerviosas/patología , Masculino , Enfermedades del Nervio Óptico/genética , Enfermedades del Nervio Óptico/metabolismo , Tomografía de Coherencia ÓpticaRESUMEN
Calcium is involved in vision processes in the retina and implicated in various pathologies, including glaucoma. Rod cells rely on store-operated calcium entry (SOCE) to safeguard against the prolonged lowering of intracellular calcium ion concentrations. Zebrafish that lacked the endoplasmic reticulum Ca2+ sensor Stim2 (stim2 knockout [KO]) exhibited impaired vision and lower light perception-related gene expression. We sought to understand mechanisms that are responsible for vision impairment in stim2 KO zebrafish. The single-cell RNA (scRNA) sequencing of neuronal cells from brains of 5 days postfertilization larvae distinguished 27 cell clusters, 10 of which exhibited distinct gene expression patterns, including amacrine and γ-aminobutyric acid (GABA)ergic retinal interneurons and GABAergic optic tectum cells. Five clusters exhibited significant changes in cell proportions between stim2 KO and controls, including GABAergic diencephalon and optic tectum cells. Transmission electron microscopy of stim2 KO zebrafish revealed decreases in width of the inner plexiform layer, ganglion cells, and their dendrites numbers (a hallmark of glaucoma). GABAergic neuron densities in the inner nuclear layer, including amacrine cells, as well as photoreceptors significantly decreased in stim2 KO zebrafish. Our study suggests a novel role for Stim2 in the regulation of neuronal insulin expression and GABAergic-dependent vision causing glaucoma-like retinal pathology.
Asunto(s)
Glaucoma , Molécula de Interacción Estromal 2 , Proteínas de Pez Cebra , Pez Cebra , Animales , Molécula de Interacción Estromal 2/metabolismo , Molécula de Interacción Estromal 2/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Glaucoma/metabolismo , Glaucoma/patología , Glaucoma/genética , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/patología , Fenotipo , Técnicas de Inactivación de Genes , Retina/metabolismo , Retina/patología , Modelos Animales de Enfermedad , Colículos Superiores/metabolismo , Colículos Superiores/patología , Calcio/metabolismo , Células Amacrinas/metabolismo , Células Amacrinas/patologíaRESUMEN
Glaucoma and Alzheimer's disease are critical degenerative neuropathies with global impact. Previous studies have indicated that glaucomatous damage could extend beyond ocular structures, leading to brain alterations potentially associated with Alzheimer's disease risk. This study aimed to explore the causal associations among glaucoma, brain alterations, and Alzheimer's disease. We conducted a comprehensive investigation into the genetic correlation and causality between glaucoma, glaucoma endophenotypes, cerebral cortical surficial area and thickness, and Alzheimer's disease (including late-onset Alzheimer's disease, cognitive performance, and reaction time) using linkage disequilibrium score regression and Mendelian randomization. This study showed suggestive genetic correlations between glaucoma, cortical structures, and Alzheimer's disease. The genetically predicted all-caused glaucoma was nominally associated with a decreased risk of Alzheimer's disease (OR = 0.96, 95% CI: 0.93-0.99, P = 0.013). We found evidence for suggestive causality between glaucoma (endophenotypes) and 20 cortical regions and between 29 cortical regions and Alzheimer's disease (endophenotypes). Four cortical regions were causally associated with cognitive performance or reaction time at a significant threshold (P < 6.2E-04). Thirteen shared cortical regions between glaucoma (endophenotypes) and Alzheimer's disease (endophenotypes) were identified. Our findings complex causal relationships among glaucoma, cerebral cortical structures, and Alzheimer's disease. More studies are required to clarify the mediation effect of cortical alterations in the relationship between glaucoma and Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Corteza Cerebral , Glaucoma , Análisis de la Aleatorización Mendeliana , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Glaucoma/genética , Corteza Cerebral/patología , Femenino , Masculino , Anciano , Predisposición Genética a la Enfermedad/genética , Endofenotipos , Polimorfismo de Nucleótido SimpleRESUMEN
Purpose: Glaucoma, one of the leading causes of irreversible blindness, is a common progressive optic neuropathy characterised by visual field defects and structural changes to the optic nerve head (ONH). There is extracellular matrix (ECM) accumulation and fibrosis of the lamina cribrosa (LC) in the ONH, and consequently increased tissue stiffness of the LC connective tissue. Integrins are cell surface proteins that provide the key molecular link connecting cells to the ECM and serve as bidirectional sensors transmitting signals between cells and their environment to promote cell adhesion, proliferation, and remodelling of the ECM. Here, we investigated the expression of αVß3 integrin in glaucoma LC cell, and its effect on stiffness-induced ECM gene transcription and cellular proliferation rate in normal (NLC) and glaucoma (GLC) LC cells, by down-regulating αVß3 integrin expression using cilengitide (a known potent αVß3 and αVß5 inhibitor) and ß3 integrin siRNA knockdown. Methods: GLC cells were compared to age-matched controls NLC to determine differential expression levels of αVß3 integrin, ECM genes (Col1A1, α-SMA, fibronectin, vitronectin), and proliferation rates. The effects of αVß3 integrin blockade (with cilengitide) and silencing (with a pool of four predesigned αVß3 integrin siRNAs) on ECM gene expression and proliferation rates were evaluated using both reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting in the human NLC cells cultured on soft (4 kPa) and stiff (100 kPa) substrate and in GLC cells grown on standard plastic plates. Results: αVß3 integrin gene and protein expression were enhanced (p < 0.05) in GLC cells as compared to NLC. Both cilengitide and siRNA significantly reduced αVß3 expression in GLC. When NLC were grown in the stiff substrate, cilengitide and siRNA also significantly reduced the increased expression in αVß3, ECM components, and proliferation rate. Conclusions: Here, we provide evidence of cilengitide- and siRNA-mediated silencing of αVß3 integrin expression, and inhibition of ECM synthesis in LC cells. Therefore, αVß3 integrin may be a promising target for the development of novel anti-fibrotic therapies for treating the LC cupping of the ONH in glaucoma.
Asunto(s)
Proliferación Celular , Glaucoma , Integrina alfaVbeta3 , Mecanotransducción Celular , Humanos , Integrina alfaVbeta3/metabolismo , Integrina alfaVbeta3/genética , Glaucoma/patología , Glaucoma/metabolismo , Glaucoma/genética , Matriz Extracelular/metabolismo , Disco Óptico/metabolismo , Disco Óptico/patología , Venenos de Serpiente , Persona de Mediana Edad , Masculino , Anciano , FemeninoRESUMEN
Primary congenital glaucoma (PCG) occurs in children due to developmental abnormalities in the trabecular meshwork and anterior chamber angle. Previous studies have implicated rare variants in CYP1B1, LTBP2, and TEK and their interactions with MYOC, FOXC1, and PRSS56 in the genetic complexity and clinical heterogeneity of PCG. Given that some of the gene-encoded proteins are localized in the centrosomes (MYOC) and perform ciliary functions (TEK), we explored the involvement of a core centrosomal protein, CEP164, which is responsible for ocular development and regulation of intraocular pressure. Deep sequencing of CEP164 in a PCG cohort devoid of homozygous mutations in candidate genes (n = 298) and controls (n = 1757) revealed CEP164 rare pathogenic variants in 16 cases (5.36%). Co-occurrences of heterozygous alleles of CEP164 with other genes were seen in four cases (1.34%), and a physical interaction was noted for CEP164 and CYP1B1 in HEK293 cells. Cases of co-harboring alleles of the CEP164 and other genes had a poor prognosis compared with those with a single copy of the CEP164 allele. We also screened INPP5E, which synergistically interacts with CEP164, and observed a lower frequency of pathogenic variants (0.67%). Our data suggest the potential involvements of CEP164 and INPP5E and the yet unexplored cilia-centrosomal functions in PCG pathogenesis.
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Cilios , Citocromo P-450 CYP1B1 , Glaucoma , Humanos , Cilios/genética , Cilios/metabolismo , Cilios/patología , Masculino , Glaucoma/genética , Glaucoma/congénito , Glaucoma/patología , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Femenino , Mutación , Células HEK293 , Niño , Alelos , LactanteRESUMEN
Metabolic dysfunction plays a crucial role in the pathogenesis of glaucoma. In this study, we used Olink proteomics profiling to identify potential biomarkers for glaucoma. Aqueous humor samples were obtained from 44 cataract patients and 44 glaucoma patients. We identified 84 differentially expressed metabolic proteins between the glaucoma and the cataract group. Gene Ontology enrichment analysis highlighted the involvement of these proteins in ER-associated degradation pathway, regulation of interleukin-13 production, and DNA damage response pathway. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis further revealed links to pathways, such as tyrosine and pyrimidine metabolism. Among these, ALDH1A1 emerged as a candidate with a significant diagnostic potential for glaucoma. ALDH1A1 also exhibited a prominent role in the protein-protein interaction network. Elevated levels of ALDH1A1 in the aqueous humor of glaucoma patients were confirmed both in clinical samples and in an ischemia/reperfusion model. Functional assays confirmed that elevated ALDH1A1 induced retinal ganglion cell (RGC) apoptosis in vitro and demonstrated its pro-apoptotic role in RGCs in vivo. Collectively, these findings not only underscore the significance of ALDH1A1 in glaucoma but also provide valuable insights into clinical decision-making and therapeutic strategies.
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Familia de Aldehído Deshidrogenasa 1 , Humor Acuoso , Biomarcadores , Glaucoma , Proteómica , Humanos , Glaucoma/metabolismo , Glaucoma/genética , Glaucoma/patología , Biomarcadores/metabolismo , Proteómica/métodos , Humor Acuoso/metabolismo , Familia de Aldehído Deshidrogenasa 1/metabolismo , Familia de Aldehído Deshidrogenasa 1/genética , Retinal-Deshidrogenasa/metabolismo , Retinal-Deshidrogenasa/genética , Femenino , Masculino , Mapas de Interacción de Proteínas , Apoptosis/genética , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Anciano , Persona de Mediana Edad , Animales , Catarata/metabolismo , Catarata/genéticaRESUMEN
Congenital microcoria (MCOR) is a rare hereditary developmental defect of the iris dilator muscle frequently associated with high axial myopia and high intraocular pressure (IOP) glaucoma. The condition is caused by submicroscopic rearrangements of chromosome 13q32.1. However, the mechanisms underlying the failure of iris development and the origin of associated features remain elusive. Here, we present a 3D architecture model of the 13q32.1 region, demonstrating that MCOR-related deletions consistently disrupt the boundary between two topologically associating domains (TADs). Deleting the critical MCOR-causing region in mice reveals ectopic Sox21 expression precisely aligning with Dct, each located in one of the two neighbor TADs. This observation is consistent with the TADs' boundary alteration and adoption of Dct regulatory elements by the Sox21 promoter. Additionally, we identify Tgfb2 as a target gene of SOX21 and show TGFΒ2 accumulation in the aqueous humor of an MCOR-affected subject. Accumulation of TGFB2 is recognized for its role in glaucoma and potential impact on axial myopia. Our results highlight the importance of SOX21-TGFB2 signaling in iris development and control of eye growth and IOP. Insights from MCOR studies may provide therapeutic avenues for this condition but also for glaucoma and high myopia conditions, affecting millions of people.
Asunto(s)
Glaucoma , Miopía , Factor de Crecimiento Transformador beta2 , Animales , Glaucoma/genética , Glaucoma/metabolismo , Glaucoma/patología , Ratones , Factor de Crecimiento Transformador beta2/genética , Factor de Crecimiento Transformador beta2/metabolismo , Miopía/genética , Miopía/metabolismo , Humanos , Iris/metabolismo , Iris/patología , Iris/anomalías , Presión IntraocularRESUMEN
OBJECTIVE: This investigation was to determine the relationship between changes in the expression levels of miR-134 and the E2F transcription factor 6 (E2F6) in mediating control of apoptosis in N-methyl-D-aspartate (NMDA)-induced glaucomatous mice. METHODS: Morphological and structural changes were quantitatively analyzed along with apoptosis in the retinal ganglion cell (RGC) layer, internal plexiform layer and RGCs. Glaucomatous RGCs were transfected, and cell viability and apoptosis were examined. The targeting relationship between miR-134 and E2F6 was analyzed, as well as their expression pattern. RESULTS: Intravitreal injection of NMDA induced a significant reduction in the number of RGCs and thinning of IPL thickness. miR-134 was highly expressed and E2F6 was lowly expressed in glaucoma mice. Suppression of miR-134 or E2F6 overexpression inhibited apoptosis in the glaucomatous RGCs and instead their proliferative activity. MiR-134 targeted inhibition of E2F6 expression. Suppressing rises in E2F6 expression reduced the interfering effect of miR-134 on glaucomatous RGC development. CONCLUSION: Depleting miR134 expression increases, in turn, E2F6 expression levels and in turn reduces glaucomatous RGC apoptosis expression.
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Apoptosis , Factor de Transcripción E2F6 , Glaucoma , MicroARNs , N-Metilaspartato , Células Ganglionares de la Retina , Animales , Masculino , Ratones , Apoptosis/efectos de los fármacos , Apoptosis/genética , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Factor de Transcripción E2F6/genética , Factor de Transcripción E2F6/metabolismo , Glaucoma/genética , Glaucoma/patología , Glaucoma/metabolismo , Glaucoma/inducido químicamente , Inyecciones Intravítreas , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , N-Metilaspartato/toxicidad , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/efectos de los fármacosRESUMEN
Purpose: Adeno-associated virus (AAV) demonstrates promise in delivering therapeutic genes to retinal ganglion cells (RGCs). Delivery of neuroprotective genes is constrained by packaging size and/or cell selectivity. This study compares the ability of the RGC-selective gamma-synuclein (SNCG) promoter and the smaller RGC-selective neurofilament heavy chain (NEFH) promoter, as well as portions of the RGC-selective atonal bHLH transcription factor 7 (ATOH7) enhancer, to drive gene expression in RGCs. Methods: AAV2 constructs with green fluorescent protein (GFP) or human sirtuin 1 (hSIRT1) driven by cytomegalovirus (CMV) enhancer and NEFH promoter (AAV2-eCMV-NEFH) or distal active sequences of the ATOH7 enhancer (DiATOH7) with the SNCG promoter (AAV2-DiATOH7-SNCG) were intravitreally injected into C57BL/6J mice. RGCs were immunolabeled with Brn3a antibodies and counted. AAV constructs with the utmost transduction efficiency were used to test the therapeutic efficacy of the hSIRT1 gene in 12-week-old C57BL/6J mice subjected to microbead (MB)-induced intraocular pressure (IOP) elevation. Visual function was measured using optokinetic responses (OKRs). Results: The eGFP transduction efficiency of AAV2-eCMV-NEFH was similar to that of AAV2-eCMV-SNCG and AAV2-DiATOH7-SNCG. When combined with the SNCG promoter, a larger ATOH7 enhancer was less efficient than the shorter DiATOH7 enhancer. Similarly, the hSIRT1 efficiency of AAV2-eCMV-NEFH was similar to that of AAV2-eCMV-SNCG. The latter two vectors were equally efficient in increasing RGC survival and improving visual function in the mouse model of MB-induced IOP elevation. Conclusions: SNCG and NEFH promoters represent two equally efficient and comparable RGC selective promoter sequences; however, the NEFH promoter offers a smaller packaging size. Translational Relevance: Smaller enhancer-promoter combinations can be used to deliver larger genes in human cells and for treatment in optic neuropathies including glaucoma.
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Dependovirus , Modelos Animales de Enfermedad , Glaucoma , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas , Células Ganglionares de la Retina , Sirtuina 1 , gamma-Sinucleína , Animales , Sirtuina 1/genética , Sirtuina 1/metabolismo , Ratones , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Humanos , Glaucoma/genética , Glaucoma/terapia , Glaucoma/metabolismo , Dependovirus/genética , gamma-Sinucleína/genética , gamma-Sinucleína/metabolismo , Inyecciones Intravítreas , Terapia Genética/métodos , Vectores Genéticos/genética , Vectores Genéticos/administración & dosificación , Presión Intraocular/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Regulación de la Expresión GénicaRESUMEN
PURPOSE: Glaucoma is a leading public health concern globally. This summary discusses barriers to glaucoma screening and novel strategies for a cost-effective glaucoma screening. METHODS/RESULTS: We discuss barriers to glaucoma screening and recent advancements in glaucoma detection and care, including targeted screening approach as well as telemedicine, genetic testing, and artificial intelligence (AI). A major barrier to glaucoma screening is the cost-effectiveness of case finding resulting from the low prevalence of the disease and the complexity of the diagnosis. Targeted-screening, as well as multi-level screening, can reduce the false positive rate and increase the cost-effectiveness of the program. Telemedicine, availability of genetic testing and polygenic risk scores, and AI provide the opportunity for novel glaucoma screening programs in primary care, portable, and home-based settings and will be helpful for lowering the costs, identifying patients in need of urgent treatment and enabling timely diagnosis and early intervention. CONCLUSIONS: Screening of glaucoma is challenging and changing. Recent advancements in digital technology and genetics have led to the development of tools that are promising for novel screening methodologies. Clinical trials are needed to demonstrate the long-term effect of targeted screening on the burden of glaucoma worldwide.
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Glaucoma , Tamizaje Masivo , Humanos , Glaucoma/diagnóstico , Glaucoma/genética , Tamizaje Masivo/métodos , Telemedicina , Consenso , Análisis Costo-Beneficio , Pruebas Genéticas , Inteligencia Artificial , Presión Intraocular/fisiologíaRESUMEN
BACKGROUND: Age-related eye diseases (AREDs) have become increasingly prevalent with the aging population, serving as the leading causes of visual impairment worldwide. Epigenetic clocks are generated based on DNA methylation (DNAm) levels and are considered one of the most promising predictors of biological age. This study aimed to investigate the bidirectional causal association between epigenetic clocks and common AREDs or glaucoma endophenotypes. METHODS: Instrumental variables for epigenetic clocks, AREDs, and glaucoma endophenotypes were obtained from corresponding genome-wide association study data of European descent. Bidirectional two-sample Mendelian randomization (MR) was employed to explore the causal relationship between epigenetic clocks and AREDs or glaucoma endophenotypes. Multivariable MR (MVMR) was used to determine whether glaucoma endophenotypes mediated the association of epigenetic clocks with glaucoma. Multiple sensitivity analyses were conducted to confirm the robustness of MR estimates. RESULTS: The results showed that an increased intrinsic epigenetic age acceleration (HorvathAge) was significantly associated with an increased risk of primary open-angle glaucoma (OR = 1.04, 95% CI 1.02 to 1.06, P = 6.1E-04). The epigenetic age acceleration (EEA) of HannumAge was related to a decreased risk of primary angle-closure glaucoma (OR = 0.92, 95% CI 0.86 to 0.99, P = 0.035). Reverse MR analysis showed that age-related cataract was linked to decreased HannumAge (ß = -0.190 year, 95% CI -0.374 to -0.008, P = 0.041). The EEA of HannumAge (ß = -0.85 µm, 95% CI -1.57 to -0.14, P = 0.019) and HorvathAge (ß = -0.63 µm, 95% CI -1.18 to -0.08, P = 0.024) were associated with decreased central corneal thickness (CCT). PhenoAge was related to an increased retinal nerve fiber layer thickness (ß = 0.06 µm, 95% CI 0.01 to 0.11, P = 0.027). MVMR analysis found no mediation effect of CCT in the association of HannumAge and HorvathAge with glaucoma. DNAm-based granulocyte proportions were significantly associated with presbyopia, rhegmatogenous retinal detachment, and intraocular pressure (P < 0.05). DNAm-based plasminogen activator inhibitor-1 levels were significantly related to age-related macular degeneration and intraocular pressure (P < 0.05). CONCLUSION: The present study revealed a causal association between epigenetic clocks and AREDs. More research is warranted to clarify the potential mechanisms of the biological aging process in AREDs.
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Envejecimiento , Metilación de ADN , Endofenotipos , Epigénesis Genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Epigénesis Genética/genética , Estudio de Asociación del Genoma Completo/métodos , Metilación de ADN/genética , Masculino , Envejecimiento/genética , Femenino , Glaucoma/genética , Persona de Mediana Edad , Glaucoma de Ángulo Abierto/genética , Anciano , Predisposición Genética a la EnfermedadRESUMEN
PRCIS: As additional glaucoma genes are identified and classified, polygenic risk scores will be refined, facilitating early diagnosis and treatment. Ensuring genetic research is equitable to prevent glaucoma blindness worldwide is crucial. PURPOSE: To review the progress in glaucoma genetics over the past 25 years, including the identification of genes with varying contributions to the disease and the development of polygenic risk scores. METHODS/RESULTS: Over the last 2 and a half decades, glaucoma genetics has evolved from identifying genes with Mendelian inheritance patterns, such as myocilin and CYP1B1, to the discovery of hundreds of genes associated with the disease. Polygenic risk scores have been developed, primarily based on research in Northern European populations, and efforts to refine these scores are ongoing. However, there is a question regarding their applicability to other ethnic groups, especially those at higher risk of primary open angle glaucoma, like individuals of African ancestry. Glaucoma is highly heritable and family history can be used for cascade clinical screening programs, but these will not be feasible in all populations. Thus, cascade genetic testing using well-established genes such as myocilin may help improve glaucoma diagnosis. In addition, ongoing investigations seek to identify pathogenic genetic variants within genes like myocilin. CONCLUSIONS: The expanding availability of genetic testing for various diseases and early access to genetic risk information necessitates further research to determine when and how to act on specific genetic results. Polygenic risk scores involving multiple genes with subtle effects will require continuous refinement to improve clinical utility. This is crucial for effectively interpreting an individual's risk of developing glaucoma and preventing blindness.
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Proteínas del Citoesqueleto , Proteínas del Ojo , Pruebas Genéticas , Glicoproteínas , Humanos , Proteínas del Ojo/genética , Proteínas del Citoesqueleto/genética , Pruebas Genéticas/métodos , Glicoproteínas/genética , Glaucoma/genética , Glaucoma/diagnóstico , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Glaucoma de Ángulo Abierto/genética , Glaucoma de Ángulo Abierto/diagnósticoRESUMEN
Childhood glaucoma is a heterogeneous group of ocular disorders defined by an age of onset from birth to 18 years. These vision-threatening disorders require early diagnosis, timely treatment, and lifelong management to maintain vision and minimise irreversible blindness. The genetics of childhood glaucoma is complex with both phenotypic and genetic heterogeneity. The purpose of this review is to summarise the different types of childhood glaucoma and their genetic architecture to aid in the genetic counselling process with patients and their families. We provide an overview of associated syndromes and discuss implications for genetic counselling, including genetic testing strategies, cascade genetic testing, and reproductive options.
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Asesoramiento Genético , Pruebas Genéticas , Glaucoma , Humanos , Glaucoma/genética , Glaucoma/diagnóstico , Niño , Fenotipo , Predisposición Genética a la Enfermedad , Adolescente , PreescolarRESUMEN
Glaucoma affects approximately 80 million individuals worldwide, a condition for which current treatment options are inadequate. The primary risk factor for glaucoma is elevated intraocular pressure. Intraocular pressure is determined by the balance between the secretion and outflow of aqueous humor. Here we show that using the RNA interference tool CasRx based on shH10 adenovirus-associated virus can reduce the expression of the aqueous humor circulation related genes Rock1 and Rock2, as well as aquaporin 1 and ß2 adrenergic receptor in female mice. This significantly reduced intraocular pressure in female mice and provided protection to the retina ganglion cells, ultimately delaying disease progression. In addition, we elucidated the mechanisms by which the knockdown of Rock1 and Rock2, or aquaporin 1 and ß2 adrenergic receptor in female mice, reduces the intraocular pressure and secures the retina ganglion cells by single-cell sequencing.
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Acuaporina 1 , Sistemas CRISPR-Cas , Glaucoma , Presión Intraocular , Células Ganglionares de la Retina , Quinasas Asociadas a rho , Animales , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Quinasas Asociadas a rho/metabolismo , Quinasas Asociadas a rho/genética , Femenino , Acuaporina 1/metabolismo , Acuaporina 1/genética , Ratones , Glaucoma/genética , Glaucoma/metabolismo , Humor Acuoso/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Interferencia de ARN , HumanosRESUMEN
Purpose: Activation of the classical complement pathway is thought to contribute to the development and progression of glaucoma. The role of alternative complement or amplification pathways in glaucoma is not well understood. We evaluated complement factor B (FB) expression in postmortem human ocular tissues with or without glaucoma and the effect of FB inhibition and deletion in a mouse ocular hypertensive model of glaucoma induced by photopolymerized hyaluronic acid glycidyl methacrylate (HAGM). Methods: Human CFB mRNA in human eyes was assessed by RNAscope and TaqMan. HAGM model was performed on C57BL6/J mice. The effect of FB in HAGM model was evaluated with an oral FB inhibitor and Cfb-/- mice. Complement mRNA and proteins in mouse eyes were assessed by TaqMan and western blot, respectively. Results: CFB mRNA in human glaucomatous macular neural retina and optic nerve head was upregulated. Cfb mRNA is also upregulated in the HAGM model. Oral FB inhibitor, ED-79-GX17, dosed daily at 200 mg/kg for 3 days after intraocular pressure (IOP) induction in wild-type mice showed complement inhibition in ocular tissues and significantly inhibited systemic complement levels. Daily dosing of ED-79-GX17 for 30 days or Cfb deletion was also unable to prevent retinal ganglion cell or axon loss 30 days after IOP induction in mice. Conclusion: The alternative complement component FB may not substantially contribute to RGC loss in the HAGM mouse glaucoma model despite upregulation of Cfb expression and activation of the alternative pathway. The relevance of these findings to human glaucoma remains to be determined.
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Factor B del Complemento , Modelos Animales de Enfermedad , Glaucoma , Ratones Endogámicos C57BL , Animales , Glaucoma/prevención & control , Glaucoma/genética , Glaucoma/patología , Humanos , Ratones , Factor B del Complemento/genética , Factor B del Complemento/metabolismo , Presión Intraocular/efectos de los fármacos , Ratones Noqueados , ARN Mensajero/metabolismo , ARN Mensajero/genética , Masculino , Femenino , Hipertensión Ocular/prevención & control , Ácido HialurónicoRESUMEN
BACKGROUND: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). CONCLUSION: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.