Exosomal STK39 is a Predictive Biomarker for Anti-VEGF Treatment Response in Neovascular Age-Related Macular Degeneration
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PROVIDER: PRJNA1226192 | ENA |
REPOSITORIES: ENA
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Project description:Background: Age-related macular degeneration (AMD) is the leading cause of blindness worldwide, predominantly affecting individuals over 60. AMD is classified into two clinical forms: dry (DAMD) and neovascular (NAMD). NAMD, characterized by choroidal neovascularization and increased vascular endothelial growth factor (VEGF) levels, is treated with anti-VEGF therapy, the gold standard for preventing vision loss. However, challenges including non-response to treatment, persistent disease activity, and unnecessary anti-VEGF administration necessitate the identification of predictive biomarkers to optimize therapy. Exosomes (exo) are extracellular vesicles known for their stability and role in cellular communication, carrying diverse molecular contents, including RNA. Although the role of exo-RNA in AMD pathogenesis is well known, their role in the response to anti-VEGF treatment has not yet been investigated. Current study aim to investigate the role of exo-RNAs as potential biomarkers for predicting anti-VEGF treatment response in NAMD patients. Methods: Plasma-derived exo-RNA were analyzed pre- and post-treatment to identify predictive biomarkers from 41 NAMD patients treated with intravitreal bevacizumab. Exo were isolated using exoRNAeasy midi kit and characterized by TEM, NTA, and Western blot. Then, RNA-seq was performed to profile exo-RNAs and key candidates were validated using RT-qPCR. Results: Following anti-VEGF therapy, 68.3% of NAMD patients (mean age: 70.8 ± 6.14), demonstrated anatomical success, while 53.7% achieved functional success. Based on RNA-seq comparative analysis between the two groups revealed that translation mechanisms were significantly regulated, particularly within the context of upregulated pathways. Genes associated with molecular functions such as insulin response, transport, angiogenesis, and oxygen transport were prominently implicated. Conversely, the evaluation of downregulated pathways indicated substantial alterations in RNA catabolic processes and the regulation of gene expression. RNA-seq revealed BMP6 and STK39 as key candidate genes, with post-treatment dysregulation in hsa-miR-4692 expression, a microRNA targeting STK39. Finally, RT-qPCR validation show that elevated pre-treatment exo-STK39 levels were significantly associated with anatomical success (*p=0.04).
2025-05-13 | GSE290090 | GEO
Project description:The standard treatment for neovascular age-related macular degeneration (nAMD) consists of intravitreal anti-vascular endothelial growth factors (VEGF). However, for some patients, even maximal anti-VEGF treatment does notentirely suppress exudative activity. The goal of this study was to identify molecular biomarkers in nAMD with incomplete response to anti-VEGF treatment. Aqueous humor (AH) samples were collected from three groups of patients: 18 patients with nAMD responding incompletely to anti-VEGF, 19 patients affected by nAMD with normal treatment response, and 14 control patients without any retinopathy. Proteomic and multiplex analyses were performed on these samples. Proteomic analyses showed that nAMD patients with incomplete anti-VEGF response displayed an increased inflammatory response, complement activation, cytolysis, protein-lipid complex, and vasculature development pathways. Multiplex analyses revealed a significant increase of soluble vascular cell adhesion molecule-1 (sVCAM-1) [p=0.001], interleukin-6 (IL-6) [p=0.009], bioactive interleukin-12 (IL-12p40) [p=0.03], plasminogen activator inhibitor type 1 (PAI-1) [p=0.004], and hepatocyte growth factor (HGF)[p=0.004] levels in incomplete responders in comparison to normal treatment response. Interestingly, The same biomarkers showed a high intercorrelation with r2 values between 0.58 and 0.94. In addition, we confirmed by AlphaLISA the increase of sVCAM-1 [p<0.0001] and IL-6 [p=0.043] in incomplete responder group. Incomplete responders in nAMD are associated with activated angiogenic and inflammatory pathways. The residual exudative activity of nAMD despite maximal anti-VEGF treatment may be related to both angiogenic and inflammatory responses requiring specific adjuvant therapy.
2021-01-18 | PXD022471 | Pride
Project description:Mononuclear phagocytes (MPs), including monocytes and macrophages, play complex roles in the pathogenesis of age-related macular degeneration (AMD). We aimed to perform global transcriptome analysis on monocytes from AMD patients to obtain additional insight to the role of MPs in AMD. Peripheral blood was taken from treatment-naïve neovascular AMD (nvAMD) patients (n=14), and age-matched controls (n=15). Peripheral blood mononuclear cells (PBMCs) were separated and monocytes were isolated via negative selection. Gene expression was evaluated with Affymetrix Gene1.0 ST microarrays. Statistical/bioinformatics analysis was performed using open sourceware programs.
2017-02-10 | GSE76237 | GEO
Project description:Subretinal fibrosis permanently impairs the vision of patients with neovascular age-related macular degeneration. Despite emerging evidence revealing the association between disturbed metabolism in retinal pigment epithelium (RPE) and subretinal fibrosis, the underlying mechanism remains unclear. In the present study, single-cell RNA sequencing revealed, prior to subretinal fibrosis, genes in mitochondrial fatty acid oxidation are downregulated in the RPE lacking very low-density lipoprotein receptor (VLDLR), especially the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). We found that overexpression of CPT1A in the RPE of Vldlr-/- mice suppresses epithelial-to-mesenchymal transition and fibrosis. Mechanistically, TGFβ2 induces fibrosis by activating a Warburg-like effect, i.e. increased glycolysis and decreased mitochondrial respiration through ERK-dependent CPT1A degradation. Moreover, VLDLR blocks the formation of the TGFβ receptor I/II complex by interacting with unglycosylated TGFβ receptor II. In conclusion, VLDLR suppresses fibrosis by attenuating TGFβ2-induced metabolic reprogramming, and CPT1A is a potential target for treating subretinal fibrosis.
2024-08-08 | GSE221952 | GEO
Project description:Visual outcome of patients with neovascular age-related macular degeneration has significantly improved during the last years as a result of anti-VEGF therapy. However, some patients show persistent exudation and decreasing visual acuity despite recurrent anti-VEGF injections, indicating a role of other proangiogenic mediators. The present study applied transcriptional profiling of human and mouse CNV membranes each with reference to healthy control tissue to identify novel mediators of CNV. Following this approach, the study identifies Fibroblast growth factor induci-ble-14 (FN14) as a novel phylogenetically conserved mediator of CNV. Blocking the pathway by intravitreal injection of an FN14 decoy receptor modulates the cytokine profile - most notably IL-6 - and leads to a significant and IL-6 mediated reduction of CNV size in vivo. These results identify FN14 as a promising new therapeutic target for neovascular AMD, which may potentially be beneficial in patients with exudative AMD with special regard to anti-VEGF resistant cases.
2022-06-30 | GSE163090 | GEO
Project description:To investigate a potential therapeutic effect of ABTAA on NV-AMD, we employed a mouse model of laser-induced CNV, that mimics human NV-AMD. A laser photocoagulation on mouse retinas was performed to rupture RPE and Bruch’s membrane, and then the effects of ABTAA were compared with those of VEGF-Trap.
2018-10-01 | GSE88730 | GEO
Project description:Impaired RPE Mitochondrial Energetics Leads Subretinal Fibrosis in Neovascular Age-related Macular Degeneration
| PRJNA916923 | ENA
Project description:Although genome-wide association studies, animal models, and cell culture systems have yielded important insights into the pathogenesis of neovascular age-related macular degeneration (nAMD), the underlying molecular pathways remain ill defined. Recent studies have deciphered the transcriptional profile of choroidal neovascularisation (CNV) of body donor eyes and were thus limited by the time span from death to preservation and the associated rapid 5'-RNA degradation. In this study, CNVs were therefore formalin-fixed immediately after surgical extraction from patients with nAMD and analyzed using a 3’ RNA sequencing approach called Massive Analysis of cDNA Ends (MACE). Age-matched formalin-fixed paraffin-embedded (FFPE) RPE-choroidal specimens obtained from the macular region of enucleated eyes with ciliary body melanoma served as controls. Transcriptome profiles were generated and disease-associated gene signatures were identified using statistical and bioinformatic methods. Calprotectin (S100A8/A9) protein expression was investigated by immunohistochemistry and ELISA.We identified 158 differentially-expressed genes (DEG) that were significantly increased in CNV compared to control tissue. Gene ontology enrichment analysis demonstrated that these DEG contributed to biological processes, such as Blood Vessel Development, Extracellular Structure Organization, Response to Wounding and several immune-related terms. The S100 calcium-binding protein A8 (S100A8) and S100A9 emerged among the top DEG, as confirmed by immunohistochemistry on CNV tissue and protein analysis of vitreous samples from nAMD patients and controls. This study provides a high-resolution RNA-sequencing-based transcriptional signature of choroidal neovascular membranes in AMD patients and reveals S100A8/A9 as a novel biomarker and promising target for AMD-directed therapeutics and diagnostics.
2020-04-09 | GSE146887 | GEO
Project description:Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population associated with focal inflammation, however, understanding of the precise immune components governing this process is still limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions. O-link analysis and single-cell RNA sequencing approaches identified CCR5-expressing NK cells is essential for further NK cell recruitment and extravasation in CNV site. NK cells suppress pathological angiogenesis via through clearance of senescent vasculatures, a process that requires neutrophil extracellular traps (NETs). Mechanistically, the release of NETs results from NKG2D-dependent NK cell activation and production of IFN-γ at CNV lesions. Notably , age is the strongest risk factor for AMD to an aged immune system; our human and mouse data showed that aged NK cells exhibited compromised protective effects. Additionally, expansion of NK cells by IL-2 complex improved CNV formation. Collectively, our results revealed a previously unrecognized role of NK cells in suppressing nvAMD progression, suggesting these cells as a potential target for future immune therapies for patients with nvAMD.
2024-10-31 | GSE271038 | GEO
Project description:Neovascular age-related macular degeneration (nAMD) remains a major cause of visual impairment and puts considerable burden on patients and health care systems. L-DOPA-treated Parkinson Disease (PD) patients have been shown to be partially protected from nAMD, but the mechanism remains unknown. Using murine models combining 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and laser-induced nAMD, standard PD treatment of L-DOPA/DOPA-decarboxylase inhibitor, or specific dopamine receptor inhibitors, we here demonstrate that L-DOPA treatment-induced increase of dopamine receptor D2 (DRD2) signaling inhibits choroidal neovascularization independently of MPTP-associated nigrostriatal pathway lesion. Analyzing a retrospective cohort of more than two hundred thousand nAMD patients receiving anti-VEGF treatment from the French nationwide insurance database, we show that DRD2-agonist treated (PD) patients have a significantly delayed age of onset for nAMD (81.4 (±7.0) vs 79.4 (±8.1) years old, respectively, p<0.0001) and reduced need for anti-VEGF therapies (-0.6 injections per 100 mg/day daily dose of DRD2 agonists the second year of treatment), similar to the L-DOPA treatment. While providing a mechanistic explanation for an intriguing epidemiological observation, our findings suggest that systemic DRD2 agonists might constitute an adjuvant therapy to delay and reduce the need for anti-VEGF therapy in nAMD patients.
2024-09-13 | GSE266525 | GEO