A humanized therapeutic monoclonal anti-ASC antibody alleviates oxygen-induced retinopathy in mice
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PROVIDER: PRJNA1087306 | ENA |
REPOSITORIES: ENA
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Project description:This study was to test the efficacy of a humanized monoclonal antibody, IC100 for ASC, an apoptosis-associated speck-like protein containing a caspase recruitment domain that is pivotal in inflammasome assembly, in the prevention and treatment of an oxygen-induced retinopathy (OIR) mouse model.
2025-05-01 | GSE261490 | GEO
Project description:BackgroundRetinopathy of prematurity (ROP), which often presents with bronchopulmonary dysplasia (BPD), is among the most common morbidities affecting extremely premature infants and is a leading cause of severe vision impairment in children worldwide. Activations of the inflammasome cascade and microglia have been implicated in playing a role in the development of both ROP and BPD. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly. Utilizing mouse models of both oxygen-induced retinopathy (OIR) and BPD, this study was designed to test the hypothesis that hyperoxia induces ASC speck formation, which leads to microglial activation and retinopathy, and that inhibition of ASC speck formation by a humanized monoclonal antibody, IC100, directed against ASC, will ameliorate microglial activation and abnormal retinal vascular formation.MethodsWe first tested ASC speck formation in the retina of ASC-citrine reporter mice expressing ASC fusion protein with a C-terminal citrine (fluorescent GFP isoform) using a BPD model that causes both lung and eye injury by exposing newborn mice to room air (RA) or 85% O2 from postnatal day (P) 1 to P14. The retinas were dissected on P14 and retinal flat mounts were used to detect vascular endothelium with AF-594-conjugated isolectin B4 (IB4) and citrine-tagged ASC specks. To assess the effects of IC100 on an OIR model, newborn ASC citrine reporter mice and wildtype mice (C57BL/6 J) were exposed to RA from P1 to P6, then 75% O2 from P7 to P11, and then to RA from P12 to P18. At P12 mice were randomized to the following groups: RA with placebo PBS (RA-PBS), O2 with PBS (O2-PBS), O2 + IC100 intravitreal injection (O2-IC100-IVT), and O2 + IC100 intraperitoneal injection (O2-IC100-IP). Retinal vascularization was evaluated by flat mount staining with IB4. Microglial activation was detected by immunofluorescence staining for allograft inflammatory factor 1 (AIF-1) and CD206. Retinal structure was analyzed on H&E-stained sections, and function was analyzed by pattern electroretinography (PERG). RNA-sequencing (RNA-seq) of the retinas was performed to determine the transcriptional effects of IC100 treatment in OIR.ResultsASC specks were significantly increased in the retinas by hyperoxia exposure and colocalized with the abnormal vasculature in both BPD and OIR models, and this was associated with increased microglial activation. Treatment with IC100-IVT or IC100-IP significantly reduced vaso-obliteration and intravitreal neovascularization. IC100-IVT treatment also reduced retinal microglial activation, restored retinal structure, and improved retinal function. RNA-seq showed that IC100 treatment corrected the induction of genes associated with angiogenesis, leukocyte migration, and VEGF signaling caused by O2. IC100 also corrected the suppression of genes associated with cell junction assembly, neuron projection, and neuron recognition caused by O2.ConclusionThese data demonstrate the crucial role of ASC in the pathogenesis of OIR and the efficacy of a humanized therapeutic anti-ASC antibody in treating OIR mice. Thus, this anti-ASC antibody may potentially be considered in diseases associated with oxygen stresses and retinopathy, such as ROP.
| S-EPMC11303442 | biostudies-literature
Project description:Analysis of gene expression changes in oxygen-induced retinopathy mice treated intravitreally with inhibitors. oxygen-induced retinopathy(OIR)mice is one of the experimental systems that mimic retinal ischemic diseases. This model is widely used as an evaluation system for various surgical procedures.
2024-04-18 | GSE230668 | GEO
Project description:Schemic retinopathies such as diabetic retinopathy (DR) and retinopathy of prematurity (ROP), are the main causes of blindness in working age and pediatric populations in industrialized countries. It is estimated that close to 100 million individuals worldwide suffer from DR and 15 million preterm infants born each year are predisposed to ROP. Regrettably, relatively little is known of the cellular processes at play during late stages of pathological angiogenesis in these diseases and consequently current standards of care target all neovascularization. Oxygen-induced retinopathy (OIR) allows to reproduce experimentally in the mouse retina the pathological features observed in human pathological retina such as ischemic avascular regions as well as epi-retinal neovascularization. Using agnostic and orthogonal approaches, in our work we demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cell cycle arrest, resulting in cellular senescence. These findings combined with further genetic and pharmacological approaches provide mechanistic evidence supporting that targeting selectively senescent vessels in DR represents a potential treatment for neovascular retinal disease.
2021-02-22 | GSE158799 | GEO
Project description:RATIONALE: Monoclonal antibodies, such as maytansinoid DM4-conjugated humanized monoclonal antibody huC242, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them.
PURPOSE: This phase I trial is studying the side effects and best dose of maytansinoid DM4-conjugated humanized monoclonal antibody huC242 in treating patients with solid tumors that cannot be removed by surgery or have spread to other parts of the body.
| 2030868 | ecrin-mdr-crc
Project description:Comparative gene expression profiles of human retinal pericytes (HRMPC) and lipoaspirate derived mesenchymal stromal cells (adipose stromal cells, ASC) cultivated either in normal (1g/l) or high (4.5g/l) glucose medium to identify similarities and discrepancies and elucidate high glucose effects considering cell-based therapies in diabetic retinopathy. A hallmark of diabetic retinopathy is pericyte- dropout increased vascular permeability and progressive vascular occlusion. ASC and HRMVPC were cultured in NG or HG for 7 days. Then cells were trypsinized, washed and RNA isolated using Qiagen RNeasy mini Kit (Qiagen, Hilden, Germany). RNA quality was tested by capillary electrophoresis on an Agilent 2100 Bioanalyzer (Agilent) and high quality (RNA integrity values ≥ 9) was confirmed.
2020-05-26 | GSE144605 | GEO
Project description:We have recently demonstrated that the ectonucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) is upregulated in the heart after myocardial infarction (MI) and initiates an aberrant metabolic cascade that worsens cell death and heart repair. Genetic loss of function approaches demonstrated that animals deficient in ENPP1 exhibited enhanced heart repair and had significantly superior post MI heart function. Whether human ENPP1 protein can be therapeutically targeted after heart injury remains unknown. Here, we engineer a humanized monoclonal antibody targeting human ENPP1 (hENPP1mAb) and demonstrate high affinity and specificity of binding to the catalytic domain of human ENPP1. In mice, genetically engineered, to express the human ENPP1 ortholog instead of murine ENPP1 (humanized ENPP1 mice), we demonstrate that administration of hENPP1mAb significantly rescued post MI heart function compared to IgG injected animals. Using metabolomics, single nuclear transcriptomics, and cellular respiration assays, we demonstrate that administration of the hENPP1mAb induces organ wide metabolic and transcriptional reprogramming of the heart that enhances myocyte cellular respiration and decreases cell death and fibrosis in the infarcted heart. Biodistribution and safety studies with radiolabeled hENPP1mAb showed specific organ wide distribution without any organ toxicity. Finally, in humanized ENPP1 animals that have also been genetically engineered to exhibit antibody clearance kinetics similar to humans, we demonstrate that a single "shot" of the hENPP1mAb after MI is sufficient to rescue post infarct cardiac dysfunction. Taken together our observations provide proof of concept on how the human ectonucleotidase ENPP1 can be therapeutically targeted to prevent heart failure after MI.
2024-10-14 | GSE255826 | GEO
Project description:Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC’s role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knock-out mice in the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and delayed tumor onset. Premalignant lesions in cerebella of ASC-/-;ND2:SmoA1 mice displayed a striking decrease in number of ectopic progenitors. While proliferation rates decreased with ASC deletion, apoptosis and differentiation markers remained unchanged. Interestingly, ASC deficiency disrupted expression of genes in the TGF-ß pathway and increased the level of nuclear Smad3 in this medulloblastoma model. Together, these results demonstrate an unexpected requirement for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for anti-tumor therapy. reference x sample
2014-05-23 | E-GEOD-48682 | biostudies-arrayexpress
Project description:To explore the spatiotemporal regulation of ASC speck formation and inflammasome activation, we infected primary WT and Asc–/– bone marrow-derived macrophages (BMDMs) with the bacterium Francisella novicida to induce AIM2 inflammasome activation and then performed ASC IP-MS to identify proteins that interacted with ASC. We compared the IP products between WT BMDMs and Asc–/– BMDMs, and found that many proteins specifically interacted with ASC.
2024-05-29 | PXD052497 | Pride
Project description:A Humanized Monoclonal Antibody Targeting an Ectonucleotidase Rescues Heart Function after Myocardial Infarction
| PRJNA1076596 | ENA