Transcriptomic analysis of microglia 4 month old ML4 Fabry and control mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE112895 | GEO | 2019/01/01
REPOSITORIES: GEO
Similar Datasets
Project description:Recent studies in non-human model systems have shown therapeutic potential of modified mRNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the α-galactosidase (GLA) gene in a human cardiac model generated from induced-pluripotent stem cell-derived from two patients with Fabry disease. In line with the clinical phenotype, cardiomyocytes from Fabry patient’s induced pluripotent stem cells show accumulation of the glycosphinolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Further, the patient-specific cardiomyocytes have significant upregulation of lysosomal associated proteins. Upon modRNA treatment, a subset of lysosomal proteins were partially restored to wildtype levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA treated cardiomyocytes demonstrating that α-galactosidase enzymatic activity was restored. Together, our results validate the utility of patient IPSC-derived cardiomyocytes as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart.
2023-07-20 | PXD038361 | Pride
Project description:Transcriptomic analysis of microglia 4 month old ML4 Fabry and control mice
| PRJNA449393 | ENA
Project description:Fabry disease, an X-linked lysosomal storage disorder caused by galactosidase alpha (GLA) gene mutations, exhibits diverse clinical manifestations, and poses significant diagnostic challenges. Early diagnosis and treatment are crucial for improved patient outcomes, pressing the need for reliable biomarkers. In this study, we aimed to identify miRNA candidates as potential biomarkers for Fabry disease using the KingFisher™ automated isolation method and NanoString nCounter® miRNA detection assay. Clinical serum samples were collected from both healthy subjects and Fabry disease patients. RNA extraction from the samples was performed using the KingFisher™ automated isolation method with the MagMAX mirVana™ kit or manually using the Qiagen miRNeasy kit. The subsequent NanoString nCounter® miRNA detection assay showed consistent performance and no correlation between RNA input concentration and raw count, ensuring reliable and reproducible results. Interestingly, the detection range and highly differential miRNA between the control and disease groups were found to be distinct depending on the isolation method employed. Nevertheless, enrichment analysis of miRNA-targeting genes consistently revealed significant associations with angiogenesis pathways in both isolation methods. Additionally, our investigation into the impact of enzyme replacement therapy on miRNA expression indicated that some differential miRNAs may be sensitive to treatment. Our study provides valuable insights to identify miRNA biomarkers for Fabry disease. While different isolation methods yielded various detection ranges and highly differential miRNAs, the consistent association with angiogenesis pathways suggests their significance in disease progression. These findings lay the groundwork for further investigations and validation studies, ultimately leading to the development of non-invasive and reliable biomarkers to aid in early diagnosis and treatment monitoring for Fabry disease.
2024-09-30 | GSE275830 | GEO
Project description:Current therapies for Fabry disease are based on reversing intra-cellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement (ERT) or chaperone mediated stabilization, thereby alleviating lysosome dysfunction. However, the therapeutic effect in the regression of end-organ damage (ie. kidney damage) is limited. Ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not alter podocyte injury. A novel CRISPR-/CAS9-mediated -Galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptomic-based connectivity mapping and SILAC-based quantitative proteomics identified alpha-synuclein (SNCA) accumulation as a key event mediating podocyte injury.
2023-04-10 | GSE186258 | GEO
Project description:Fabry nephropathy (FN) is a rare disorder caused by mutations in the alpha-galactosidase A gene. In this study we aim at providing a framework allowing selection of biomarkers and drug-targets. Two independent Fabry Nephropathy cohorts (FA.NO and CH.RO) were subjected to RNAseq from archival kidney biopsies taken prior and up to 10 years of Enzyme Replacement Therapy. Four compartments were laser capture microdissected (glomeruli, proximal tubuli, distal tubuli and arteries). We found several pathways that were consistently altered and that these kidney compartments’ transcriptional landscapes can be leveraged in the search for drug-targets and biomarkers.
2023-07-17 | GSE178947 | GEO
Project description:Fabry nephropathy transcriptome
| PRJNA741535 | ENA
Project description:Kidney organoids in vitro model enabled identification of a novel mechanism that may be used for the treatment of Fabry disease.
2021-01-16 | GSE164941 | GEO
Project description:Current therapies for Fabry disease are based on reversing intra-cellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement (ERT) or chaperone mediated stabilization, thereby alleviating lysosome dysfunction. However, the therapeutic effect in the regression of end-organ damage (ie. kidney damage) is limited. Ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not alter podocyte injury. A novel CRISPR-/CAS9-mediated -Galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptomic-based connectivity mapping and SILAC-based quantitative proteomics identified alpha-synuclein (SNCA) accumulation as a key event mediating podocyte injury.
2023-07-20 | PXD029618 | Pride
Project description:Podocyte injury in Fabry nephropathy
| PRJNA773084 | ENA
Project description:Fabry disease (FD) is a rare metabolic disorder of X-linked lysosomal storage caused by mutations of the GLA gene that induce a deficiency in the activity of the enzyme α-galactosidase A (α-GalA). This deficiency leads to the lysosomal accumulation of globotriaosylsphingosine (lyso-GB3), resulting in multisystem involvement. Clinical heterogeneity, frequent inconclusive results in biochemical and genetic tests, and the lack of compensation between these markers and clinical evolution often represent a significant challenge in early diagnosis and in the evolutionary prediction of the disease. For this reason, we propose as the study's main objective the identification of new biomarkers of FD that help to understand in depth the disease’s pathophysiology and biomarkers that help to predict the clinical phenotype of the disease. For this purpose, we compared the plasma from 50 patients with FD and 50 healthy controls, matched by sex and age, by a quantitative mass spectrometry study (SWATH-MS). This study has managed to identify more than 30 proteins significantly differentially expressed between patients with FD and healthy controls, also stratifying the results according to sex. Furthermore, the comparative analysis between the predominant clinical phenotypes identifies differential proteomic profiles between the clinical manifestations. These results will help to deepen and discuss the presence of potential biomarkers that will increase the pathophysiological knowledge of FD and the heterogeneity in the presentation of clinical manifestations.
2024-04-23 | PXD045528 | Pride