Transcriptomic analysis of microglia 4 month old ML4 Fabry and control mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE112895 | GEO | 2019/01/01
REPOSITORIES: GEO
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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: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
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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: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
Project description:The clinical symptoms of Fabry disease are caused by progressive accumulation of unprocessed globotriaosylceramide metabolite within cells, inducing multiple organ damage. Enzyme replacement therapy (ERT) is the only strategy to restore enzymatic activity, but a reliable biomarker to assess treatment response does not exist. Here, we identify circulating miR-184 as a sensitive marker of response to ERT and of clinical outcome for cardiac and kidney involvement.
2021-11-06 | GSE162042 | GEO
Project description:<p>Mucolipidosis type IV (MLIV) is an autosomal recessive disorder typically characterized by severe psychomotor delay evident by the end of the first year of life and slowly progressive visual impairment during the first decade as a result of a combination of corneal clouding and retinal degeneration.</p> <p>The purpose of this research study is to look at the brain and eye in patients with mucolipidosis type IV (MLIV). MLIV is a lysosomal storage disease that primarily affects the brain and the eyes. The disease is caused by a defect in a gene called MCLON1 that makes a protein called mucolipin-1. Patients with MLIV do not make enough normal mucolipin. The disease begins early in life and the neurological problems seem to stabilize later in life. On the other hand, the eye abnormalities usually progresses over time. The exact course of the disease has not been determined, and until now, no study has addressed this question carefully.</p> <p>The research objectives are: <ol> <li>To learn about the natural history of cognitive function for individuals with mucolipidosis type IV.</li> <li>To measure brain volume over time in individuals with mucolipidosis type IV</li> </ol> </p> <p>This is an observational study of individuals with MLIV disorder. Those participating in this study will be evaluated annually for five years following a baseline visit.</p>
| phs001329 | dbGaP