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Differential Molecular Effects of Imiglucerase and Velaglucerase Alfa in Gaucher Disease Mice [Affymetrix]

ABSTRACT: Gaucher disease type 1 is an inborn error of metabolic disease with the defective activity of the lysosomal enzyme acid b-glucosidase (GCase). Enzyme replacement/reconstitution therapy (ERT), infusions with purified recombinant GCases, is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations in Gaucher type 1 patients. However, the tissue specific molecular events in Gaucher disease and their response to therapy are not known yet. To explore the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela). Using microarray and mRNA-Seq techniques, differentially expressed genes (DEGs) were identified in the spleen and liver by the direct comparison of imig- vs. vela-treated mice. Among them three gene expression networks were derived from these spleens: 1) cell division/proliferation, 2) hematopoietic system and 3) inflammatory/macrophage response. Our study showed the occurrence of differential molecular pathophysiologic processes in the mice treated with imig compared with vela even though these two biosimilars had the same histological and biochemical efficacy 9V/null mice (Gaucher mouse model) were injected weekly via tail vein with 60U/kg/wk of imig or vela for 8 wks and were sacrificed one week after the injection for RNA isolation from different tissues like liver, lung and spleen.

ORGANISM(S): Mus musculus

SUBMITTER: nupur dasgupta

PROVIDER: E-GEOD-44569 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Differential Molecular Effects of Imiglucerase and Velaglucerase Alfa in Gaucher Disease Mice [RNA-Seq]

Project description:Gaucher disease type 1 is an inborn error of metabolic disease with the defective activity of the lysosomal enzyme acid b-glucosidase (GCase). Enzyme replacement/reconstitution therapy (ERT), infusions with purified recombinant GCases, is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations in Gaucher type 1 patients. However, the tissue specific molecular events in Gaucher disease and their response to therapy are not known yet. To explore the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela). Using microarray and mRNA-Seq techniques, differentially expressed genes (DEGs) were identified in the spleen and liver by the direct comparison of imig- vs. vela- treated mice. Among them three gene expression networks were derived from these spleens: 1) cell division/proliferation, 2) hematopoietic system and 3) inflammatory/macrophage response. Our study showed the occurrence of differential molecular pathophysiologic processes in the mice treated with imig compared with vela even though these two biosimilars had the same histological and biochemical efficacy 9V/null mice (Gaucher mouse model) were injected weekly via tail vein with 60U/kg/wk of imig or vela for 8 wks. To understand the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela).

2013-09-07 | E-GEOD-44640 | biostudies-arrayexpress

Gaucher Disease: Transcriptome Analyses Using Microarray or mRNA Sequencing in a Mouse Model Treated with velaglucerase alfa or imiglucerase [RNA-Seq]

Project description:The comparative whole genome transcriptome effects of two similar pharmaceuticals, imig or vela, on a Gaucher disease mouse model, 9V/null, were evaluated by two commonly used platforms, mRNA-Seq and microarray. Also, statistical methods, DESeq and edgeR for mRNA-Seq and Mixed Model ANOVA for microarray, were compared for differential gene expression detection. The biological pathways were similar between two platforms. Cell growth and proliferation, cell cycle, heme metabolism, and mitochondrial dysfunction were the most altered functions associated with the disease process. Although the two biopharmaceuticals have a very similar structure and function, imig- and vela- treatment in the mice differentially affected disease-specific pathways indicating the action of the two drugs on the disease process in the visceral tissues of Gaucher mouse model differ significantly at the molecular level. This study provides a comprehensive comparison between the two platforms (mRNA-Seq and microarray) for gene expression analysis and addresses the contribution of the different methods involved in the analysis of such data. The results also provide insights into the differential molecular effects of two similar biopharmaceuticals for Gaucher disease treatment 9V/null mice (Gaucher mouse model) were injected weekly via tail vein with 60U/kg/wk of imig or vela for 8 wks. Control 9V/null mice were injected with same volume of saline. Wt mice were untreated. Age and strain matched mice were used for the study. Also, statistical methods, DESeq and edgeR for mRNA-Seq and Mixed Model ANOVA for microarray, were compared for differential gene expression detection. Cell growth and proliferation, cell cycle, heme metabolism, and mitochondrial dysfunction were the most altered functions associated with the disease process. The results also provide insights into the differential molecular effects of two similar biopharmaceuticals for Gaucher disease treatment.

2013-09-07 | E-GEOD-44674 | biostudies-arrayexpress

Gaucher Disease: Transcriptome Analyses Using Microarray or mRNA Sequencing in a Mouse Model Treated with velaglucerase alfa or imiglucerase [Affymetrix]

Project description:The comparative whole genome transcriptome effects of two similar pharmaceuticals, imig or vela, on a Gaucher disease mouse model, 9V/null, were evaluated by two commonly used platforms, mRNA-Seq and microarray. Also, statistical methods, DESeq and edgeR for mRNA-Seq and Mixed Model ANOVA for microarray, were compared for differential gene expression detection. The biological pathways were similar between two platforms. Cell growth and proliferation, cell cycle, heme metabolism, and mitochondrial dysfunction were the most altered functions associated with the disease process. Although the two biopharmaceuticals have a very similar structure and function, imig- and vela- treatment in the mice differentially affected disease-specific pathways indicating the action of the two drugs on the disease process in the visceral tissues of Gaucher mouse model differ significantly at the molecular level. This study provides a comprehensive comparison between the two platforms (mRNA-Seq and microarray) for gene expression analysis and addresses the contribution of the different methods involved in the analysis of such data. The results also provide insights into the differential molecular effects of two similar biopharmaceuticals for Gaucher disease treatment. 9V/null mice (Gaucher mouse model) were injected weekly via tail vein with 60U/kg/wk of imig or vela for 8 wks. Control 9V/null mice were injected with same volume of saline. Wt mice were untreated. Age and strain matched mice were used for the study. Also, statistical methods, DESeq and edgeR for mRNA-Seq and Mixed Model ANOVA for microarray, were compared for differential gene expression detection.Cell growth and proliferation, cell cycle, heme metabolism, and mitochondrial dysfunction were the most altered functions associated with the disease process. The results also provide insights into the differential molecular effects of two similar biopharmaceuticals for Gaucher disease treatment.

2013-09-07 | E-GEOD-44647 | biostudies-arrayexpress

Differential Molecular Effects of Imiglucerase and Velaglucerase Alfa in Gaucher Disease Mice [RNA-Seq]

2013-09-07 | GSE44640 | GEO

Differential Molecular Effects of Imiglucerase and Velaglucerase Alfa in Gaucher Disease Mice [Affymetrix]

Project description:Gaucher disease type 1 is an inborn error of metabolic disease with the defective activity of the lysosomal enzyme acid b-glucosidase (GCase). Enzyme replacement/reconstitution therapy (ERT), infusions with purified recombinant GCases, is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations in Gaucher type 1 patients. However, the tissue specific molecular events in Gaucher disease and their response to therapy are not known yet. To explore the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela). Using microarray and mRNA-Seq techniques, differentially expressed genes (DEGs) were identified in the spleen and liver by the direct comparison of imig- vs. vela-treated mice. Among them three gene expression networks were derived from these spleens: 1) cell division/proliferation, 2) hematopoietic system and 3) inflammatory/macrophage response. Our study showed the occurrence of differential molecular pathophysiologic processes in the mice treated with imig compared with vela even though these two biosimilars had the same histological and biochemical efficacy

2013-09-07 | GSE44569 | GEO

Global gene expression profiles and the progression of pro- and anti-inflammatory pathways in mouse models

Project description:Gaucher Disease (GD) is caused by defective glucocerebrosidase (GCase) activity and the consequent accumulation of its substrate, glucosylceramide (GC). This excess of accumulation of GC leads to broad functional impairments in multiple organs, but the pathogenic pathways leading to lipid laden macrophages (Gaucher cells) in visceral organs and their abnormal function is obscure. To understand the molecular pathogenesis of GD, developmental global gene expression was conducted by microarray analyses of total mRNAs from lung and liver of two distinct GCase point-mutated mice (V394L/V394L and D409V/null) and genetic background matched wild-type controls. INFg regulated pro-inflammatory and IL-4 regulated anti-inflammatory cytokine/mediator network were constructed in the lung and liver of GCase mutant mice. Progressive alterations of the INFg and IL-4 pathways were similar, but to different degrees, in visceral tissues from the two different GCase mutated mice. These analyses implicate IFNg regulated pro-inflammatory and IL-4 regulated anti-inflammatory networks in the differential pathophysiological progression. In order to understand the molecular pathogenesis of GD, the disease progression in those models were inverstigated in two visceral tissues (lung and liver) at four time points according to the genotypes. 9V/null: 4 weeks (4w), 12 weeks (12w), 18 weeks (18w), 28 weeks (28w); 4L: weeks (4w), 12 weeks (12w), 18 weeks (18w), 28 weeks (28w). The data from those models were analyzed relative to the adult wild type at 28 weeks.

2011-08-01 | E-GEOD-23408 | biostudies-arrayexpress

Gaucher Disease: Transcriptome Analyses Using Microarray or mRNA Sequencing in a Mouse Model Treated with velaglucerase alfa or imiglucerase

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-09-07 | E-GEOD-44675 | biostudies-arrayexpress

Differential Molecular Effects of Imiglucerase and Velaglucerase Alfa in Gaucher Disease Mice

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-09-07 | E-GEOD-44641 | biostudies-arrayexpress

Single cell analysis of iPSC-derived midbrain organoids (GBA1 mutant and controls)

Project description:Mutations in the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher´s disease, are the most frequent genetic risk factor for Parkinson’s disease (PD). Here, we employed single-cell genomic approaches in induced pluripotent stem cell (iPSC)-derived midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration.

2023-03-06 | GSE198033 | GEO

GBA1 regulates the CLEAR network through Calcineurin and TFEB in cellular models of Parkinson´s disease

Project description:The GBA1 gene encodes the lysosomal enzyme acid-β-glucocerebrosidase (GCase). GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD) and are a genetic risk factor for Parkinson´s disease (PD). Many GBA1 mutations cause aberrant GCase folding and processing but how these impinge on PD pathogenesis remains unclear. We addressed GCase functions in human dopaminergic (DA) neurons derived from engineered GBA1-deficient (GBA1-/-) embryonic stem cells (hESCs) and GBA1N370S PD patient-derived induced pluripotent cells (hiPSCs). GBA1-mutant DA neurons displayed aberrant morphologies and gene expression that were rescued by recombinant GCase treatment. GBA1-/- neurons have hyperactive Calcineurin (CaN) and nuclear localization of the Transcription Factor EB (TFEB). Expression of TFEB targets and lysosomal CLEAR network components were increased in GBA1-/- DA neurons and rescued by GCase replacement and CaN inhibition. Our findings reveal a link between increased CaN activity and loss of GCase, providing a mechanism for the disturbed lysosomal/autophagy pathways in GBA1-associated PD.

2022-12-31 | GSE118511 | GEO

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