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Disease-drug pairs revealed by computational genomic connectivity mapping on GBA1 deficient, Gaucher disease mice.

ABSTRACT: We have reported that, in addition to recapitulating the classical human Gaucher disease (GD1) phenotype, deletion of the glucocerebrosidase (GBA1) gene in mice results in the dysfunction of a diverse population of immune cells. Most of immune-related, non-classical features of GD1, including gammopathies and autoimmune diathesis, are resistant to macrophage-directed therapies. This has prompted a search for newer agents for human GD1. Here, we used high-density microarray on splenic and liver cells from affected GBA1(-/-) mice to establish a gene "signature", which was then utilized to interrogate the Broad Institute database, CMAP. Computational connectivity mapping of disease and drug pairs through CMAP revealed several highly enriched, non-null, mimic and anti-mimic hits. Most notably, two compounds with anti-helminthic properties, namely albendazole and oxamniquine, were identified; these are particularly relevant for future testing as the expression of chitinases is enhanced in GD1.

SUBMITTER: Yuen T

PROVIDER: S-EPMC3377787 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Disease-drug pairs revealed by computational genomic connectivity mapping on GBA1 deficient, Gaucher disease mice.

Yuen Tony T Iqbal Jameel J Zhu Ling-Ling LL Sun Li L Lin Aiping A Zhao Hongyu H Liu Jun J Mistry Pramod K PK Zaidi Mone M

Biochemical and biophysical research communications 20120512 4

We have reported that, in addition to recapitulating the classical human Gaucher disease (GD1) phenotype, deletion of the glucocerebrosidase (GBA1) gene in mice results in the dysfunction of a diverse population of immune cells. Most of immune-related, non-classical features of GD1, including gammopathies and autoimmune diathesis, are resistant to macrophage-directed therapies. This has prompted a search for newer agents for human GD1. Here, we used high-density microarray on splenic and liver c ...[more]

PMID: 22588172

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Project description:In non-neuronopathic type 1 Gaucher disease (GD1) mutations in GBA1 gene results in deficiency of glucocerebrosidase and the accumulation of glucocerebroside in lysosomes of mononuclear phagocytes. The metabolic defect leads to a complex phenotype involving the viscera, the bone marrow and the skeleton. However the prevailing macrophage-centric view of the disease does not explain emerging aspects of the disease such as hematological malignancies, autoimmune diathesis, ParkinsonM-bM-^@M-^Ys disease and osteoporosis poorly responsive to macrophage targeted enzyme therapy or anti-resorptive therapies. We developed a conditional KO mouse model of GD1 to delineate cells and pathways in GD1. By targeting the cells of the hematopoetic and mesenchymal cell lineages through an Mx1 promoter, we recapitulated human GD1. We show that, in addition to significant visceral and hematologic disease, GD1 mice show profound osteopenia due to a bone formation defect. Cytokine measurements, microarray analysis and cellular immunophenotyping together point to widespread dysfunction of macrophages and other immune cells together with a striking abnormality in thymic T-cell development. Our study provides the first direct evidence for the involvement of cell lineages other than mononuclear phagocytes, most notably osteoblasts and T cells, in the pathophysiology of the clinical spectrum of type 1 GD. These findings have important implications for treatment of GD1. We hypothesize that regulation of gene expression is different in Gaucher disease compared with the normal controls. This difference may even be evident in the different stages of this disease. In order to gain insight to the genes that are potentially involved in the development of Gaucher disease in its different clinical stages, exon-array is chosen for this genome-wide association studies. Mouse liver and spleen samples from normal control, GD with moderate to severe splenomegaly/hepatomegaly, together nine samples were chosen. The goal is to find out genes of which the expression may relate to the GD or the severity of GD and thus help identify genetic modifier genes that may contribute to the onset and development of Gaucher disease.

Dataset Information

Disease-drug pairs revealed by computational genomic connectivity mapping on GBA1 deficient, Gaucher disease mice.

Publications

Disease-drug pairs revealed by computational genomic connectivity mapping on GBA1 deficient, Gaucher disease mice.

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