title: 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.
authors.affiliation: The Mount Sinai Bone Program, Mount Sinai School of Medicine, NY, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Yuen
authors.forename: Jameel
authors.initials: J
authors.lastname: Iqbal
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Zhu
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Aiping
authors.initials: A
authors.lastname: Lin
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mistry
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
mesh_terms: D015766:Albendazole / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods*; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000379:methods*; D005776:Gaucher Disease / Q000188:drug therapy* / Q000235:genetics*; D017353:Gene Deletion; D023281:Genomics / Q000379:methods*; D005962:Glucosylceramidase / Q000172:deficiency* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010073:Oxamniquine / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism
chemical_list: D000871:Anthelmintics; D010073:Oxamniquine; D005962:Glucosylceramidase; D015766:Albendazole