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.