New Macrophage Models of Gaucher Disease Offer New Tools for Drug Development

Abstract

Gaucher disease is an inherited enzyme deficiency resulting in the lysosomal accumulation of specific glycolipids in macrophages and, in some cases, neurons. While current treatments are effective at reducing this glycolipid storage in macrophages, they are expensive and ineffective in treating neurological manifestations of the disease, driving the search for novel therapeutics. Moreover, mutations in GBA1, the gene implicated in Gaucher disease, are an important risk factor for the development of Parkinson disease and related disorders, an association that has further heightened interest in Gaucher disease research. However, the development of therapeutic strategies has been hampered by a shortage of appropriate cellular models of Gaucher disease. We have generated two novel macrophage models of Gaucher disease, one through the differentiation of peripheral blood monocytes from patients with Gaucher disease and the other through the differentiation of induced pluripotent stem cells derived from patient fibroblasts. Both disease models demonstrate similar cellular phenotypes and exhibit extensive glycolipid storage when exposed to exogenous lipid sources such as erythrocyte membranes. Furthermore, we have used these models to confirm the efficacy of a novel small molecule in clearing glycolipid storage and restoring normal macrophage function. These results demonstrate the usefulness of these models in exploring new therapeutics for Gaucher disease and related disorders.