The development of a macrophage model of Gaucher disease for testing new small molecular therapies

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NHGRI	CLIN/TRANS-3

* FARE Award Winner

Authors

• E. Aflaki
• B.K. Stubblefield
• G. Lopez
• E. Maniwang
• N. Tayebi
• J. Marugan
• E. Sidransky

Abstract

Gaucher disease (GD), as lysosomal storage disorder, is caused by mutations in the gene encoding glucocerebrosidase. GD is characterized by the accumulation of glucosylceramide (GlcCer)-laden macrophages. Enzyme replacement therapy currently used to treat GD, which does not cross the blood-brain barrier. Chemical chaperone therapy is an alternative treatment strategy; small molecules bind to misfolded proteins and facilitate trafficking of the enzyme to the lysosome. High throughput screening of large compound libraries led to the identification of a novel lead glucocerebrosidase (GCase) activator, NCGC00188758. We studied macrophages from patients with type 1 GD and iPS-macrophage from type 2 GD, we show accumulation of GluCer, not seen in control macrophages. Upon treatment with the NCGC00188758, GCase activity in human Gaucher macrophages (GMac) and iPS-macrophage increased eight-fold. Moreover, NCGC00188758 specifically reduced GlcCer storage in human and iPS- GMac. The effect of the chaperone on macrophage function was evaluated by testing phagocytosis and efferocytosis. Following the expression of FcgammaRI/II in GMac, we found that the high phagocytic index and lower efferocytic index seen in GMac reversed to basal level after treatment with NCGC00188758. Thus human and iPSC macrophage models and new lead compound demonstrate great promise for the development of new therapies for GD.

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