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Macrophage Models of Gaucher Disease for Evaluating Disease Pathogenesis and Candidate Drugs

Sci Transl Med 11 June 2014: 
Vol. 6, Issue 240, p. 240ra73 
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3008659

• RESEARCH ARTICLE

GAUCHER DISEASE

Macrophage Models of Gaucher Disease for Evaluating Disease Pathogenesis and Candidate Drugs

1. Elma Aflaki1, 
2. Barbara K. Stubblefield1, 
3. Emerson Maniwang1,
4. Grisel Lopez1, 
5. Nima Moaven1, 
6. Ehud Goldin1,*, 
7. Juan Marugan2,
8. Samarjit Patnaik2, 
9. Amalia Dutra3, 
10. Noel Southall2, 
11. Wei Zheng2,
12. Nahid Tayebi1 and 
13. Ellen Sidransky1,†

+Author Affiliations

1. ¹Section on Molecular Neurogenetics, Medical Genetics Branch, National Institutes of Health, Bethesda, MD 20892, USA.
2. ²National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
3. ³Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

+Author Notes

• ↵* Present address: SENS Research Foundation, 110 Pioneer Way, Mountain View, CA 94041, USA.

1. ↵†Corresponding author. E-mail: sidranse@mail.nih.gov

Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. Available cell lines modeling Gaucher disease do not demonstrate lysosomal storage of glycolipids; therefore, we set out to develop two macrophage models of Gaucher disease that exhibit appropriate substrate accumulation. We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candidate drugs for its treatment. We generated and characterized monocyte-derived macrophages from 20 patients carrying different Gaucher disease mutations. In addition, we created induced pluripotent stem cell (iPSC)–derived macrophages from five fibroblast lines taken from patients with type 1 or type 2 Gaucher disease. Macrophages derived from patient monocytes or iPSCs showed reduced glucocerebrosidase activity and increased storage of glucocerebroside and glucosylsphingosine in lysosomes. These macrophages showed efficient phagocytosis of bacteria but reduced production of intracellular reactive oxygen species and impaired chemotaxis. The disease phenotype was reversed with a noninhibitory small-molecule chaperone drug that enhanced glucocerebrosidase activity in the macrophages, reduced glycolipid storage, and normalized chemotaxis and production of reactive oxygen species. Macrophages differentiated from patient monocytes or patient-derived iPSCs provide cellular models that can be used to investigate disease pathogenesis and facilitate drug development.