Identification of Modulators of the N370S Mutant Form of Glucocerebrosidase as a Potential Therapy for Gaucher Disease

National Center For Advancing Translational Sciences

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Abstract

The project team has continued to develop and characterize small molecule modulators of glucocerebrosidase to serve as starting points for therapeutics for Gaucher's disease, which is currently only treatable through enzyme replacement therapy. We have made advancements in developing relevant cell-based assays to study the effect of the compounds in preventing lysosomal storage of glucosyl ceramides and other lipids in the lysosomes of patient-derived cells. The project team worked to design, optimize and miniaturize assays to monitor glucocerebrosidase, its functional activity, and accumulated lipids, specifically in the lysosome of disease cells derived from patients. These assays enable high-throughput screening of glucocerebrosidase activity to potentially discover and develop small molecule modulators of this important target.