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

To this end, the project team is developing small molecule modulators of glucocerebrosidase to help study cellular trafficking in these patients, and serve as starting points for therapeutics for Gaucher's disease, which is currently only treatable through enzyme replacement therapy. We are also developing physiologically relevant high throughput 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. Gaucher disease results due to a lack of activity of the lysosomal hydrolase, glucocerebrosidase. During this period, the project team worked to design, optimize and miniaturize assays to monitor glucocerebrosidase, its functional activity, and accumulated lipids, in the lysosome of disease cells derived from patients. These assays will enable high-throughput screening of glucocerebrosidase to potentially discover and develop small molecule modulators of this important target.