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

During this period, 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 implemented a new approach to perform a cell-based high throughput screen to identify molecules that increase levels of the L444P variant of GBA1. We have also continued to develop and test fluorogenic probes that can report on lysosomal activity of GBA1. Additionally, molecular modeling studies and virtual screening have been performed to predict molecules that would function as non-inhibitory chaperones; activity of these compounds has been characterized in the high-thoroughput assay. Finally, we have continued to advance our capbililties for large scale production of iPSC derived cells that show disease relevant phenotypes.