Glucocerebrosidase Activators as a Treatment for Gaucher Disease

This technology is a collection of small molecule activators of a genetically defective version of the enzyme called glucocerebrosidase (GCase), which causes Gaucher disease. Gaucher disease is a rare disease affecting 1 in 40,000 babies born. Ashkenazi Jews of eastern European descent (about 1 in 800 live births) are at particular risk of carrying this genetic defect. It is caused by inherited genetic mutations in the gene that encodes GCase, which result in reduced activity of the enzyme. This enzyme is normally made and then transported to an organelle called a lysosome, which is dedicated to the degradation and disposal of molecules the cell no longer needs. GCase is responsible for the breakdown of a fatty material called glucocerebroside (or glucosylceramide). The accumulation of this lipid occurs inside specific cells called macrophages and macrophage-derived cells. The disease has been categorized into three types: neuronopathic (types 2, 3) and non-neuronopathic (type 1) with mild to severe symptoms that can appear at anytime from infancy to adulthood. Clinical manifestations can include an enlarged spleen and liver, anemia, decreased platelets, bone disease and neurodegeneration, with varying severity depending on the type of disease and time of diagnosis. The deficient GCase activity has been attributed to insufficient GCase enzyme in the lysosome. After production in the endoplasmic reticulum (ER), defective GCase does not fold properly and is therefore degraded in the ER and not transported to the lysosome where it would hydrolyze glucocerebroside. The small molecule activators may act by increasing the concentration of GCase that reaches the lysosome by facilitating the proper folding of GCase so that it can be released from the ER and transported to lysosomes. Thus, these small molecules could be acting like “chaperones,” because they facilitate proper folding which results in some active enzyme. Prior failed attempts to use small molecule chaperones to improve GCase folding and transport were made with inhibitors of GCase, which ironically properly folded active GCase that was subsequently transported to the lysosome, but the molecule also inhibited the GCase so that it could not break down glucocerebroside. On the other hand, these proposed small molecules were screened for their ability to activate defective GCase in the presence of a fluorogenic mimic of glucocerebroside, and their ability to facilitate translocation of defective GCase to lysosomes as well. This creates the opportunity to induce proper folding, while avoiding inhibition of enzyme function.