Project 462565

Despite extensive efforts, there is only one clinically approved small molecule therapeutic that can slow the progression of any neurodegenerative disease. This compound is known as miglustat, and it is used to treat the rare orphan lysosomal disease known as Niemann-Pick Type C (NPC). Unfortunately, this compound inhibits a range of enzymes, which makes it poorly tolerated by patients. This poor tolerability decreases patient compliance and limits using doses that could result in improved efficacy. In recent years it has emerged that miglustat also inhibits a cytosolic sugar processing enzyme known as GBA2. Data strongly suggests that the primary mode of action of miglustat in brain is most likely through inhibition of GBA2. Because miglustat has been shown to be effective in various preclinical mouse models of a range of diseases that are unified by malfunctioning of a cellular waste centre known as the lysosome, GBA2 inhibitors could emerge as being useful in a range of neurodegenerative disorders where lysosomal function is well known to be impaired. We aim to create effective GBA2 inhibitors that, unlike miglustat, are selective and have generally improved properties that would make them well suited for treating neurological diseases. We will validate these selective GBA2 inhibitors in models of a rare developmental disease that occurs in children for which there is no known treatment option. Collectively, this project will enable efficient exploitation of GBA2 as a therapeutic target and unlock its potential for treating neurological diseases.