N-Acetylglucosamine (GlcNAc) residues O-linked via a β-glycosidic linkage to serine and threonine residues of nuclear and cytoplasmic proteins (O-GlcNAc) is a conserved protein modification found in all multicellular eukaryotes. This reversible modification is regulated by two enzymes. O-GlcNAc transferase (OGT) acts to install O-GlcNAc whereas O-GlcNAcase (OGA) acts to remove this modification from proteins. The protein tau, which is centrally involved in the progression of Alzheimer’s Disease (AD), has been shown to be O-GlcNAc modified in humans and the brains of AD patients appear to have lower levels of this modification. Notably, abnormally hyperphosphorylated tau which clumped together to form neurofibrillary tangles in AD patients bear no O-GlcNAc. Alectos pioneered the development of potent and selective OGA inhibitors that are highly active in brain and showed inhibition of this enzyme target was well tolerated in preclinical models. Pharmacological blockade of OGA in multiple mouse AD models robustly increases global brain and tau O-GlcNAc levels, leading to reduced levels of hyperphosphorylated tau, decreased neurofibrillary tangles, and reduced neurodegeneration. In addition, it has also been shown that ɑ-synuclein protein, which is involved in progression of Parkinson’s disease (PD) is also O-GlcNAc modified. In mouse models of PD, OGA inhibition leads to reduced levels of ɑ-synuclein aggregates in brain, as well as reduced neurodegeneration. Alectos is developing novel OGA inhibitors as a disease-modifying strategy for AD, PD, progressive supranuclear palsy, and related neurodegenerative diseases.
The non-lysosomal glucosylceramidase GBA2 is a cytoplasmic enzyme that is abundant in brain and is involved in regulating cytosolic levels of the glycosphingolipid glucosylceramide (GlcCer). Inhibition of GBA2 is an emerging strategy to correct lysosomal dysfunction in neurodegenerative disease. Small-molecule GBA2 inhibitors have been shown to reduce lysosomal pH and to increase levels of the lysosomal proton pump vATPase, which is involved in maintaining the acidic pH required for lysosomal function. GBA2 blockade has also demonstrated efficacy in a range of transgenic models of lysosomal storage disease, including Niemann-Pick type C disease, Gaucher disease, Batten disease, Sandhoff disease, and mucolipidosis type IV. Beneficial effects in these models include reduced neurodegeneration, extended lifespan, reduced neuroinflammation, and reduced ɑ-synuclein aggregates in brain. GBA2 has also been validated as a safe, druggable target in humans. Alectos is developing first-in-class selective GBA2 inhibitors as disease-modifying therapeutics for Niemann-Pick type C disease, PD, and other neurodegenerative disorders where lysosomal dysfunction plays a central role.