Multimodal Mechanism of Action
O-GlcNAcylation is a dynamic post-translational glycosylation that occurs on intracellular proteins at serine and threonine residues. O-GlcNAcylation is characterized by the presence of single N-acetylglucosamine (GlcNAc) sugar units. O-GlcNAc transferase (OGT) catalyzes the addition of GlcNAc, while O-GlcNAcase (OGA) catalyzes its removal. The maintenance of brain O-GlcNAcylation is required for overall brain health, as a fall in O-GlcNAc below a critical threshold appears to trigger both neurodegeneration and neuroinflammation, with deficient O-GlcNAc having been documented across preclinical models and human neurodegenerative diseases.
In the brain, O-GlcNAcylation substantially slows the formation of toxic aggregates of the microtubule-associated protein tau and α-synuclein, modifies synaptic scaffolding and ion channel proteins impacting motor and behavioral brain circuits, and modulates harmful neuroinflammation.
Mechanism Informs Development of OGA Inhibitors
Normal O-GlcNAc on the left, Low O-GlcNAc on the right
(Picture created with BioRender.com)
Clinical Development Opportunities
The multi-modal mechanism of action of OGA inhibitors translates to both symptomatic and disease-modifying opportunities for clinical development. Since OGA inhibitors can protect tau and α-synuclein proteins from forming toxic species and aggregates, they offer the potential to slow disease progression in Alzheimer’s and Parkinson’s Disease as well as in rare diseases like Progressive Supranuclear Palsy (PSP). Co-pathology is common in neurodegenerative diseases, and so the broad effects of OGA inhibitors on both tau and α-synuclein pathologies offer a unique advantage over narrow therapeutic approaches for complex human diseases.
Since the effects of OGA inhibitors go beyond tau and α-synuclein to other CNS proteins, they also have the potential to produce symptomatic relief for clinical indications where there remains a large unmet medical need, including cognitive dysfunction, agitation, and sleep disorders. With their multi-modal mechanism of action, OGA inhibitors can be monitored during clinical development by tracking fluid, imaging, and digital biomarkers of disease modification and symptomatology.
Our pipeline of innovative small molecules has the potential to halt and prevent neurodegeneration in certain brain diseases.