O-GlcNAcylation & mechanism of action of OGA inhibitors
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-acetyl-glucosamine (GlcNAc) sugar units. O-GlcNAc transferase (OGT) catalyzes the addition of GlcNAc, while O-GlcNAcase (OGA) catalyzes its removal.
Normal O-GlcNAc (healthy neuron)
The maintenance of brain O-GlcNAcylation is required for neuronal function, and a fall in O-GlcNAc below a critical threshold triggers both neurodegeneration and neuroinflammation. Deficient levels of brain O-GlcNAc have been documented across preclinical models of neurodegeneration and human neurodegenerative diseases, suggesting increasing O-GlcNAc may be beneficial.
In the brain, O-GlcNAcylation substantially slows the formation of toxic aggregates of the microtubule-associated protein tau and α-synuclein, modifies synaptic and ion channel proteins impacting motor and behavioral brain circuits, and modulates harmful neuroinflammation.
Clinical Development Indications
The multi-modal mechanism of action of OGA inhibitors opens symptomatic and disease-modifying indications for clinical development. Since OGA inhibitors appear to 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 across 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.
Normal O-GlcNAc on the left, Low O-GlcNAc on the right
(Picture created with BioRender.com)
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. Asceneuron leverages fluid, imaging, and digital biomarkers to monitor the treatment of patients with OGA inhibitors.
Our pipeline of innovative small molecules has the potential to halt and prevent neurodegeneration in certain brain diseases.