Our Science

Modulation of O-linked N-acetylglucosamine (O-GlcNAc) residues on proteins has emerged as a highly promising target for a range of chronic and acute neurological diseases.  Extensive independent validation of this target using both chemical and genetic methods has been established.  This conserved protein modification is found on nuclear and cytoplasmic proteins, including tau, TDP-43 and ɑ-synuclein protein. This reversible modification is regulated by two enzymes: O-GlcNAc transferase (OGT) installs O-GlcNAc whereas O-GlcNAcase (OGA) removes this modification; inhibition of OGA leads to increased protein O-GlcNAcylation. Elevated O-GlcNAc levels directly hinder pathogenic aggregation of proteins. Alectos pioneered the development of potent OGA inhibitors that are highly active in brain and OGA inhibitors have demonstrated efficacy in many neurodegenerative proteinopathy models, including those driven by tau, ɑ-synuclein, TDP-43, and amyloid. O-GlcNAcylation is also a promising therapeutic target for improving neuroprotection and recovery after stroke and other acute CNS injuries. It enhances stress tolerance through several mechanisms, including regulating calcium and redox homeostasis to protect against oxidative stress, preserving mitochondrial function and preventing harmful changes, and supporting the unfolded protein response (UPR) to manage ER stress. Additionally, O-GlcNAcylation reduces inflammation by inhibiting NF-κB signaling and boosts the expression of heat shock proteins, helping cells cope with stress. These combined effects make O-GlcNAcylation a vital adaptive response in promoting cell survival during acute stress in the brain and other high-energy organs such as the heart.  Alectos is developing novel OGA inhibitors as a disease-modifying strategy for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, as well as acute neurological conditions such as ischemic stroke and traumatic brain injury.

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 also has 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 Parkinson’s disease, Batten disease, and other neurodegenerative disorders where lysosomal dysfunction plays a central role.