OGA Inhibition: A disease-modifying strategy to treat neurodegenerative disease

Modulation of O-linked N-acetylglucosamine (O-GlcNAc) residues on proteins has emerged as a highly promising target for a range of neurodegenerative 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. This reversible modification is regulated by two enzymes. O-GlcNAc transferase (OGT) installs O-GlcNAc whereas O-GlcNAcase (OGA) removes this modification. Elevated O-GlcNAc levels hinder pathogenic aggregation of proteins. For example, tau protein forms aggregates in Alzheimer’s disease (AD), which is prevented by tau O-GlcNAcylation. Alectos pioneered the development of potent OGA inhibitors that are highly active in brain. Inhibition of OGA in mouse AD models increases brain and tau O-GlcNAc levels, leading to reduced levels of aggregated tau and reduced neurodegeneration. In addition, inhibition of OGA also decreases aggregation of ɑ-synuclein protein, which is involved in Parkinson’s disease (PD), and TDP-43, which is involved in frontotemporal dementia (FTD) and ALS. Notably, recent studies in mouse PD models show that OGA inhibition reduces levels of ɑ-synuclein aggregates in brain and also reduces neurodegeneration. Alectos is developing novel OGA inhibitors as a disease-modifying strategy for AD, PD, FTD, and related diseases.

GBA2 Inhibition: A novel strategy to enhance lysosomal activity in neurodegenerative disease

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, Niemann-Pick type C disease, and other neurodegenerative disorders where lysosomal dysfunction plays a central role.