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 mouse tauopathy models robustly increases global brain and tau O-GlcNAc levels, leading to reduced levels of hyperphosphorylated tau, decreased neurofibrillary tangles, and reduced neurodegeneration. Alectos has partnered with Merck to develop OGA modulators as a disease modifying strategy for AD, Progressive Supranuclear Palsy, and related tauopathies.
Recently it has been shown that the most common genetic risk factor for development of Parkinson’s disease (PD) is loss of function mutations in the gene GBA1, which codes the enzyme glucocerebrosidase (GCase). This glycoside hydrolase cleaves the glycolipid termed glucocerebroside that is particularly abundant in the brain. Many PD patients carry mutations in GBA1 that impair the function of the resulting mutant GCase and, moreover, the overall PD patient population shows abnormally low levels of GCase in the central nervous system. Those patients having GBA1 mutations show a high incidence of parkinsonism and suffer from more severe symptoms. Animal models of PD that are deficient in GCase show similarly increased brain pathology. A link has been established between GCase deficiency and increased toxicity of the α-synuclein protein, which is a central driver of disease progression in PD. Recent data has emerged showing that genetic augmentation of GCase in the brain of preclinical PD models leads to reduced α-synuclein accumulation and delayed disease onset. Alectos is leveraging its deep expertise in carbohydrate processing enzymes to develop small molecules that can be used to increase GCase levels in brain as a disease modifying strategy to treat Parkinson’s Disease.