Given the clinical failures of β-amyloid targeting drug candidates in Alzheimer’s disease (AD), there is an urgent need for alternative approaches. One of the key hallmarks of AD which is shared with a considerable number of neurodegenerative diseases (commonly referred to as tauopathies) is the intraneuronal accumulation of insoluble tau aggregates as neurofibrillary tangles (NFT). Since the progression of tau pathology correlates with the worsening of the clinical symptoms, it is conceivable that a drug that slows down the accumulation of tau can potentially modify disease progression and halt the cognitive decline. As a result, academic researchers and biopharmaceutical companies have moved their focus to drugs that can interfere with the progression of tau pathology.

The pathological mechanism by which tau aberrantly oligomerizes into toxic aggregates is believed to involve tau hyperphosphorylation, but is also affected by other post-translational modifications. One such modification is the addition of O-linked-N-acetylglucosamine (O‑GlcNAc) sugar moieties on tau by the glycosyltransferase O‑linked-N-acetylglucosaminyltransferase (OGT). O‑GlcNAcylation of tau is a dynamic process and the competing removal of O‑GlcNAc sugar moieties from tau is mediated by the glycoside hydrolase, O-linked-β-N-acetylglucosaminidase (O-GlcNAcase). Inhibition of O-GlcNAcase consequently results in an increase of the average number of O-GlcNAc sugar moieties attached to tau. It has been directly demonstrated that O-GlcNAc sugars when attached to tau prevent the deleterious aggregation of tau into toxic forms of the protein without disturbing the normal function of tau. Accordingly, we have developed the second-generation O-GlcNAcase inhibitor ASN121151 and this grant supports the first investigation of this molecule in healthy volunteers. This clinical study will explore the general safety and tolerability of ASN121151. In addition, we will examine how the body absorbs, distributes, and eliminates the drug and how much of the drug binds to the O-GlcNAcase enzyme in living human brain. These studies are a pre-requisite for subsequent investigations in AD patients.