Chunk #24 — Therapeutic approaches to toxic tau gain of function — Approach 2: modulate tau post-translational modification (PTM) — O-GlcNAcase inhibitors
Supporting the hypothesis that targeting O-GlcNAcylation can decrease tau hyperphosphorylation, an OGA inhibitor (Thiamet-G) was found to reduce the levels of pathologic tau aggregates in P301 L transgenic mice. [66] Subsequently, the small molecule OGA inhibitor MK-8719 was developed by Alectos Therapeutics in collaboration with Merck, which showed similar effects in transgenic mouse models, and, in a follow-up Phase 1 trial in 16 healthy controls, MK-8719 was found to be well-tolerated and engaged the target, as demonstrated by use of a novel radiotracer [18F]MK-8553 [67]. In 2016, Alectos announced they would be moving MK-8719 into clinical trials for patients with progressive supranuclear palsy [68], however the trial was never initiated and Merck has since discontinued development.
