Can O-GlcNAcase inhibitors achieve therapeutic selectivity for pathological tau without disrupting normal cellular O-GlcNAcylation?

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Composite

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Description

While O-GlcNAcylation was identified as the top translational target, the debate didn’t address whether systemic O-GlcNAcase inhibition can selectively restore tau O-GlcNAcylation without affecting other essential cellular processes. This selectivity question is crucial for clinical development.

Source: Debate session sess_SDA-2026-04-09-gap-debate-20260409-201742-1e8eb3bd_20260412-091129 (Analysis: SDA-2026-04-09-gap-debate-20260409-201742-1e8eb3bd)

Resolution criteria

Resolved when O-GlcNAcase inhibitor selectivity is quantified across pathological tau and global cellular O-GlcNAcylation in neuronal and in vivo systems. Required evidence: tau-site O-GlcNAc stoichiometry, global O-GlcNAc proteomics, tau phosphorylation/aggregation assays, neuronal viability and synaptic function, and dose-response pharmacology for at least one brain-penetrant inhibitor. Closure requires a therapeutic index showing tau-pathology rescue at exposures that do not materially disrupt essential O-GlcNAc cycling, or evidence that such selectivity is not achievable.

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