Oral N-Acetylglucosamine as Anti-Neuroinflammatory Add-on therapy for Multiple Sclerosis (NANA-MS) - Abstract In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduce episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans age- associated increases in endogenous GlcNAc promote T cell senescence. A polymorphism linked to dysregulation of GlcNAc metabolism most strongly associates with MS severity. In a recent mechanistic open- label trial assessing oral GlcNAc at 6g (n=18) and 12g daily for four weeks in MS patients not in relapse and on the immunomodulator glatiramer acetate, we reported that oral GlcNAc therapy was safe, raised serum levels, modulated N-glycan branching in lymphocytes and lowered serum levels of pro-inflammatory IFNg, IL-17 and IL- 6. Oral GlcNAc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is elevated in the brain of MS patients. As glatiramer acetate acts peripherally, the reduction in inflammatory cytokines and IL-10 by oral GlcNAc may arise from crossing the BBB to target chronic-active CNS inflammation. Consistent with this, oral GlcNAc dose-dependently reduced serum neurofilament light chain (sNfL), a specific marker of brain inflammation/neurodegeneration. Moreover, 30% of treated patients displayed confirmed improvement in neurological disability; consistent with reduced brain inflammation and/or re-myelination. As these observations were based on unblinded analysis, no placebo and small sample sizes, here we propose to develop a multi-center double-blind randomized control trial to validate GlcNAc’s potential to improve residual brain inflammation, myelin repair, neurodegeneration and neurological function. The study “Oral N- Acetylglucosamine as Anti-Neuroinflammatory Add-on therapy for Multiple Sclerosis” (NANA-MS) will include MS patients with ongoing chronic-active CNS inflammation (i.e. non-gadolinium enhancing paramagnetic rim lesions (PRLs) on brain MRI) despite best available or no therapy. Primary outcome is the number of patients with reductions in disability of at least 0.5 EDSS points. Secondary outcomes are change in 1) chronic CNS inflammation based on brain MRI (i.e. decreased PRLs) and/or cerebrospinal fluid analysis, 2) peripheral inflammatory markers, 3) myelination as assessed by Visual Evoked Potentials and 4) Quality of life measures.
