[Animal model of distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy and preclinical trial with sugar compounds].

Sialic acids are terminal sugars of glycolipids and glycoproteins and are involved in several cellular processes. Sialic acid biosynthesis occurs in the cytosol, where UDP-N-acetylglucosamine (GlcNAc) is sequentially converted to N-acetylmannosamine (ManNAc) 6-phosphate by UDP-GlcNAc-2-epimerase/ManNAc kinase enzymes, both of which are encoded by the GNE gene. Since the only existing mouse model of DMRV/hIBM (Gne(-/-)hGNED176VTg) exhibited decreased sialic acid levels in most organs, DMRV/hIBM is thought to be secondary to the metabolic defect in sialic acid production. Theoretically, replenishing sialic acid could be employed as a therapeutic option. It has been reported that N-acetylneuraminic acid (NeuAc) and ManNAc are well incorporated into cells and converted to sialic acid. Thus, we evaluated the efficacy and safety of ManNAc, NeuAc, and sialyllactose in the Gne(-/-)hGNED176VTg, by orally administering these agents to mice from 5-15 weeks continuously until they reached 54-57 weeks of age. The treatment showed beneficial effects in terms of survival rate, overall motor performance, myofiber size, ex vivo skeletal muscle contractile properties, and pathology. These low-dose compounds showed acceptable kidney and liver toxicity profiles. Thus our results show that the oral therapy with NeuAc and ManNAc or their derivatives is safe and effective in preventing myopathic symptoms in Gne(-/-)hGNED176VTg mice, and could be considered as a guide for further therapeutic trials.