Résumé :
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Distal myopathy with rimmed vacuoles (DMRV), also called hereditary inclusion body myopathy (hIBM), is an autosomal recessive debilitating disorder affecting young adults with the age of onset ranging from 15 years to late thirties. The disease is characterized clinically by preferential involvement of tibialis anterior and hamstring muscles and relative sparing of quadriceps, and pathologically by the presence of rimmed vacuoles, which are seen as clusters of autophagic vacuoles on electron microscopy, in addition to scattered atrophic fibers and muscle degeneration. Up to this time, treatment for this myopathy remains elusive. DMRV/hIBM is caused by missense mutations in GNE gene that encodes the essential enzyme in sialic acid biosynthesis. In the serum and skeletal muscles of patients, we have noted a reduction in sialic acid levels. We recently generated a model mouse for DMRV that expressed human GNE with the missense mutation D176V, but lacks the endogenous mouse GNE. This DMRV model (DMRV mouse) exhibited hyposialylation in serum and various organs which predated the skeletal muscle weakness, atrophy, rimmed vacuole formation, and deposition of amyloid and various proteins within the myofibers, supporting the theory of hyposialylation in the pathomechanism of DMRV. We treated DMRV mice with GNE metabolites, ManNAc, NeuAc, and sialic acid conjugate, sialyllactose from around 15 weeks of age and continued to around 55 weeks. Interestingly, by any agent, clinicopathological manifestations were almost completely suppressed even at 55 weeks during all mice are expected to show all clinicopathological features. Our results indicate that sialic acid deficiency is the cause of DMRV/hIBM and that the disease can be suppressed by sialic acid supplementation. We therefore provided a "proof of concept" that DMRV/hIBM is treatable by GNE metabolites.Currently phase I clinical trial to check PK/PD is undergoing at Tohoku University Medical School, Sendai, Japan.
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