Résumé :
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Hereditary inclusion body myopathy (HIBM) is a myopathy caused by recessive mutations in the UDP-N-acetylglucosamine 2-epimerase/ N-acetylmannosamine kinase gene (GNE), encoding the key enzyme in the biosynthetic pathway of sialic acid. In an attempt to develop a possible treatment for HIBM patients, we are establishing a platform for gene therapy trials based on adeno associated virus (AAV 8) vectors harboring the wild type GNE gene. These viral constructs proved to be efficient in the infection of cultured human muscle cells derived from biopsies of HIBM patients. Similar constructs were used in normal C57Bl6 mice which were injected either IM ( gastrocnemius or quadriceps) or IV (tail vein) with human wtGNE engineered AAV2/8 virus. No mice present any physical or behavioral change. Tissues were analyzed for histology, inflammation and GNE expression. 35 days post IM infection. hGNE was expressed mostly in the injected muscle. For mice injected I, tissue analysis was performed at 35, 90 and 180 days post injection. There were no pathological findings nor inflammation in any of the tissues analyzed. Real Time PCR analysis of the expression of human GNE showed it is expressed in all tissues analyzed, including skeletal muscles of the upper and lower limbs. Control virus, harboring the luciferase gene instead of GNE , showed the expression of luciferase was disseminated in all organs, and remained over time. To assess the efficacity of the IV injection of AAV8/GNE virus, it is necessary to inject the virus into an animal model of HIBM. These experiments are now underway in collaboration with Dr Nishino's laboratory. We believe that the assessment of the effects of GNE viral delivery will be of great value by setting the stage for potential human trials and will provide the basis for human trial approval.
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