G.P.55

GNE Myopathy is a unique neuromuscular disorder characterized by adult onset and slowly progressive distal and proximal muscle and a typical histology including rimmed vacuoles and filamentous inclusions. The disease is 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 GNE Myopathy patients.) We have established a platform for gene therapy trials based on adeno associated virus (AAV 8) vectors harboring the wild type human GNE gene driven by an MCK promoter. These viral constructs proved to be safe when injected systemically (tail vein) in healthy C57Bl6 mice. No mice presented any physical or behavioral change. All tissues analyzed for histology 35 days post infection showed no pathological findings. 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. This was confirmed by the expression of a control virus, where GNE was replaced by the luciferase gene, which showed luciferase expression disseminated in all organs. To assess the efficacy of the system, this AAV8/MCKGNE viral vectors are being assayed in the GNE Myopathy mouse model generated by Malicdan et al. (2007) 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.