Development of a novel HIBM2 mouse model and therapy

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DESCRIPTION (provided by applicant): Hereditary Inclusion Body Myopathy Type II (HIBM2), also called Nonaka distal myopathy, quadriceps sparing myopathy and distal myopathy with rimmed vacuoles, is an autosomal genetic disorder that results in progressive muscle weakness and is associated with the development of inclusion bodies within skeletal myofibers. The gene responsible for HIBM2 has been identified as GNE, which encodes the UDP-N-acetylglucosamine epimerase/N- acetylmannosamine-6 kinase. GNE is gene required for biosynthesis of sialic acid, an essential glycan found in all human tissues. Despite the identification of the genetic basis for HIBM2, no effective therapies are currently available for this disease. This proposal will accomplish two specific aims. First, it will create a new mouse model for HIBM2 where the mouse sialic acid repertoire reflects the sialic acid repertoire normally found in humans. Humans lack the ability to synthesize certain forms of sialic acid that are present in all lower mammals. HIBM2 is a disease related to defective sialic acid biosynthesis, and CMP-sialic acid also negatively regulates GNE activity. Therefore, creating a mouse model that mimics human glycans is essential to understanding the role of human sialic acids in the disease. This new model will also provide a tool that will allow easier assessment of potential glycan therapies. Second, this grant will directly test a novel hypothesis regarding HIBM2 pathogenesis and develop a novel gene therapy that, if successful, could be applied to patients.