N-Acetylmannosamine treatment rescues a mouse model of Hereditary Inclusion Body Myopathy. M. Huizing¹, E. Klootwijk¹, B. Galeano¹, I. Manoli¹, M-S. Sun¹, C. Cicone¹, D. Darvish², D. Krasnewich¹, W.A. Gahl¹. 1) MGB,NHGRI, NIH, Bethesda, MD; 2) HIBM Research Group, Encino, CA.
   Hereditary Inclusion Body Myopathy (HIBM) is an adult onset autosomal recessive neuromuscular disorder characterized by slowly progressive distal and proximal muscle atrophy and weakness. This myopathy is caused by deficiency of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE), the rate-limiting, bifunctional enzyme catalyzing the first two committed steps of sialic acid biosynthesis. Decreases in GNE activity impair sialic acid production and interfere with sialylation of muscle glycoproteins such as -dystroglycan. Levels of polysialic acid on neural cell adhesion molecule (PSA-NCAM) may also be affected. To study the pathogenesis and treatment of HIBM, we created a GNE knock-in mouse mimicking the human Persian-Jewish GNE founder mutation, M712T. Homozygous (-/-) mutant mice were born in a Mendelian distribution, but did not survive beyond postnatal day 3 (P3). GNE enzyme activity in skeletal muscle tissues of -/- mice at age P2 was 20% of normal. However, histological examination did not reveal any muscle pathology. Rather, the kidneys of -/- mice showed petechial hemorrhages, proteinuria, and signs of glomerular disease. As a treatment option, we administered to pregnant females ManNAc (1 g/kg/d), an uncharged sugar intermediate located within the sialic acid pathway after the GNE feedback inhibition step. Upon feeding +/- matings ManNAc in their drinking water, 44% of the -/- pups survived beyond P3. At P2, -/- mice that received ManNAc had less severe kidney hemorrhages, and their muscle GNE activities increased to 50% of normal mouse levels, suggesting that ManNAc might stabilize the mutant enzyme. Surviving -/- mice were smaller than their littermates, but appeared healthy otherwise, even after weaning (P21), when they no longer received ManNAc. It remains to be determined if the surviving -/- mice (now ages 3 and 6 mo) will develop a muscular pathology later in life. Taken together, survival of -/- mice, improved kidney pathology and increased GNE activity after ManNAc administration strongly support consideration of a clinical trial of ManNAc for the myopathy of HIBM.