Evaluation of Lectin Staining Biomarkers in Skeletal Muscle of Patients with GNE Myopathy

GNE myopathy (GNEM) is a rare, autosomal recessive disease characterized by progressive muscle weakness and wasting. GNEM is caused by hypomorphic mutations in the GNE (UDP‐N‐acetylglucosamine (GlcNAc) 2‐epimerase/N‐acetylmannosamine (ManNAc) kinase) gene; this gene encodes a bifunctional enzyme responsible for the rate‐limited and subsequent steps of sialic acid (SA) biosynthesis. As such, these mutations typically lead to a decreased production of SA, causing muscle pathology through an unclear mechanism. One important therapy in development for GNEM is gene therapy, which seeks to deliver the correct GNE gene to rescue SA biosynthesis and improve muscle function in GNEM patients. However, given that GNEM is a slowly progressing disease that causes muscle decline over a period of decades, it can be challenging to resolve improved muscle function over the relatively short course of a clinical trial. As such, we have used immunostaining with lectins, which bind specific glycan structures, to determine which most reliably reflects differences in SA abundance in skeletal muscle biopsies from GNEM or non‐GNEM patients. We found that the lectins within our panel, each binding unique glycan linkages reflecting SA presence or absence, differed in their ability to robustly reflect such SA changes. These experiments provide a direct comparison of the suitability of these lectins as biomarkers for GNE gene therapy.