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Abstract Details

Utilizing patient-derived induced pluripotent stem cells to investigate GNE myopathy
Neuromuscular and Clinical Neurophysiology (EMG)
Neuromuscular and Clinical Neurophysiology (EMG) Posters (7:00 AM-5:00 PM)
014
Generation of a novel model of UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy utilizing patient-derived induced pluripotent stem cells (iPSCs) used to elucidate underlying mechanisms for development of novel therapeutic treatments.
Many neuromuscular diseases (NMDs), including GNE myopathy, do not have curative treatments and can lead to increased pain, dependency, morbidity, and a decreased quality of life. GNE myopathy is an autosomal recessive distal myopathy that typically presents in early adulthood and very little is understood regarding its causative mechanisms. GNE is necessary for the biosynthesis of sialic acid which is important for numerous biological processes. Based on previous studies, the alteration in the synthesis of sialic acid does not appear to be the only contributing factor leading to GNE myopathy. Our lab is working to elucidate other such possible contributors.
Fibroblasts from healthy and GNE myopathy patients were reprogrammed into iPSCs. Cells were differentiated down the myogenic lineage via a three stage process reminiscent of muscle regeneration. Immunofluorescence was used to assess standard myogenic regulatory factors and for the presence of GNE characteristics. In addition, a longitudinal single-cell RNA sequencing study (scRNAseq) was also performed. 
In severe GNE iPSC clones, there is evidence that they demonstrate recapitulation of key characteristics of the human pathology including TDP-43 accumulation and evidence of dysregulated autophagy, have a defect in myogenic progression, and scRNAseq time course studies corroborate the observed myogenesis defects. In addition, cluster-based bioinformatics studies implicate EIF2 signaling as a top signaling pathway altered in GNE iPSCs undergoing myogenesis. 
The present data describes a novel patient-derived iPSC model to investigate contributing mechanisms in GNE myopathy with the end goal of identify novel therapeutic treatments to improve patient quality of life. Thus far this in vitro model can recapitulate key features of the human disease and is implicating previously unidentified contributing mechanisms in GNE myopathy. 
Authors/Disclosures
Rebecca E. Schmitt, PhD (Mayo Clinic)
PRESENTER 		Rebecca Schmitt has nothing to disclose.
No disclosure on file
Rebecca E. Schmitt, PhD (Mayo Clinic) Rebecca Schmitt has nothing to disclose.
Margherita Milone, MD, FÂ鶹´«Ã½Ó³»­ (Mayo Clinic) Dr. Milone has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cartesian Therapeutics. Dr. Milone has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics, Â鶹´«Ã½Ó³»­. The institution of Dr. Milone has received research support from Mayo Clinic, CCaTS-CBD. The institution of Dr. Milone has received research support from Mayo Clinic, SGP Award. The institution of Dr. Milone has received research support from MDA for Care Center grant. The institution of Dr. Milone has received research support from Regenerative medicine Minnesota.
No disclosure on file