HSIANG-PO HUANGChen P.-H.WUH-LIANG HWUChuang C.-Y.YIN-HSIU CHIENStone L.CHUNG-LIANG CHIENLi L.-T.Chiang S.-C.HSIN-FU CHENHONG-NERNG HOChen C.-H.Kuo H.-C.2021-06-032021-06-0320110964-6906https://www.scopus.com/inward/record.uri?eid=2-s2.0-81855172517&doi=10.1093%2fhmg%2fddr424&partnerID=40&md5=e1296df636ff33da3496c1dc378cd01bhttps://scholars.lib.ntu.edu.tw/handle/123456789/565031Pompe disease is caused by autosomal recessive mutations in the acid alpha-glucosidase (GAA) gene, which encodes GAA. Although enzyme replacement therapy has recently improved patient survival greatly, the results in skeletal muscles and for advanced disease are still not satisfactory. Here, we report the derivation of Pompe disease-induced pluripotent stem cells (PomD-iPSCs) from two patients with different GAA mutations and their potential for pathogenesis modeling, drug testing and disease marker identification. PomD-iPSCs maintained pluripotent features and had low GAA activity and high glycogen content. Cardiomyocyte-like cells (CMLCs) differentiated from PomD-iPSCs recapitulated the hallmark Pompe disease pathophysiological phenotypes, including high levels of glycogen and multiple ultrastructural aberrances. Drug rescue assessment showed that exposure of PomD-iPSC-derived CMLCs to recombinant human GAA reversed the major pathologic phenotypes. Furthermore, l-carnitine treatment reduced defective cellular respiration in the diseased cells. By comparative transcriptome analysis, we identified glycogen metabolism, lysosome and mitochondria-related marker genes whose expression robustly correlated with the therapeutic effect of drug treatment in PomD-iPSC-derived CMLCs. Collectively, these results demonstrate that PomD-iPSCs are a promising in vitro disease model for the development of novel therapeutic strategies for Pompe disease. ? The Author 2011. Published by Oxford University Press. All rights reserved.[SDGs]SDG3carnitine; glucan 1,4 alpha glucosidase; glycogen; article; cell differentiation; cell respiration; drug screening; gene mutation; glycogen metabolism; glycogen storage disease type 2; heart muscle cell; human; human cell; lysosome; mitochondrion; pathogenesis; pluripotent stem cell; priority journal; Adenine; alpha-Glucosidases; Animals; Base Sequence; Biological Markers; Carnitine; Cell Differentiation; Drug Monitoring; Fibroblasts; Glycogen Storage Disease Type II; Humans; Induced Pluripotent Stem Cells; Mice; Models, Biological; Molecular Sequence Data; Myocytes, Cardiacjournal article10.1093/hmg/ddr424219260842-s2.0-81855172517