Journal Article

Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification

Hsiang-Po Huang, Pin-Hsun Chen, Wuh-Liang Hwu, Ching-Yu Chuang, Yin-Hsiu Chien, Lee Stone, Chung-Liang Chien, Li-Tzu Li, Shu-Chuan Chiang, Hsin-Fu Chen, Hong-Nerng Ho, Chung-Hsuan Chen and Hung-Chih Kuo

in Human Molecular Genetics

Volume 20, issue 24, pages 4851-4864
Published in print December 2011 | ISSN: 0964-6906
Published online September 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr424
Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification

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Pompe 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.

Journal Article.  7233 words.  Illustrated.

Subjects: Genetics and Genomics

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