| Summary: | 碩士 === 國立陽明大學 === 解剖學及細胞生物學研究所 === 102 === Fabry disease (FD) is an X-linked lysosomal storage disorder, due to mutations in the α-galactosiase A gene (GLA) leads to deficient or absent lysosomal enzyme, α-galactosidase A activity, progressive accumulation of globotriaosylceramide (Gb3) in lysosome of a variety of cell types. As the disease progresses, left ventricular hypertrophy, renal failure and strokes may occur. According to the newborn screening study in Taiwan, an unexpected high prevalence of the cardiac variant mutation IVS4+919G>A. Enzyme replacement therapy (ERT) is currently the only effective therapy to reduce Gb3 accumulations in Fabry disease. Although it improves cardiac function and left ventricular mass, Gb3 clearance upon ERT has been demonstrated in cardiac capillary endothelium but not in cardiomyocytes of patients. It is also limited to trace and analyze the efficacy of ERT from patient’s biopsy, especially from heart. In current study, we would like to investigate how the cardiac function is improved via ERT in differentiated cardiomyocytes of Fabry patients. In brief, the induced pluripotent stem cells (iPSC) generated from Fabry patients’ PBMCs and differentiated into patient-specific cardiomyocytes. Immunofluorescence results showed Gb3 accumulates in the cardiomyocytes and results in phenotype changes (cell enlargement), which is correspond to those found in cardiac tissue from Fabry patients. Using the patient-specific differentiated cardiomyocyte model, we demonstrated that ERT was able to prevent accumulation of lysosomal Gb3 in cardiomyocyte. The gene expression profile of Fabry-derived cardiomyocyte may provide some candidates for further investigation on pathogenic mechanisms of cardiac manifestations in Fabry disease.
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