Abstract 15204: Modelling Pompe Glyocogen Storage Disease with Induced Pluripotent Stem Cells
Pompe disease (glyocogen storage disease type-II) is an inherited deficiency of acid α-glucosidase (GAA), a lysosomal enzyme required for glycogen breakdown. This results in accumulation of glycogen in skeletal muscle and cardiac cells, progressive muscle weakness, cardiac hypertrophy and failure. We report establishment of a human induced pluriptent stem cells (hiPSCs) model of Pompe disease by reprogramming dermal fibroblasts from a patient with severe infantile disease (C341InsT). Pompe hiPSCs were then differentiated into cardiac lineage. No detectable GAA activity was found in Pompe fibroblasts, undifferentiated or differentiated hiPSCs. Live cell imaging, PAS staining, immunostaining and transmission electron microscopy revealed the presence of enlarged glyocogen containing lysosomes and “glycogen-lakes” in Pompe-hiPSCs-derived cardiomyocytes, leading to regional sarcomere destruction. Glygocen filled lysosomes were interspersed between sarcomers with perinuclear prominence. Lysosomal expansion progressed from subtle pathology to occupation of most of the cellular area. In addition, accumulation of enlarged autophagosoms was noted, supporting a potential role of abnormal autophagy. Treatment with recombinant-human GAA (rhGAA) restored sustainable enzyme activity in the hiPSCs-derived cardiomyocytes. RhGAA both prevented lysosomal storage and reversed it, but only partially treated the defective autophagy. Cellular lysosmal area decreased from 17.9±6.9% to 3.7±1.6% (p<0.01). Our study demonstrates the ability of hiPSCs technology to model an inherited progressive metabolic aberration. It demonstrates the progression of lysosomal pathology and for the first time supports existence of pathologic autophagy in Pompe cardiomyopathy. The inability to clear autophagic pathology may contribute to partial clinical response to enzyme replacement observed in some patients and provides a model to target it therapeutically.
- © 2011 by American Heart Association, Inc.