A Liver Model of Infantile-Onset Pompe Disease Using Patient-Specific Induced Pluripotent Stem Cells

Area of Science:

• Biomedical research
• Stem cell biology
• Rare disease modeling

Background:

• Infantile-onset Pompe disease (IOPD) results from deficient acid α-glucosidase (GAA), leading to glycogen accumulation in multiple organs.
• Current enzyme replacement therapy (ERT) effectiveness varies, necessitating better understanding of organ-specific disease mechanisms.
• Existing models do not fully capture the multi-organ nature of IOPD.

Purpose of the Study:

• To establish a functional in vitro liver model for infantile-onset Pompe disease.
• To utilize patient-specific induced pluripotent stem cells (iPSCs) for disease modeling.
• To investigate the efficacy of enzyme replacement therapy in a liver-specific context.

Main Methods:

• Generation of hepatocytes from iPSCs of IOPD patients.
• Assessment of lysosomal glycogen accumulation in differentiated hepatocytes.
• Evaluation of dose-dependent response to recombinant human GAA (rhGAA) treatment.

Main Results:

• Hepatocytes derived from IOPD patient iPSCs exhibited characteristic lysosomal glycogen accumulation.
• Glycogen buildup in the iPSC-derived hepatocytes was significantly reduced by rhGAA treatment in a dose-dependent manner.
• Successful establishment of a patient-specific in vitro liver model for IOPD.

Conclusions:

• Patient-specific iPSC-derived hepatocytes provide a valuable in vitro model for studying IOPD.
• This liver model can facilitate elucidation of disease mechanisms and drug screening for IOPD.
• iPSC-based modeling is a promising approach for multi-organ diseases like Pompe disease.