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Background <p>Pompe disease is an autosomal recessive lysosomal storage disorder caused by mutations in the <i>GAA</i> gene, leading to acid alpha-glucosidase deficiency and pathological glycogen accumulation, primarily in cardiac and skeletal muscle. While enzyme replacement therapy (ERT) has improved clinical outcomes, its limited efficacy especially in skeletal muscle underscores the need for improved disease models and novel therapeutic strategies. Induced pluripotent stem cells (iPSCs) from Pompe patients have facilitated mechanistic studies; however, their utility is restricted by limited patient sample availability.</p> Methods <p>To address this limitation, we employed CRISPR-Cas9 genome editing to disrupt <i>GAA</i> in a well-characterized human embryonic stem cell (hESC) line, BJNhem20, thereby generating a Pompe disease model independent of patient material.</p> Results <p>The edited hESC line exhibited markedly reduced <i>GAA</i> enzymatic activity while maintaining pluripotency and trilineage differentiation potential. Upon directed differentiation, cardiac and skeletal muscle cells displayed pronounced lysosome and glycogen accumulation.</p> Conclusions <p>These findings demonstrate that genome-edited hESC for Pompe disease can recapitulate key pathological features, providing a robust and scalable platform for disease modelling and therapeutic screening. This approach offers a valuable alternative to patient-derived iPSCs for studying rare genetic disorders and for the development of targeted interventions.</p>

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A genome-edited isogenic human embryonic stem cell model of pompe disease recapitulates cardiac and skeletal muscle pathology

  • 期刊论文

  • 发表日期：

    2026年4月3日

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  • Vibhaa Kokkanda Kumar,
  • Vasanth Thamodaran

摘要

Background

Pompe disease is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene, leading to acid alpha-glucosidase deficiency and pathological glycogen accumulation, primarily in cardiac and skeletal muscle. While enzyme replacement therapy (ERT) has improved clinical outcomes, its limited efficacy especially in skeletal muscle underscores the need for improved disease models and novel therapeutic strategies. Induced pluripotent stem cells (iPSCs) from Pompe patients have facilitated mechanistic studies; however, their utility is restricted by limited patient sample availability.

Methods

To address this limitation, we employed CRISPR-Cas9 genome editing to disrupt GAA in a well-characterized human embryonic stem cell (hESC) line, BJNhem20, thereby generating a Pompe disease model independent of patient material.

Results

The edited hESC line exhibited markedly reduced GAA enzymatic activity while maintaining pluripotency and trilineage differentiation potential. Upon directed differentiation, cardiac and skeletal muscle cells displayed pronounced lysosome and glycogen accumulation.

Conclusions

These findings demonstrate that genome-edited hESC for Pompe disease can recapitulate key pathological features, providing a robust and scalable platform for disease modelling and therapeutic screening. This approach offers a valuable alternative to patient-derived iPSCs for studying rare genetic disorders and for the development of targeted interventions.